The History of Endocrine Surgery:

The History of Endocrine Surgery Theodor E. Kocher. Courtesy of Theodor-Kocher-Institute, University of Bern, Switzer...

Author: Richard B. Welbourn | Stanley R. Friesen | Ivan D.A. Johnston | Ronald A. Sellwood

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The History of Endocrine Surgery

Theodor E. Kocher. Courtesy of Theodor-Kocher-Institute, University of Bern, Switzerland.

THE HISTORY OF ENDOCRINE SURGERY Richard B. Welbourn,

M.A.,M.D. (Cantab), Hon. M.D. (Karolinska), Hon. D.Sc. (QUB), FRCS, FWACS, Hon. FACS, Hon. MRCS (Denmark)

With Contributions by Stanley R. Friesen, M.D. (Kansas), Ph.D. (Minnesota), FACS Ivan D.A. Johnston, M.ch. (QUB), FRCS, Hon. FACS Ronald A. Sellwood, M.Ch. (Bristol), FRCS Foreword by O l i v e r H . B e a h r S , M.D. (Northwestern), M.S. (Minnesota), FACS

PMEGER

New York Westport, Connecticut London

Library of Congress Cataloging-in-Publication Data Welbourn, R. B. (Richard Burkewood) The history of endocrine surgery / Richard B. Welbourn, with contributions by Stanley R. Friesen, Ivan D. Johnston, Ronald A. Sellwood; foreword by Oliver H. Beahrs. p. cm. Includes bibliographies and index. ISBN 0-275-92586-2 (alk. paper) 1. Endocrine glands—Surgery—History. I. Title. [DNLM: 1. Endocrine Glands—surgery. 2. Endocrinology-history. WK 11.1 W438h] RD599.W45 1990 617.4'4'09—dc20 89-16118 Copyright © 1990 by Praeger Publishers All rights reserved. No portion of this book may be reproduced, by any process or technique, without the express written consent of the publisher. Library of Congress Catalog Card Number: 89-16118 ISBN: 0-275-92586-2 First published in 1990 Praeger Publishers, One Madison Avenue, New York, NY 10010 A division of Greenwood Press, Inc. Printed in the United States of America

The paper used in this book complies with the Permanent Paper Standard issued by the National Information Standards Organization (Z39.48-1984). 10

9 8 7 6 5 4 3 2 1

In gratitude to my friends: Sherman M. Mellinkoff, Dean, William P. Longmire, Jr., James V. Maloney, Jr., and W. Eugene Stern, Chairmen, Department of Surgery, and their colleagues at the U.C.L.A. School of Medicine, Los Angeles who welcomed me as a Visiting Scholar and enabled me to write this book.

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Contents

Foreword Oliver H. Beahrs

ix

Preface

xi

Acknowledgments General Sources How to Use This Book 1

2

(E).

(T).

Evolution of Endocrine Surgery

xiii xv xvii 1

Illustrations

16

The Thyroid Thyroid cancer Coauthor ed by I. D.A. Johnston

19 64

Illustrations

83

3

(P).

The Pituitary Illustrations

89 140

4

(A).

The Adrenal Glands Illustrations

147 211

viii • Contents 5

(PT).

The Parathyroid Glands Illustrations

217 236

6

(G).

The Endocrine Gut and Pancreas General anatomy, physiology, and pathology by S.R. Friesen

237 237

Endocrine syndromes by S.R.Friesen

239

Islet cell transplantation by I.D.A. Johnston

255

Illustrations

265

Multiple Endocrine Adenopathy and Paraendocrine Syndromes Illustrations

269 282

7

(M).

8. Various Topics I (C). Cancer of the breast and prostate by R.A. Sellwood Illustrations II (H). Essential and renal hypertension III (S). Surgical stress Illustrations

283 284 294 296 302 306

Appendix: Chronology

307

Biographical Index

329

Subject Index

371

About the Contributors

383

Foreword

The history of medical science forms the very foundation of the body of knowledge which has evolved into our present understanding of medicine and pathologic processes. Too often today we become involved in current advances and new information and forget the basics reported in earlier years. If we constantly keep in mind the classic descriptions of disease and their importance in clinical practice, the management of patients with pathologic conditions would be simpler and the costs to the patient and those underwriting the expenses of health care most likely less. Although our knowledge of etiology, pathophysiology, pharmacology, and availability of modern technical capability might make the care of patients more effective and safer, these 'technical advances' are not always necessary in the overall care of disease states. As an example, in reviewing the classical contributions and publications of Parry, v. Basedow, Graves, Plummer, Kocher, Mayo, Dunhill, and v. Mikulicz, little further information would be needed to diagnose and treat patients with exophthalmic goiter. The same would be true for many other endocrine diseases as well as other diseases elsewhere in the body. Richard Welbourn has done the physician community and especially those physicians interested in endocrinology a great service in bringing together in one publication the contributions of the giants of the past and the historical facts that, for the most part, remain pertinent in the practice of endocrinology today. The history of any subject is the basis of its culture and should not be forgotten since it remains the foundation of our current knowledge and is necessary for our present education, research, and clinical practice.

x • Foreword The History of Endocrine Surgery is an excellent recording of the contributions of each generation to the next one which follows. Oliver H. Beahrs Emeritus Professor of Surgery, Mayo Foundation President, American College of Surgeons, 1988-89

Preface

"Only the man who is familiar with the art and science of the past is competent to aid in its progress in the future." So wrote Theodor Billroth of Vienna, one of the founders of modern surgery in the second half of the nineteenth century and a major contributor to the surgery of the thyroid. By the middle of the twentieth century operations had been performed on all known endocrine glands, and those on the thyroid and the pituitary were practiced widely and well. Operations on other glands were undertaken rarely, and some of them were fraught with danger. The term "endocrine surgery" had hardly been heard. After the advent of cortisone, however, surgeons began to undertake endocrine surgical procedures more often and with greater safety than before. The endocrine glands had long been recognized as an integrated system, and now their surgery also came to be viewed as a whole. Thus endocrine surgery began to emerge as a new discipline within general surgery. On the other hand, the pituitary, which had once been within the domain of general surgeons, had already, for purely technical reasons, passed entirely into the hands of neurological and rhinological surgeons. I became interested in the surgery of the endocrine glands in 1951 and 1952, while working at the Mayo Clinic, where cortisone had just been discovered and used therapeutically. The surgeons employed it with astonishing success to support patients undergoing adrenalectomy for Cushing's syndrome. Eventually endocrine surgery became my main concern. I knew that its history was fascinating and, when I retired in 1982,1 began to study it systematically. The early surgical histories of some of the glands— the thyroid, the pituitary, and the parathyroids—and of surgical stress had

xii • Preface been described already, but the full story of endocrine surgery had not been told. And so I came to write this book. The existing histories provided good introductions to the early literature, but most of my work involved reading many hundreds of original articles, the most important of which are listed after each chapter. When secondary sources only have been used (mainly textbooks, monographs, and review articles), they are cited as references. For various reasons I had to rely largely on these in writing about thyroid cancer and the parathyroids and about stress. I have also talked and corresponded with friends and colleagues in many countries and have referred to some of their interesting letters as personal communications. In addition I have visited many of the places where endocrine surgical history has been (and is being) made. In several places my accounts of events differ from those given elsewhere, but they are fully supported by the references that I have quoted. The story of endocrine surgery is traced from its origins to about 1980. More recent work, most of which cannot yet be seen in perspective, is described in current textbooks and reviews. The emphasis is on endocrine surgery, but related branches of medicine, surgery, and science are discussed when appropriate. I have not included chapters on the gonads and the thymus, because I ran out of time and space for them here; I hope to relate their endocrine surgical histories elsewhere. Thomas Carlyle, the nineteenth-century Scottish writer, correctly stated that history was the biography of great men, and I have included a biographical index and portraits of surgeons and others who have made important contributions. This index includes the basic information—who, when, what, and where—about all the men and women named in the text, so far as I have been able to discover it, and additional notes about some of the major contributors. The chronology shows the main events described in the different chapters in their temporal relationships, and also lists some relevant milestones in general medicine, surgery, and science, and a few in political and social history, to provide historical perspective. I hope that historians, endocrine surgeons, endocrinologists, and many others will find as much pleasure and value in reading this history of endocrine surgery as I have found in its preparation.

Acknowledgments

I am very grateful to many people who have helped me so kindly with the book. These include: Oliver Beahrs, who wrote the foreword, Stanley Friesen, Ivan Johnston, and Ronald Sellwood, who wrote parts of the text and graciously accepted my editing to bring their contributions into line with the rest. Agnes Bartels, B . S c , A.K.C., F.R.C.S., my research assistant, who contributed much, particularly to the thyroid chapter, the indexes, and the chronology, and helped with the proofreading and photocopying. Many librarians for their unfailing and skilled cooperation. These include Lindsay Curtis and her staff at the Royal Postgraduate Medical School and especially Elizabeth Davis and Judith Stone, Assistant Librarians; Ian Lyle and his staff at the Royal College of Surgeons of England; Victoria Steele, Katharine Donohue and their staff at the University of California, Los Angeles; Susan Alon at Yale University; and Eric Freeman and his staff at the Wellcome Institute for the History of Medicine, London. Those who supplied the illustrations, many of whom are acknowledged in the lists of sources. In addition I was helped by Susan Alon, Marco Baggiolini, John Cameron, the late Charles Clarke, Peter Edmund, S. R. Friesen, Yoshihide Fujimoto, R. Haering, Michael Hobsley, B. Langer, Robert Macbeth, H. Marberger, S. Mellinkoff, Edward Passaro, J. Paul, Mark Ravitch, Brooke Roberts, Sir Keith Ross, Bt., Manfred Skopec, Lars Thoren, David Thomas, Michael Trede. Those who provided biographical information, particularly Ulrich Trohler, Jean Vague, and Torgny Svenberg.

xiv * Acknowledgments Omar Khan and Josef Pflug, who devoted much time to translating and discussing German papers. Oliver Cope, Vilen Kertsman, William Bynum, Yoshihide Fujimoto, Tom Reeve, and Philip Sandblom, who gave much general help. Many who advised on individual chapters, particularly those asterisked (*), who read and commented on complete scripts: (Ch. 1): Hilary Wade,* O. Khan,* Julia Polak,* Charles Proye, and John Shepherd; (Ch. 2): H. Wade,* Sir Harold Himsworth, Pierre Konig, Selwyn Taylor; (Ch. 3): Eugene Stern,* Jules Hardy, John Angell-James, Sir Geoffrey Bateman, Per-Ola Granberg, Keith Hainan, Ray Kjellberg, Hans von Leyden, Fritz Linder, Ronald Macbeth, Niels Riskaer, John Shaw, Graham Teasedale; (Ch. 4): Jon van Heerden,* Harold Ellis, Glenn Geelhoed, P.-O. Granberg, Bernard Harries, Al Hayles, F. Linder, Niall O'Higgins, Nicola Pitt, C. Proye, William ReMine, Alastair Robertson, Robert Salassa, Norman Thompson, J. Vague, Waltman Walters; (Ch. 5): I. Johnston,* Claude Organ, Colin Thomas; (Ch. 6): William Strodel; (Ch. 7): Aidan Carney*; (Ch. 8, II): Marion de Weese*; (Ch. 8, III): I. Johnston.* I am responsible for any errors in the book. My research and writing have been generously funded by two grants in the United States, the Ahmanson Foundation, and the Henry J. Kaiser Family Foundation, and by Yvonne Gregory, a British philanthropist. I am very grateful to all of them. The American funds were obtained in 1983 through the good offices of S. Mellinkoff. Doris Smith was very helpful in their administration. The Dean of the Royal Postgraduate Medical School, David Kerr, and my two successors as Directors of the Department of Surgery, Leslie Blumgart and Robin Williamson, generously provided facilities for my work. Dr. Stern and his staff gave generous help when I visited Los Angeles. Anne Marie Mulgrew and Kathleen Wilder undertook the bulk of the wordprocessing and typing, respectively, and performed the work cheerfully, efficiently, and fast. Above all I am grateful to Rachel, my wife, for her loving support, encouragement, and practical help throughout. Richard Welbourn

General Sources

The following sources were used throughout the book: GENERAL MEDICAL AND SURGICAL HISTORY Garrison, F.H. An introduction to the history of medicine. Philadelphia: Saunders, 1929. Guthrie, D. A history of medicine. London: Nelson, 1945. Major, R.H. Classic descriptions of disease. Springfield, IL: Charles C Thomas, 1945. Zimmerman, L.M., and Veith, I. Great ideas in the history of surgery. London: Bailliere, Tindall and Cox, 1961. HISTORY OF ENDOCRINOLOGY Medvei, V.C. A history of endocrinology. Lancaster, England: MTP Press, 1982. Rolleston, H.D. The endocrine organs in health and disease. Oxford: Oxford University Press, 1936. GENERAL ENDOCRINOLOGY Hall, R., Anderson, J., Smart, G.A., and Besser, G.A. Fundamentals of clinical endocrinology. 3rd ed. Tunbridge Wells: Pitman Medical, 1980.

xvi • General Sources Montgomery, D.A.D., and Welbourn, R.B. Clinical endocrinology for surgeons. London: Arnold, 1963. Medical and surgical endocrinology. London: Arnold, 1975. Weber, F.P. Endocrine tumours. London: Lewis, 1936. Other general sources are listed at the end of each chapter.

How to Use This Book

The reader will find that each paragraph in the text is followed by a lettered/ numbered key in parentheses. The letter corresponds to the current chapter title. The number indicates which paragraph is being read in the chapter. There are many cross-references in the text and by quickly flipping through the pages the reader can locate the corresponding material. The same system has been applied to entries located in the Biographical and Subject Indices. For quick reference, a key to the location of the lettered paragraphs is provided inside the back cover.


The History of Endocrine Surgery


1 (E) Evolution of Endocrine Surgery

Endocrine surgery has been practiced for hundreds of years, but has only been recognized as such since the beginning of this century. It has undergone many successive, overlapping waves of change, varying in magnitude, speed, and duration, but three main phases of evolution can be recognized. In the first, surgery of the endocrine glands formed part of surgery in general. T h e second phase followed the emergence of endocrinology as a science in the early 1900s, when surgeons appreciated that they were operating on endocrine glands, often to relieve the effects of oversecretion. The third, or present, phase started in the 1950s, after the advent of cortisone, when surgeons began to view endocrine surgery as a whole instead of concentrating on separate glands. (E.I) Most of the glands and tissues that form the endocrine system were recognized by the end of the nineteenth century. At first they were described and studied individually, like other organs, and only later grouped as ductless glands or as sources of internal secretions. T h e gonads were recognized in prehistoric times. The testes were probably noticed first because of their situation, but the ovaries were known to the Ancient Egyptians ( l a ) . Galen, the R o m a n physician who dominated medicine for fifteen centuries, described the pituitary in the second century (2). The great Italian Renaissance anatomist, A n d r e a s Vesalius of Padua, included a description of the thyroid in De Humani Corporis Fabrica in 1543(3) Thomas W h a r t o n , physician to St. T h o m a s ' Hospital, L o n d o n , who courageously stayed in the city throughout the great (bubonic) plague of 1665, included the thyroid, the suprarenals, and the pancreas among the glands in his Adenographia of 1656 and 1659(4) (E.2)

2

• History of Endocrine Surgery

DUCTLESS GLANDS The functions of the endocrine glands remained unknown and the subject of much speculation for many years. In 1766 the Swiss scientist Albrecht von Haller of Berne ( l b ) described the thyroid, the thymus, and the spleen as glands without ducts that p o u r e d special substances into the circulation (5a). This process was first demonstrated experimentally by the great Parisian physiologist, Claude B e r n a r d , who in 1855 described sugar, which entered the portal vein, as t h e "internal secretion" and bile as the "external secretion" of the liver. H e went on to list the spleen, the adrenals, the thyroid, and the lymphatic glands as having internal secretions only (5b). (E.3) The concept of internal secretion received support in other ways. T h e general effects of castration in both sexes had been recognized in ancient times, and John H u n t e r of L o n d o n , the founder of surgical science, h a d noted in 1786 that the testes controlled the development of secondary sex characters in m a n and animals (6). T h o m a s Addison, physician to Guy's Hospital, L o n d o n , provided evidence that absence or destruction of endocrine glands caused disease when, in 1855, he published his work " O n the constitutional, and local effects of disease of the suprarenal capsules" (p. A . 4 ) . T h e o d o r Kocher (Fig. E . l ) , Professor of Surgery at B e r n e , confirmed this principle in 1883, when he described the condition of "cachexia strumipriva" after total extirpation of the thyroid gland in m a n (p. T.40). Soon hypothyroidism from this and other causes was recognized, and thyroid extracts, which were sometimes effective, were prepared for replacement therapy. T h u s , by the end of the nineteenth century there was clear evidence that t h e product of a ductless gland was physiologically active, that its absence caused disease, and that its replacement brought relief. In the 1890s a potent vasoconstrictor was extracted from the adrenal medulla by George Oliver, a general medical practitioner from H a r r o g a t e , England, and E d w a r d Schafer (later Sharpey-Schafer), Professor of Physiology at University College, L o n d o n . T h e active principle, "epinephrine" or "adrenalin," was isolated in 1897 and 1901—the first internal secretion to be identified (p. A . 7 ) . (E.4)

ENDOCRINOLOGY At this time—the turn of the century—the physiological climate was dominated by Ivan Pavlov of St. Petersburg (now Leningrad), who believed in nervism—the view that the nervous system controlled most bodily activities (7a). Perhaps for this reason few people regarded the ductless glands seriously. However, in 1902 two other physiologists at University College, William Bayliss (Fig. E.2) and Ernest Starling (Fig. E.3), made a startling discovery, "breathtaking in its elegant simplicity" (7b). They found that acid in the gut stimulated secretion in the pancreas when both organs were

Evolution of Endocrine Surgery (E)

• 3

denervated, that acid introduced directly into the circulation did not stimulate it, and that injection of an extract of jejunal mucosa mimicked the action of acid in the gut (8). They realized that these findings required the operation of a chemical reflex rather than a nervous o n e , and proposed the n a m e "secretin" for the hypothetical "chemical messenger" involved. This represented a new class of substance, not adequately described as an internal secretion, and in 1905 Starling proposed the n a m e " h o r m o n e " from a Greek word (dpjuavEiv) meaning to excite (7c). This was soon adopted generally. A n " e n d o c r i n e " ( G K evdov = within + Kpivziv — separate) function had been attributed to the Islets of Langerhans in 1893 by E d o u a r d Laguesse of Lille, F r a n c e ( 8 A ) , and this term also came into general use within a few years. Thus a new principle in physiology was established, and the science of endocrinology was born. (E.5) The science grew rapidly, soon assuming great importance, and many who contributed to it were awarded Nobel Prizes. The first was Kocher, in 1909, "for his works on the physiology, pathology and surgery of the thyroid gland." M o r e endocrine tissues and many m o r e hormones were identified in subsequent years and their functions and complex interrelationships explored. T h e Ley dig cells of the testes, the Islets of Langerhans, the Kulchitsky cells in the gut, and the parathyroid glands, all of which had been described in the nineteenth century, were recognized as endocrine organs. Early functional studies led to the isolation of thyroxine from the thyroid in 1914 by E d w a r d Kendall, a chemist at the Mayo Clinic (p. T.51), and the extraction of insulin from the pancreatic islets in 1921 by Frederick Banting, an orthopedic surgeon and physiologist from L o n d o n , Ontario, and his colleagues in T o r o n t o (p. G.13). Banting shared a Nobel Prize in 1923. (E 6) As more was learned of the endocrine glands, the central role of the anterior pituitary in regulating growth and controlling other glands became clear. In 1931 Walter Langdon Brown of L o n d o n , England, described it as "the leader in the endocrine orchestra" (9). The endocrine glands were thus seen not only to share a common m o d e of action, but to be functionally interdependent. T h e endocrine system provided an integrated mechanism for controlling bodily functions which complemented that of the nervous system. (E.7) Already, however, there were indications that the separation of the two systems was artificial. In 1911 Walter C a n n o n , Professor of Physiology at Harvard University, Boston, had described how emotional nervous stimuli caused the secretion of a h o r m o n e , adrenaline, by the adrenal medulla, which was not only an endocrine gland but also part of the autonomic nervous system (10). T h e n , in 1921, O t t o Loewi, a pharmacologist at Graz, Austria, established the chemical nature of nerve transmission(lc). In the 1930s secretory cells were observed in the hypothalamus, which is part of the brain, and this was later found to exert neurohumoral control over the anterior pituitary ( I d ) . T h e hypothalamus was itself governed both by the hormonal products of its own stimuli (by feedback mechanisms) and by

4


higher nervous c e n t e r s ( l e ) . Pierre Masson, a pathologist in Montreal, had suggested in 1914 that t h e Kulchitsky cells in the gut formed a diffuse endocrine organ, and later (in 1928) described them as being neural also (p. G . l ) . A few years later (in t h e 1930s) t h e Austrian pathologist, Friedrich Feyrter of Gdansk (Danzig), P o l a n d ( 1 1 ) , described a system of helle Zellen (clear cells), which were distributed widely in the tissues but were most prominent in t h e gastrointestinal tract and in the pancreas, and suggested that they might secrete h o r m o n e s that acted locally. All these findings, which indicated that the nervous and endocrine systems were inseparable, were brought together and extended in the 1960s by Everson Pearse, a histochemist in L o n d o n , who found that Masson's and Feyrter's cells shared important functional characteristics with cells in some of the major endocrine glands and in the hypothalamus. All were concerned with the handling of amines and the production of peptides, and were conveniently described by the acronym A P U D (amine precursor uptake and decarboxylation) (12). M o r e recently an enzyme (neuronspecific enolase), previously found only in neurons, was demonstrated in all these cells also (13). These and many other observations further confirmed t h e concept of a single neuroendocrine system, pervading all the tissues of the body, but most conspicuous in t h e gut and the brain. (E.8) Knowledge about h o r m o n e s progressed all this time, and thyroxine was synthesized by Charles Harington in L o n d o n in 1927(If). T h e pursuit of steroids in t h e adrenal cortex and gonads occupied the center of the chemical stage next a n d reached its climax with t h e isolation and synthesis of cortisone by Kendall and t h e Swiss chemist Tadeus Reichstein in t h e 1940s (p. A.41). In the late 1960s the emphasis changed again, and peptides came to the fore, largely as a result of three developments: the invention of radioimmunoassay ( R I A ) by Solomon Berson and Rosalyn Yalow of N e w Y o r k in 1959 ( l g ) , t h e application of immunocytochemistry, and t h e advent of Pearse's A P U D concept. A t the same time the regulatory peptides and amines of the neuroendocrine system were seen to function in three different ways, namely, endocrine (secreted into the circulation and acting at a distance), paracrine (secreted and acting locally), and neurocrine (secreted at synapses and acting as neurotransmitters)(14). (E.9) ENDOCRINE DISEASE The first disturbances of endocrine function to be recognized were those of deficient secretion, and Addison's disease and hypothyroidism were described before hormones were discovered. Hypopituitarism was recognized soon after (p. P.5). The idea that diseases might be associated with endocrine hyperixmciion emerged more slowly. Hyperthyroidism in Graves' disease (p. T.88) and hyperpituitarism in acromegaly (p. P.4) were proposed in the nineteenth century, but were not generally accepted at first.


• 5

Once they had been, many syndromes of hormonal excess were described, and new ones continue to be recognized. (E.IO) The diagnosis of endocrine disease was made first on clinical grounds, on the basis of clinico-pathological correlations (e.g., signs of an adrenal or pituitary tumor with appropriate clinical features) and on nonspecific chemical measurements (e.g., blood sugar or calcium). Bioassays and chemical analyses of hormones followed, and finally RIA and related procedures. Static measurements often gave way to dynamic assays of the effects of stimulating and inhibitory factors. All these, together with routine biochemical screening, facilitated the recognition of endocrine disease. Anatomical definition of lesions depended mainly on x-rays and later on radioisotopic imaging. X-rays were discovered by Wilhelm Rontgen of Wurzburg, Germany, in 1895 (15a) and within six years were found to show enlargement of the sella turcica by a pituitary tumor (p. P.7). Each advance in radiological technique was applied, when appropriate, to the endocrine glands, and progressively better images were obtained. Isotopes of iodine, introduced in 1938, revolutionized the investigation of thyroid structure and function, and other isotopes were applied later to this and other glands (p. T.51).

(E.II)

Treatment of endocrine lesions involved mainly the replacement of defective secretion, the reduction of excessive secretion, and the removal or destruction of tumors. Organotherapy, which was practiced for centuries before the advent of endocrinology(5c), involved feeding organs, tissue extracts, or body fluids to replace the functions of defective members, such as the heart, spleen, testes, blood, and semen. Although ineffective, it evolved imperceptibly into replacement therapy. Indeed, George Murray of Newcastle-upon-Tyne, who first treated myxedema successfully by the injection of thyroid extract (p. T.43), was told that he might as well inject an emulsion of the spinal cord for locomotor ataxia (lh). The specific secretions of most endocrine glands were, however, purified, and many of them synthesized, and they came to be used effectively for the treatment of deficiency syndromes. (E.12) ENDOCRINE SURGERY By the end of the nineteenth century endocrine glands were being excised increasingly for the treatment of glandular enlargement, hyperfunction, and neoplasia, and also for certain other diseases. Before hormonal replacement therapy was available, transplantation of endocrine tissues seemed a rational method of restoring defective function, but was rarely effective because its immunological principles were not understood. All these operations formed the basis of endocrine surgery. (E.13) Up to the middle of the nineteenth century the scope of surgery in general was very limited(16a). Surgeons treated simple fractures, dislocations, and

6


abscesses, and performed amputations with dexterity, but high mortality, for compound fractures and severe sepsis of the limbs. They ligated major arteries for aneurysms, which were common, and made heroic attempts to remove external tumors. Some specialized in the management of anal fistulae and bladder stones. Abdominal surgery was almost unknown, although pointing abscesses were drained, strangulated herniae were reduced, and lumbar colostomy was sometimes performed for colonic obstruction. A few bold operators opened the abdomen to divide obstructing bands and adhesions or even to ligate the abdominal aorta for aneurysm. (Ei4) Endocrine surgery began empirically with castration, which was practiced, especially in males, before the dawn of history as a social or religious, rather than a medical, procedure, and was sometimes self-inflicted(li). In some countries it continued in these roles until modern times, especially to provide attendants for harems and castrati for choirs. Ovariotomy, the removal of ovarian cysts for general, not endocrinological, reasons, opened the door to abdominal surgery years before the introduction of anesthesia, antisepsis, and hemostasis. It was performed successfully by Ephraim McDowell, a country practitioner in Danville, Kentucky, in 1809, and was subsequently developed and popularized by others, notably Thomas Spencer Wells in London. Despite their best efforts, the operative mortality long remained at about 20 percent (16b). (E.IS) During this first phase the most important endocrine surgical procedures were operations for goiter, which has always been common in endemic areas. Goiters were usually obvious, often unsightly, and sometimes suffocating, and surgeons began to treat them at least 800 years ago when they threatened life. Roger Frugardi at the great Italian School of Salerno provided the first credible description of operations for goiter in general in about 1170 (p. T.8). Pierre-Joseph Desault of Paris is the first surgeon who is known to have published an account of an actual operation for the successful removal of a goiter, which he performed in 1791 during the French Revolution (p. T.12). His and some other results were remarkably good, but in general thyroid operations were so hazardous, carrying a mortality rate of about 40 percent from bleeding and sepsis, that many leading surgeons would not perform them (p. T.24). (E.i6)

THE SURGICAL REVOLUTION The second half of the nineteenth century, however, saw a revolution in surgery, equivalent to that in transport which followed the invention of the steam engine. Three separate developments in thirty years combined to bring this about: general anesthesia, antisepsis (followed by asepsis), and effective hemostasis. (E.n)


• 7

General anesthesia was introduced in the 1840s. E t h e r was used first by Crawford Long, a physician in Jefferson, Georgia, in 1842, and demonstrated by William M o r t o n , a dentist, in Boston, Massachusetts, in 1846. Later that year it was used by R o b e r t Liston in London for an amputation. Nitrous oxide was employed next, by H o r a c e Wells, a dentist in Hartford, Connecticut, and chloroform by James Young Simpson, Professor of Obstetrics in Edinburgh (17a). Anesthesia was soon adopted widely and was used for removal of a goiter by Nikolai Pirogoff of St. Petersburg in 1849 (p. T.25). Its obvious benefit of abolishing the pain of operations enabled surgeons to perform their work without hurry, and one immediate result was that they u n d e r t o o k m o r e operations. The problems of sepsis and bleeding, however, remained. W o u n d s were expected to suppurate before healing, and pus had been regarded as "laudable" since the time of Galen. More sinister infections caused death from secondary hemorrhage, erysipelas, septicemia, pyemia, and hospital gangrene. The last, a lethal infection of surgical wounds, was held in awe and increased to such an extent that some hospitals were threatened with closure (18a). (E.IS) Joseph Lister, Professor of Surgery in Glasgow, Scotland, published in 1867 the first remarkable account of antisepsis with carbolic acid, with which he saved the lives of patients with compound fractures(17b, 19) (Fig. E . 4 ) . By 1870, when he had moved to Edinburgh, he was using antisepsis for elective operations, his wounds healed by first intention, and sepsis had been almost eliminated. However, Lister's work was not appreciated for many years in Britain or America, and he was opposed vehemently, especially in L o n d o n , where he had graduated, when he returned there in 1877. But on the continent of E u r o p e antisepsis was soon adopted widely, with results similar to Lister's. Ernst von Bergmann of Berlin introduced steam sterilization in 1886 and asepsis in 1891 (15b). (E.i9) Control of bleeding in surgical operations had always been a problem for lack of suitable instruments, and hemorrhage was a common cause of death. The simplest devices were manual pressure with sponges and the application of chemical styptics or the cautery. Ligatures of thread, silk, or catgut were applied to vessels with the aid of tenacula and aneurysm needles. Divided arteries were grasped with torsion forceps and twisted. Traditionally, ligatures were left long, hanging out of the wounds until they separated. It was some time after the advent of antisepsis before it was appreciated that short ligatures, especially of sterilized catgut, and the small portions of tissue that they strangulated could be left safely in the depths of a wound. Self-retaining artery forceps of several types were devised early in the nineteenth century, and t h o s e of J o h a n n Dieffenbach of Berlin, and of Liston w e r e well known(16c, 20). All, however, were clumsy and had little influence on surgical technique. To compound the problem of h e m o r r h a g e , the practice of "therapeutic" blood-letting for many diseases continued well into the nineteenth century (p. T. 18) (17c). It was often employed during and after

8 • History of Endocrine Surgery operations for various complications, even when hemorrhage had been copious(18b). Well before the end of the century, however, some pioneers were transfusing blood, and Theodor Billroth, Professor of Surgery in Vienna, was doing so by 1877(21). (E.20) All these considerations applied to ovariotomy and operations for goiter. Management of the pedicle was a special problem in the former (16b), and hemorrhage a hazard in the latter, because the thyroid is such a vascular organ(18b). The breakthrough in hemostasis was made by Spencer Wells, who devised simple self-retaining artery forceps, with one catch, which he used first in about 1872 and reported in 1874 (22) (Fig. E.5). Wells' forceps were improved by the addition of a ratchet and by being made lighter, and were modified in many other ways by him and by others. Artery forceps transformed surgical technique and greatly reduced operative bleeding and its attendant mortality (18c). (E.21) A last, small part of the surgical revolution was t h e introduction of cocaine for local infiltration anesthesia by William Halsted, then of N e w Y o r k , in t h e 1880s (23). Cocaine and its analogues have been used extensively in operations for goiter. Unwittingly, Halsted and his colleagues became addicted, with tragic consequences. (E 22) In t h e last quarter of t h e nineteenth century most of E u r o p e enjoyed relative peace and stability, while travel and communication b e c a m e easier and faster than ever before (24). M a n y branches of science and medicine burgeoned, and great improvements in hospital design and in the nature and quality of nursing were emerging. All these factors combined to create an environment in which t h e surgical revolution could flourish. Anesthesia, antisepsis, and hemostasis not only r e n d e r e d existing procedures much safer, but enlarged t h e scope of surgery in general, allowing t h e body cavities and joints t o b e o p e n e d with relative impunity. A t t h e same time outstanding surgeons were ready to grasp the new opportunities and to meet the challenges provided by surgery as a whole. F o r many years, however, the dexterous surgeon could work effectively under primitive conditions, as in patients' o w n h o m e s , a n d with few assistants (p. T.27). (E.23) Progress in thyroid surgery was p h e n o m e n a l , particularly in Central E u r o p e in t h e hands of Billroth a n d Kocher, in Vienna and B e r n e , respectively ( p . T.29). By t h e e n d of t h e century Kocher's operative mortality for simple goiter was 0.2 percent a n d , as this first phase of endocrine surgery drew to a close, h e did m o r e than any other o n e surgeon before or since to develop t h e practice and science of thyroid surgery. T h e operative mortality for ovariotomy was halved (16b). In the 1890s orchiectomy was proposed for prostatic enlargement by William White of Philadelphia and was undertaken by many surgeons (p. C.5). O o p h o r e c t o m y was performed for advanced breast cancer by G e o r g e Beatson of Glasgow (p. C.2). (E.24) A t t h e close of t h e century also surgeons began to tackle lesions in t w o other endocrine glands. A d r e n a l tumors were not then diagnosed until they were found at operation or at autopsy, but progress in abdominal surgery


• 9

allowed some to be excised, and in 1889 Knowsley Thornton, a junior colleague of Spencer Wells in London, removed one successfully (p. A. 10). The same year Victor Horsley, also of London, who was already active in thyroid research (p. T.42) and a pioneer of neurosurgery, operated for the relief of pressure caused by a pituitary tumor (p. P.8). At about the same time the first ineffective attempts at transplantation of endocrine glands were made—for hypothyroidism in 1890 (p. T.43) and for Addison's disease in 1897 (p. A.64). Both were continued until reliable replacement therapy was available—thyroxine in the 1940s and cortisone a decade later. (E.25)

SECOND PHASE OF ENDOCRINE SURGERY As endocrinology developed and syndromes of hormonal excess were recognized, surgeons became increasingly involved because of the success of surgical operations for their relief. This opened the second phase of endocrine surgery, which extended into the latter half of this century. Endocrine glands were removed not only because they were neoplastic, but also because, whether tumorous or hyperplastic, they secreted excessive quantities of h o r m o n e s . In this way metabolic diseases were cured by surgical operations, and a new principle in surgery was established. Some achievements resulted from surgeons and their colleagues rising to the opportunities provided by first encounters with newly recognized diseases, while others were t h e outcome of disciplined attacks upon successive difficulties until the long-sought goals were achieved. Sometimes individuals contributed most, sometimes groups and institutions. (E 26) T h e second phase of endocrine surgery afforded several examples of first encounters with syndromes, which surgeons tackled, eventually with success. These included hyperparathyroidism by Felix Mandl in Vienna in 1925 (p. P. 10), pheochromocytoma by Cesar R o u x in Lausanne, Switzerland, and Charles Mayo in 1926, and hyperinsulinism by William Mayo (Charles' elder brother and colleague) in 1927 (p. G.16) and Roscoe G r a h a m in Toronto in 1929 (p. G.17). O n the other hand, prolonged efforts by many people were required before operations for toxic goiter or pituitary tumors could be approached with confidence. Thyroidectomy for hyperthyroidism began to emerge in t h e nineteenth century (p. T.99), but only became safe and effective as the result of four important developments in the twentieth. First, in 1908 T h o m a s Dunhill of Melbourne led the way in resecting sufficient thyroid tissue to cure t h e disease (p. T.101). Second, in 1922 C. Mayo and H e n r y Plummer, at the Mayo Clinic, started to use iodine preoperatively (p. T.106). Third, t h e introduction of radioiodine in 1942 provided a valuable adjunct or alternative to operations (p. T.109). Last, in 1943, Edwin Astwood of Boston introduced antithyroid drugs, and the next year Oliver C o p e , Francis M o o r e , and H o w a r d Means, also of Boston, reported t h e use of thiouracil preoperatively (p. T.113). Many surgeons have tackled the pituitary since Horsley's transcranial operations. In his day

10 • History of Endocrine Surgery few of them were ready to u n d e r t a k e neurosurgical procedures, and general surgeons, ear, nose, and throat ( E N T ) surgeons, and neurosurgeons in E u r o p e and t h e United States turned to an extracranial, transsphenoidal approach. H e r m a n n Schloffer of Innsbruck, Austria, was the first to operate thus, in 1907 (p. P.9), b u t pride of place belongs to Harvey Cushing of Baltimore and Boston, w h o founded t h e first school of neurosurgery and whose brilliant work spanned thirty years (Fig. E . 6 ) . During this second phase n o o n e else contributed so much to t h e surgery of the pituitary or any other endocrine gland. His work culminated in 1932 with t h e bold hypothesis that a basophil a d e n o m a of the pituitary was the causative lesion in t h e fatal disease that now bears his n a m e (p. P.32). (E.27) W h e n groups of clinicians and basic scientists cooperate, t h e crucial contributions come sometimes from one person or discipline and sometimes from another. A striking example is provided by the Mayo Clinic, whose staff contributed m o r e than any other group to the development of many branches of endocrinology and endocrine surgery at this time. These included the surgery of toxic goiter, the isolation of thyroxine, the first study of an insulinoma, remarkable results in t h e treatment of adrenocortical tumors by W a l t m a n Walters in t h e 1930s and 1940s (p. A.33), and t h e isolation of cortisone. T h e effect of its use to cover adrenalectomy for Cushing's syndrome by James Priestley, Walters, and their colleagues, published in 1951, was revolutionary (p. A.54). In the 1950s and 1960s Priestley and others, following C. Mayo's lead, also led t h e world in t h e surgical treatment of pheochromocytomas (p. A . 121). (E.28) In this second p h a s e , two world wars influenced t h e development of endocrine surgery in rather different ways. U p to t h e o u t b r e a k of the G r e a t W a r (1914-18) surgery was truly international, and surgeons visited each others' clinics a n d attended international congresses. E u r o p e was the center of activity, a n d Berlin, V i e n n a , L o n d o n , B e r n e , and Paris held t h e main attractions. A m e r i c a n surgeons who later contributed to endocrine surgery and w h o visited E u r o p e included Halsted, Cushing, C. M a y o , and G e o r g e Crile of Cleveland, O h i o . Typical of t h e international congresses was that held in L o n d o n in 1913, w h e n t h e Royal College of Surgeons of England awarded h o n o r a r y fellowships to m a n y distinguished surgeons from a b r o a d (Fig. E . 7 ) , including Crile, a pioneer of surgery for toxic goiter; Cushing, who was aged only 44; A n t o n von Eiselsberg from Vienna, w h o had contributed to thyroid and pituitary surgery; a n d W . M a y o . Kocher, w h o h a d received an h o n o r a r y fellowship previously, was present also. (E.29) The first casualty of the war was communication, and the international congress due to be held in Munich in 1917 was cancelled. Kocher's last visitors' book in Berne contains about 100 signatures each year up to 1914, but a total of only 21 from then until his death in 1917. In Europe medicine and surgery were concentrated on the problems of war; much was learned about the management of wounds, and orthopedic and plastic surgery advanced, while endocrine surgery stood still. Horsley, who had contrib-

Evolution of Endocrine Surgery (E) • 11 uted much, died on active service in Mesopotamia in 1916. One fortunate gain for Europe was that Dunhill, who served with the Australian forces in Europe, was persuaded to move from Melbourne to London in 1920. America suffered much less disturbance, and endocrine surgery, particularly of the thyroid and the pituitary, continued to advance. (E.30) After t h e w a r E u r o p e recovered slowly, b u t t h e rise of t h e Nazis in G e r m a n y in t h e 1930s resulted in t h e flight of many gifted Jewish scientists and surgeons to other countries. Oscar Hirsch, a pioneer in t h e surgery of the pituitary (p. P. 12) a n d of exophthalmos (p. T.124), and Felix M a n d l left Vienna in 1938, t h e year of t h e Anschluss. Happily, they were able t o continue their work elsewhere, Hirsch in t h e U n i t e d States a n d M a n d l in Palestine. (E.3i) World W a r II (1939-45) saw t h e start of a second surgical revolution, equivalent perhaps to that caused by the jet engine in transport. Three factors contributed. Blood transfusion, which had been practiced on a small scale, was organized nationally and in the armed forces in Britain, and later in America and elsewhere. Specialized techniques in anesthesia, particularly intubation and the use of positive pressure, were taught widely in the forces and, together with relaxants, transformed anesthetic practice. Penicillin, the first antibiotic, discovered in England before the war, was developed by government support in the United States and used extensively in the latter part of the war, and other antibiotics soon followed. These advances made all operations safer, including those on the endocrine glands, and also opened up new fields, especially surgery of the heart. Surgeons were no longer self-sufficient, and skilled teams of doctors, technicians, and nurses were formed to support them in their work. All became involved with much more then operative technique, and sought, as Kocher and Cushing had done before, to understand and control the disturbances of bodily function that not only accompany disease, but are induced by operation. (E.32) Again, medicine and surgery were less disturbed in North America than in E u r o p e , Asia, and elsewhere, and after the war the United States became the center of activity, generously welcoming large numbers of visiting workers from abroad. Within a few years, however, research and practice in all branches of medicine, including endocrine surgery, became international once again, and m e n and w o m e n moved freely about the world, exchanging ideas and e x p e r i e n c e .

(E.33)

MODERN ENDOCRINE SURGERY Another advance of the 1940s resulted from an extraordinary report that German air pilots were receiving adrenal cortical extracts to prevent hypoxia. Naturally the U.S. government was persuaded to support work in this field, and cortisone was developed and released for use in 1948(25). Its arrival had an explosive effect on endocrine surgery. Adrenalectomy was

12 • History of Endocrine Surgery rendered safe almost overnight (p. A.54), and total hypophysectomy became practicable (p. P.45). T h e scope of endocrine surgery for cancer of the breast and prostate was enlarged (work for which Charles Huggins of Chicago was awarded a Nobel Prize in 1966) (p. C.7), and the adrenal cortex became a focus of work on the endocrine response to stress. F u r t h e r m o r e , cortisone rendered adrenal transplantation for Addison's disease superfluous and facilitated effective transplantation of other organs. A t the same time steroid therapy for rheumatoid arthritis and other diseases posed new surgical problems. All this brought the surgery of the endocrine system together in the 1950s, and surgeons then began to appreciate it as a whole. This was the start of the third and present phase of its evolution. O n e of t h e first surgeons to view endocrine surgery in this way was Oliver Cope of Boston, a founder of m o d e r n endocrine surgery (Fig. E.8). Starting early in the 1930s and continuing for over forty years, he m a d e important contributions to the surgery of the thyroid, the parathyroids, and the adrenals, and stimulated others to d o t h e same (26). (E.34) Many more lesions and syndromes have been recognized and treated effectively, often by surgeons, in this third period. They include Conn's (p. A.81) and t h e Zollinger-Ellison syndromes (p. G.29), medullary thyroid cancer (p. T.130), renal (p. H . 9 ) and paraendocrine tumors (p. M.20), and multiple endocrine adenopathy (p. M . 2 ) . Endocrine surgeons, concerned with t h e whole endocrine system, were ready to meet these challenges. (E.35) Pituitary surgery developed remarkably during this same period. Since the late 1960s tumors previously thought to be inactive have been found to secrete h o r m o n e s and to cause specific syndromes (p. P.90). Surgical treatment, formerly designed to relieve pressure, was undertaken increasingly for endocrinological reasons. Transsphenoidal operations, which h a d been abandoned by most neurosurgeons in about 1930 in favor of the transcranial approach, were preserved, mainly by E N T surgeons in E u r o p e . F r o m the late 1950s Lennart Gisselsson in O r e b r o , Sweden, and then others refined them by t h e adoption of microsurgical methods. Jules H a r d y , a neurosurgeon in Montreal, independently used t h e operating microscope in 1965 (p. P.70-73). Others soon followed him and now operate regularly and successfully on microadenomas, which reveal themselves clinically and biochemically but which cannot be detected anatomically. (E.36) Transplantation of thyroid and adrenal homografts h a d been superseded by effective replacement therapy, but autografts of parathyroid and adrenocortical tissue were used in some situations, the former with success (p. PT.37), t h e latter less reliably (p. A . 5 8 ) . Homografts of whole pancreatic tissue and of islets, performed u n d e r immunological control for the relief of severe diabetes, were studied experimentally and hold promise for t h e future (p. G.58). (E.37) The idea of the unity of endocrine surgery received further impetus in the 1970s, when tumors of Pearse's APUD cells were grouped as "apudomas"

Evolution of Endocrine Surgery (E) • 13 (Fig. E.9). The word was coined in 1969 by Kalman Kovacs, Ilona Szijj, and their colleagues at Szeged, Hungary, who applied it to a paraendocrine, ACTH-secreting medullary carcinoma (27). Now for the first time many diverse peptide- and amine-secreting lesions, including paraendocrine tumors and most of the multiple endocrine adenopathies, which had previously seemed unrelated and disorganized in their behavior, came together in an orderly manner and were seen as products of the diffuse neuroendocrine system, sharing common, basic secretory characteristics(28). This concept clarified the nature and properties of apudomas, and prepared surgeons for all eventualities in the diagnosis, implications, therapy, and prognosis of patients harboring these lesions (14). (E.38) Tangible expressions of the newly emerging discipline of endocrine surgery came from several quarters from the early 1950s. Books and journals devoted to the subject were published (29, 30, 31, 32). Postgraduate courses in endocrine surgery became popular in about 1970, and associations of endocrine surgeons were formed nationally and internationally in the 1970s and 1980s. (E.39) Endocrine surgery grew steadily in stature as more and more leading surgeons entered the field. Today, as always, cooperation between surgeons and m e m b e r s of other disciplines produces the best research and provides optimal patient care. The most appropriate form of therapy for each patient often depends on the facilities available locally, and surgeons share in making therapeutic decisions. Surgical operations, well performed, often have most to offer, and increasing numbers of surgeons with the requisite skills are ready to u n d e r t a k e them. The stories of individual glands and topics in endocrine surgery are told in the following chapters in the approximate order in which they first appeared prominently on the historical horizon.

(E.40)

GENERAL SOURCES Shepherd, 1965. See Ref. 16. Cope, 1978. See Ref. 26. REFERENCES 1. Medvei, V.C. A history of endocrinology. Lancaster, England: MTP Press, 1982: a 834, 844, b 742-43, c 768-70, d 419, e 746-48, f 424, g 543, h 293, i 32. 2. Lyons, M.C., and Towers, B., eds. Galen. On anatomical procedures. The later books. Translated by Duckworth, W.L.H. Cambridge: Cambridge University Press, 1962: 7. 3. Vesalii, A. De Humani Corporis Fabrica, Liber Primus. Bruxellensis, 1543: 367. 4. Whartono, T. Adenographia: sive Glandularum totius corporis descriptio. 2nd ed. (Coll: London: Socio) Amstelaedami, 1659.

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5. Rolleston, H.D. The endocrine organs in health and disease. Oxford: Oxford University Press, 1936: a 18, b 1, c 4-9. 6. Hunter, J. (a) Observations on certain parts of the animal oeconomy. London: 13 Castle-Street, Leicester-Square, 1786: 31-46; (b) Essays and observations on natural history, anatomy, physiology, psychology and geology. Owen, R., ed. London: John van Voorst, 1861: 234-38. 7. Grossman, M.I. A picture history of gastrointestinal hormones. Los Angeles: VA Wadsworth Hospital Center, 1975: a 1, b 65, c 2. 8. Bayliss, W.M., and Starling, E.H. (a) On the causation of the so-called "Peripheral Reflex Secretion" of the pancreas. Proc R Soc London (Biol) 1902; 69: 352-53; (b) The mechanism of pancreatic secretion. J. Physiol 1902; 28: 325-53. 8A. Laguesse, M.E. Sur la formation des ilots de Langerhans dans le pancreas. C.R. Soc Biol (Paris) 29 July, 1893: 819-20. 9. Brown, W.L. Recent observations on the pituitary body. Practitioner 1931; 127: 614-25. 10. Cannon, W.B., and Paz, D. dela. Emotional stimulation of adrenal secretion. Am J Physiol 1911; 28: 64-70. 11. Pearse, A.G.E. The diffuse neuroendocrine system: an extension of Feyrter's concept. In: Miyoshi, A., ed. Gut peptides and ulcer. Tokyo: Biomedical Research Foundation, 1983: 89-92. 12. Pearse, A.G.E. The APUD concept and hormone production. Clin Endocrinol Metab 1980; 9: 211-22. 13. Schmechel, D., Marangos, P.J., and Brightman, M. Neurone-specific enolase is a molecular marker for peripheral and central neuroendocrine cells. Nature 1978; 276: 834-36. 14. Welbourn, R.B., Manolas, K.J., Khan, O., andGalland, R.B. Tumors of the neuroendocrine system (APUD cell tumors—apudomas). Curr Probl Surg 1984; 21: no. 8. 15. Garrison, F.H. An introduction to the history of medicine. 4th ed. Philadelphia and London: W.B. Saunders, 1929: a 721, b 594-95. 16. Shepherd, J.A. Spencer Wells. The life and work of a Victorian surgeon. Edinburgh and London: E. & S. Livingstone, 1965: a 36, b 97, c 98-100, d 64-66. 17. Guthrie,D. A history of medicine. London: Nelson, 1945: a 302-6, b 321-28, c 276-77. 18. Halsted, W.S. The operative story of goiter. Johns Hopkins Hospital Reports 1920; 19: 71-257; a 138, b 198-230, c 189-93. 19. Zimmermann, L.M., and Veith, I. Great ideas in the history of surgery. Baltimore: Williams & Wilkins, 1961: 461-75. 20. Mitchell-Heggs, F., and Drew, H.G.R. The instruments of surgery. London: Heinemann, 1963: 18-35. 21. Billroth, T. Lectures on surgical pathology and therapeutics. Translated from 8th ed. London: New Sydenham Society, 1877: 53. 22. Wells, S. The use of torsion in surgical operations. Br Med J 1874; 1: 47. 23. Olch, P.D. William S. Halsted and local anesthesia. Anesthesiology 1975; 42: 479-86. 24. Landor, J. Silvergirl's surgery. The stomach. Austin, TX: Silvergirl, 1986: 33-34. 25. Kendall, E.C. Cortisone. New York: Charles Scribner's Sons, 1971: 99.

Evolution of Endocrine Surgery (E) • 15 26. Cope, O. Endocrine surgery. Surg Clin North Am 1978; 58: 957-66. 27. Szijj, I., Csapo, Z., Laszlo, F.A., and Kovacs, K. Medullary cancer of the thyroid gland associated with hypercorticism. Cancer 1969; 24: 167-73. 28. Pearse, A.G.E., and Welbourn, R.B. The apudomas. Br J Hosp Med 1973; 10: 617-24. 29. Hardy, J.D. Surgery and the endocrine system. Philadelphia and London: W.B. Saunders, 1952. 30. Montgomery, D.A.D., and Welbourn, R.B. Clinical endocrinology for surgeons. London: Arnold, 1963. 31. Ellison, E.H., ed. A monograph on surgery and the endocrine glands. Am J Surg 1960; 99: 393-607. 32. Endocrine Surgery 1984; 1: 1-137.

E.l.

E.2.

E.3.

E.4.

E.l. Theodor E. Kocher. Courtesy of Theodor-Kocher-Institute, University of Bern, Switzerland. E.2. William M. Bayliss. Courtesy of The Royal Society. E.3. Ernest H. Starling. Courtesy of The Royal Society. E.4. Joseph Lister, by Walter William Ouless. Courtesy of the President and Council of the Royal College of Surgeons of England. 16

E.5

E

E.7

E.5. Thomas Spencer Wells, by Rudolph Lehmann. Courtesy of the President and Council of the Royal College of Surgeons of England. E.6. Harvey W. Cushing. Courtesy of Yale Medical Historical Library, New Haven, Connecticut. E.7. Honorary Fellows of the Royal College of Surgeons of England (1913): left to right: (back) J. Nicolaysen, G. W. Crile, F. D. Bird, F. J. Shepherd, R Bastianelli, W. J. Mayo, H. W. Cushing; (front) J. B. Murphy, W. Korte, H. Hartmann, E. Fuchs, A. von Eiselsberg, T. E. Kocher, T. Tuffier (endocrin surgeons italicized). Courtesy of Southampton General Hospital, Hants. 17

E.8. E.9.

E.8. Oliver Cope. Courtesy of Oliver Cope, M.D., Harvard Medical School, Boston, Massachusetts. E.9. A. G. Everson Pearse. Courtesy of Professor A.G.E. Pearse, Royal Postgraduate Medical School, London.

2 (T) The Thyroid

The thyroid gland lies near the surface of the body and gives rise to goiters, which are often large and unsightly, sometimes obstruct the trachea and esophagus, and may threaten life. For these reasons surgeons have long attempted to provide relief, and operations on the thyroid gland have evolved through the centuries as part and parcel of surgery as a whole. Until about 100 years ago operations were undertaken with trepidation under primitive conditions and often themselves proved fatal. Today they are routine, safe procedures with little morbidity. (T.I) FROM ANTIQUITY TO THE MID-NINETEENTH CENTURY Goiter and the Thyroid Goiters (L guttur = throat) are very common in many parts of the world and were recognized long before the thyroid itself. They were formerly confused with other swellings of the neck, especially enlargement of the lymph nodes, and the terms "bronchocele" (Gk fipoyyps = trachea and bronchus + KrjXrj = t u m o r ) , "struma" (L = swollen gland), and "guttur" itself were often used interchangeably to describe them all. (T.2) Goiters are said to have been known in China in 2,700 B . C . ( l a ) . They were never endemic on the shores of the Mediterranean and, according to Franz Merke of Basle, in his authoritative History of Goitre and Cretinism, were not mentioned in Egyptian papyri (2a) or in Hippocratic or other ancient G r e e k writings (2b). They were noted by nonmedical R o m a n authors in the first three centuries A . D . in mountainous regions(2c, 2d), and Juvenal asked, " W h o is still astonished at a goiter in the A l p s ? " ( 2 e ) .

20


Many years passed before a physician wrote of goiter, the first probably being Paul of Aegina in the seventh century, who described an aneurysmatic bronchocele (2f). T h e next was A b u l Kasim (Albucasis) of C o r d o b a , Spain (eleventh century), who referred to an "elephant of the t h r o a t , " frequent in women and incurable(2g, 3). In the twelfth century physicians at the great Italian School of Salerno gave reliable accounts of goiter and distinguished it from scrofula (tuberculous lymph nodes) (2h). A century later medical and nonmedical writers wrote of goiters in particular regions, and Marco Polo described them in Turkestan (2h). rr.3) Goiters have been depicted in art for centuries, mainly in regions w h e r e they are endemic, including South America and Mexico. Pottery at B e r n e in Switzerland and a Greco-Buddhist frieze at G a n d h a r a in India in the second and third centuries show them clearly (2j). Goiters were portrayed as ordinary features in many works of art in E u r o p e from the twelfth century onwards (2j), and Michelangelo depicted himself with an imaginary one, which had d e v e l o p e d while he was painting the ceiling of the Sistine Chapel (2k)! Illustrations of goiters in medical literature first appeared in "wound m e n " in the fourteenth century (21) and later achieved a high artistic level (2m). (T.4) The normal thyroid was not recognized until the Renaissance. Galen is said to have described it much earlier, but Merke considers that he was describing the tonsils(2n) and credits the Italians with its first descriptions. In about 1500 L e o n a r d o da Vinci drew the thyroid as a globular, bilobate structure, which he regarded as two glands, filling up empty spaces in the neck, but his drawings remained unknown for three centuries(2o). In 1543 Andreas Vesalius of Padua described and illustrated in De Fabrica two "glandulae laryngis" which, he thought, lubricated the larynx (p. E . 2 ) ( 2 p ) . Bartholomaeus Eustachius of R o m e , who also discovered the adrenals (p. A . 2 ) , described a single "glandulam thyroideam" (L = shield-shaped) with an isthmus connecting its lobes, but his work was not published until the eighteenth century(2q). Julius Casserius, also of Padua, recognized the gland, shaped like a horseshoe, and regarded it as a lubricating and spacefilling organ, which also m a d e the neck pleasing to the eye(2r). Eventually, in 1619, Fabricius ab A q u a p e n d e n t e , another Paduan, recognized that goiters arose from the glandulae laryngis (2s). Thomas W h a r t o n of L o n d o n described the gland in his Adenographia in 1656 (p. E.2), named it "glandul t h y r o i d o e i s , " a n d found that o n e s p e c i m e n weighed six d r a c h m s (26 grams) (2t). H e ascribed various functions to it, including those proposed by Casserius, also remarking that it contributed to the beauty of the throat, particularly in w o m e n . Many anatomical details were described subsequently, and in 1750 microscopy revealed vesicles in the gland ( l b ) . Frederick Ruysch of Leyden suggested that the thyroid poured a peculiar fluid into the veins, and in the late eighteenth century Caleb Hillier Parry of B a t h , who also described exophthalmic goiter, suspected that it provided a vascu-

The Thyroid (T) • 21 lar reservoir to prevent engorgement of the brain (lc). In 1776 Albrecht von Haller of Berne and Gottingen classed the thyroid as a ductless gland (p. E . 3 ) ( l c ) . N o more progress was made for over a century, when thyroid deficiency was recognized (p. T.42). (T5) Treatment of Goiter Medicinal treatment of goiters took many forms, the most effective of which were said to be marine preparations (2h). Sponge may have been used in China thousands of years earlier, and in the twelfth century the Salernitan physicians employed it, together with seaweeds and algae, which were often dried or burned. rr.6) Early accounts of operations for lumps in the neck are confusing. Aulus Cornelius Celsus, a nonmedical R o m a n encyclopedist, and many others described operations for scrofula and cysts and advocated the use of setons for some lesions. Celsus(2u), Galen(2v), and Albucasis(2w, 3) are sometimes credited with operating on goiters in the first, second, and tenth centuries, respectively, but it is very unlikely that they did so. Paul of Aegina in the seventh century advised against operating on them because of their vascularity(2x), and such procedures posed formidable problems. The importance of avoiding injury to the vocal (recurrent laryngeal) nerves during operations on the neck was recognized early by Leonides(2v), and Aetius of Byzantium (sixth century) quoted him as stating that the voice was lost if they were cut. In the second century, Galen described operations on two young boys by ignorant physicians, who tore out tuberculous nodes with their fingernails, making one boy " m u t e " and the other "semim u t e " (2v). (T.7) The School of Salerno in the twelfth and thirteenth centuries was the cradle of thyroid surgery, and the first credible accounts emanated from there in the Bamberg manuscripts, in the writings of Roger Frugardi published about 1170 (the year in which Thomas a Beckett was murdered in Canterbury), and in the later glosses (commentaries) on Roger's works(2y, 2z, 4, 5a). If a single, large goiter failed to respond to medication, especially marine products, two setons were inserted at right angles, with the help of a hot iron, and manipulated toward the surface twice daily until they had cut through the flesh. If any goiter remained, asphodel powder was applied. If there were not too many arteries, a goiter could be held with the hands, the skin cut, the tumor then grasped with a hook, and the skin dissected from it. The goiter together with its capsule was then removed with a finger. If hemorrhage was excessive, a vessel was seized with a tenaculum and ligated on both sides of the tear. Styptics could also be applied. A pedunculated goiter was ligated en masse with a bootlace and then removed. Complete ablation of goiters was considered essential to prevent recurrence, and any tumor that remained at the end of an operation was treated with caustic powder. Large goiters, which were usually lobulated, were difficult to

22 • History of Endocrine Surgery remove and were not cauterized for fear of damaging vessels and nerves. If, however, operation was necessary for such cases, the patients were tied to the table and held firmly, "so that we may see exactly what we are doing." Wounds were dressed lightly with linen cloths and, when they had finished suppurating and were clean, were dusted with "red powder" and sutured. Weak or elderly patients and those with very large goiters were not subjected to operation. rr.8) These operations were liable to complications, which often proved fatal. They were, however, advocated, and in 1718 Lorenz Heister of Altdorf and Helmstadt in Germany wrote an account of thyroid surgery that differed little from that of Roger (2aa). The procedures remained much the same until the nineteenth century. rr.9) Before then it was very unusual for reports of individual operations, let alone statistics, to be published. Although many more procedures had probably been undertaken on goiters, William Halsted of Baltimore, in his monumental Operative Story of Goitre (6) could trace accounts of only eight in which the scalpel had been used between 1596 (the year of the first report) and 1800, and sixty-nine between then and 1848(6a). Of these, thirty-one were in Germany, Austria, and Switzerland, where goiter was endemic, fifteen in France, fourteen in the British Isles, twelve in Italy, and five in the United States. (T.IO) The first few known operations were described by two surgeons who had advised against them. One, reported in 1646 by Wilhelm Fabricius, was undertaken in Geneva by "an audacious doctor" (2ab). The patient, a girl of 10 with a small goiter, died on the table, and the "rash" doctor was jailed. Two more operations were described in 1773 by Benjamin Gooch, who practiced near Norwich, England(6b, 6c). One patient died from uncontrolled bleeding after an ineffectual attempt at removal of a goiter, while the other bled for eight days before constant manual pressure stopped the flow and saved her life. At that time also, Bradford Wilmer, a surgeon in Coventry, England, considered that an operation for goiter was a hazard to life and that "resolution of the tumour [could] only be expected by internal medicine" (7). He recommended the secret "Coventry treatment," a preparation rich in calcined sponge, to which he attributed its success. Only if the bronchocele was small, soft, and of recent occurrence in a young woman was it likely to be of use. (T.H) The first well-documented partial thyroidectomy was undertaken in 1791 in Paris during the Terror of the French Revolution (1789-99) by PierreJoseph Desault (Fig. T.l)(2ac, 5b, 6d, 8). He used a vertical incision and isolated and ligated the superior and inferior thyroid arteries before cutting them and dissecting the gland from the trachea with a scalpel. The tumor was about 4 cm in diameter. He packed the wound, which suppurated and healed in a month. Guillaume Dupuytren, also of Paris, undertook total thyroidectomy in 1808 (6e). He divided the four main arteries between

The Thyroid (T)

• 23

ligatures, placing the first one on the cerebral side to prevent pain when the second was applied and, like Desault, separated the goiter from the trachea by sharp dissection. T h e r e was little blood loss, but the patient died from "shock." In 1821 J o h a n n H e d e n u s (Fig. T.2) of Dresden, G e r m a n y , reported the successful removal of six "suffocating" goiters by dissection and ligation of all the arteries(9), but, unlike the two French surgeons, he transfixed and ligated the isthmus or "pedicle" in two places. This practice was then followed generally (6f). A t least fourteen more partial or total lobectomies were reported by 1850—eleven from France and one each from England, Russia, and the United States (6g). Ten were partial thyroidectomies, with only one d e a t h ( 1 0 ) , but four were total extirpations, three of them fatal. Notable achievements in France, reported in 1849 and 1850, were those of Charles Sedillot of Strasbourg, who removed three "enorm o u s " goiters, and D r . Cabaret of St. Malo, who probably performed the first successful total thyroidectomy for a midline goiter, the size of an ostrich egg, with little bleeding. H e d e n u s ' remarkable series was not equalled for nearly forty years (2ac). cr.12) Iodine Therapy Iodine was discovered in the ash of burned seaweed by Bernard Courtois of Paris in 1811 (2ad). It was recognized as a new element and was soon found in other seaweeds and sponges, all of which were effective in the treatment of goiter. J o h a n n Straub and Jean-Frangois Coindet, both Swiss, suspected that iodine was the active ingredient(2ae, 11), and in 1820 Coindet reported encouraging results with iodine therapy (2ae, 12). Many goiters disappeared and others shrank, but in grave cases, when operation was unavoidable, Coindet recommended iodine preoperatively to reduce the vascularity and size of the goiter and to lessen the surgical risks. William Prout of L o n d o n later claimed that he had taken iodine himself before 1820 to test its safety and had given it to goitrous patients ( I d ) . Coindet's report caused much controversy because others, who probably used larger doses, found that iodine was t o x i c ( l d , 2ae), and in 1824 William Gairdner of L o n d o n described features suggesting hyperthyroidism following iodine therapy(13a). Coindet, however, gave small doses for short periods, observed their effects carefully, and in 1828 described 150 patients who had come to no h a r m ( l d , 11). The use of iodine spread, although marine products were also used, and many patients derived great benefit. In 1877 T h e o d o r Billroth of Vienna wrote that iodine, while beneficial in the early stages of goiter, was useless for the established disease. Nevertheless, it was often used because there was nothing else to offer (14a). Iodine was also used in two other ways: by local application of pomades (ointments) to the skin over the goiter (6g), and by injection into its substance (p. T.96). Many, perhaps the majority, of patients coming to operation in the nineteenth century had failed to respond to iodine therapy beforehand (6h), but it was

24 • History of Endocrine Surgery rarely used as a planned preoperative measure. By the end of the century, however, iodine therapy for simple goiter lost favor because of its risks (le, 2af).

(T.13

In 1833, soon after the introduction of iodine therapy, the French chemist Jean-Baptiste Boussingault, as a result of observations in Colombia, proposed its use for goiter prophylaxis (2ag). This matter caused controversy for many years, and iodized salt was not introduced until the twentieth century, and then only in some goitrous areas. (T.i4) Thyrotoxicosis A reference to goiter with exophthalmos appeared in a Persian manuscript in the twelfth century, and several patients with these features were described in the early 1800s(If, 15). A n account of eight patients with "enlargement of the thyroid gland in connexion with enlargement or palpitation of the h e a r t " by Parry was published posthumously in 1825(16, 17a). His first patient, seen in 1786, had exophthalmos also. In 1835 R o b e r t Graves of Dublin described a "newly observed affection of the thyroid gland in females"(17b, 18). T h r e e patients suffered palpitations and thyroid enlargement, and one of t h e m was exophthalmic. Next, in 1840, Carl von Basedow in Merseburg, G e r m a n y , described three patients with "exophthalmos due to hypertrophy of the cellular tissue in the orbit," goiter, and palpitations, a syndrome that came to be known as the "Merseburg Triad" (17c, 19). Exophthalmic goiter was long known as Graves' disease in the British Isles, Basedow's disease in continental E u r o p e , and sometimes, owing to the influence of William Osier of Baltimore and Oxford, as Parry's disease. O t h e r cases were reported, but nothing important was discovered about the disease for many years. (T.IS) Conservative Thyroid Operations T h e results of thyroid operations were so poor before the last years of the nineteenth century that most surgeons used very simple procedures. These fell into three main groups: (T.i6) 1. Noncutting operations had been employed for centuries (6j, 20). Setons and bristles were inserted, cysts were punctured and injected with iodine and other irritants, and caustics and cauteries were applied. Whole goiters or prominent nodules were occluded by subcutaneous (6k) or external ligatures, and thyroid lesions were punctured, broken up with instruments, and removed piecemeal. Setons, which had been described by Roger, were probably the most effective and were used by many surgeons, including D u p u y t r e n ( 2 1 ) . In 1833 he told how one goiter, the size of two fists, "lost two thirds of its size" in seventeen days. A n o t h e r was transfixed with two setons and was cured completely after suppurating for months. H e warned that it was "important to bear in mind the situation of the arteries." In 1821,

The Thyroid (T) • 25 four years before Parry's paper, Antoine Demours of Paris prescribed a seton for a goiter that was probably toxic (If). However, deaths from hemorrhage, inflammation, and even air embolism were well known, and setons were rarely used after about 1860(20, 22). rr.17) 2. Cutting operations without removal of thyroid tissue included ligation of the thyroid arteries and division of superficial muscles and fascia. Arterial ligation was first employed in 1811 by William Blizard (Fig. T.3) of London, who apparently intended it as a simple and safe prelude to extirpation of a large goiter (61, 6m, 23). He tied both superior thyroid arteries, one of which was "nearly equal in size to the carotid," and "in a week the tumor was reduced one third in its size." Unfortunately the patient died from repeated bleeding and hospital gangrene. In 1818 Henry Coates of Salisbury, England, and Astley Cooper of London, a pioneer of vascular surgery, tied a large pulsating thyroid artery in Elizabeth Spratt, aged 17, whose tumor was obstructing the trachea and the esophagus (24). Postoperative symptoms "gave way to the abstraction of blood," the ligature separated on the ninth day, and the wound was healed in two weeks. "Her breathing was much improved, the size of the tumor reduced nearly half; and she was so materially benefitted" that she was discharged after six weeks "quite well." Several other surgeons in England (6n, 25, 26), North America(6o), France(6p), and especially Italy ligated the thyroid arteries, and two Italians, Gino Marzuttini of Bologna and Luigi Porta of Pavia, reported about ten operations (6q). One of the most remarkable results was described in 1832 by Anthony Carlisle of London. He had ligated both superior thyroid arteries in a patient who lived in Hammersmith (27). Her bronchocele, "the size of the largest melon," sloughed completely and "rolled out" after ten days. In spite of Blizard's original intention, ligation was not used as a prelude to excision, and it was generally abandoned for simple goiter at about this time. (T.IS) Two patients who were clearly thyrotoxic were treated by arterial ligation in London. In 1823 Henry Earle ligated the superior arteries of a girl aged 17 with a large goiter and a pulse rate of 120 (6m, 28). The tumor diminished in size, the dyspnea and dysphagia disappeared, and four months later her health was "greatly restored." The next year Aston Key of London ligated an artery in a woman aged 28 with goiter, marked exophthalmos, and nervousness, but she died after two days(6m). Many years later arterial ligation was revived for simple goiter (p. T.33) and often used with some success for toxic goiter (p. T.99). rr.19) In 1840 Robert Liston of London divided the sternomastoid muscle to reduce pressure on a goiter causing dyspnea (29), and in 1857 Samuel Cusack of Dublin relieved dyspnea by division of the cervical fascia and temporary laryngotomy(6r). Others rarely found similar procedures effective (6s). (T.20)

26 • History of Endocrine Surgery 3. Enucleation and ligation of goiters were practiced commonly. Solid nodules proved particularly amenable, and several successful operations were reported, especially by Porta in the 1840s(6t, 6g). Enucleation was sometimes combined with ligation of the superior thyroid artery to control bleeding, but a patient treated thus by Nathan Smith of Baltimore died from sepsis(6u). Enucleation of cysts was often fatal at first, but was undertaken successfully later. Pedunculated and other suitable goiters were exposed by incision, partially dissected, and then ligated round or through their bases, the strangulated tissue being removed at the time or allowed to slough. Sometimes the ligature was tightened gradually over a few days. In around 1829 Dupuytren operated on a girl aged 12 with a goiter as large as her head, expecting it to be pedunculated(6g). However, he found a broad base, which he constricted with ligatures without removing the tumor, but the patient died. Others were more successful. In 1840, for example, two goiters were removed in Strasbourg by gradual tightening of ligatures around their pedicles (6g), and the next year Liston described a girl of 13 whose orangesized goiter he had ligated(30). She suffered much venous bleeding, but the tumor separated in about sixteen days and she recovered. rr.2i) Thyroid Surgery Around 1850 The indications for operating on goiters were usually suffocation and dysphagia, and many patients were near to death. Liston, however, operated on one goiter because of disfigurement in 1841(30). The goiters were usually simple (p. T.52) and only occasionally toxic or malignant. (T.22) Several general technical principles were common to most operations on the thyroid. Incisions were usually longitudinal or oblique, but occasionally Y-shaped or cruciate. Once the skin had been incised, most surgeons preferred blunt dissection to cutting. Hedenus' avascular method of ligating the isthmus, instead of dissecting it off the trachea, was still in general use. Control of bleeding in general was ineffective (p. E.20), and hemorrhage was often fatal. Blood-letting was applied for complications during and after operation, even when much blood had already been lost(6g) (p. T.18). Wounds were not drained and were often left open. Dead spaces were packed with lint or left full of blood in the hope that it would organize and help cicatrization (6k). Ligatures were left long and allowed to slough off. Infection was almost invariable, and wounds usually suppurated for a month or more before healing. More severe infections often proved fatal. rr.23) Two series of patients had, however, been published by individual surgeons with excellent results. Hedenus' resections were outstanding, and Porta had performed eleven operations, mostly arterial ligations and enucleations, between 1835 and 1850 with only one death(6w). Nevertheless, the overall mortality from thyroid extirpation was over 40 percent (6x),

The Thyroid (T)

• 27

and many leading surgeons advised against operating for goiter. Liston, who had done five thyroid operations, wrote in 1846 that there was a grave risk of death from h e m o r r h a g e and that it was "a proceeding by no means to be thought of," and J o h a n n Dieffenbach of Berlin stated in 1848 that it was "one of the most thankless, most perilous undertakings" (6y, 31). Thyroid operations were in fact condemned by the French Academy of Medicine in 1850(32).

(T.24)

GOITER SURGERY COMES OF AGE

The surgical revolution, which began in the 1840s (p. E.17), had an immediate impact on thyroid surgery. Goiter was endemic in central Europe, and outstanding surgeons, particularly Theodor Billroth of Vienna and Theodor Kocher (Fig. E.l) of Berne, were ready to meet the challenge. General anesthesia was adopted rapidly, and in 1849 Nikolai Pirogoff (Fig. T.4) of St. Petersburg employed ether for a thyroid operation on a girl of 17 whose central goiter pressed on the trachea(6z, 6aa). Some surgeons, however, managed without anesthesia for many years, and some patients declined it. Even as late as 1900 Cesar Roux of Lausanne, Switzerland, a very dexterous surgeon, did not always use it for thyroidectomy (33). Antisepsis, introduced by Lister in 1867, was adopted much sooner in Europe than in Britain and the United States. Kocher used it in 1872(2ah, 34a) and Billroth (Fig. T.5) in 1875(35a), and many others followed(6g, 6ab). Both these surgeons, along with Spencer Wells, were also devising new methods of hemostasis. These three advances enabled surgeons, especially in Switzerland, Austria, and Germany, to undertake many more thyroid operations, to devise new ones, and to operate with greatly reduced mortality (6v). (T.25) The main stream of advance lay in perfecting the operations of enucleation and lobectomy, while other surgical procedures were gradually dropped. If a lobe was mostly or entirely goitrous, so that simple enucleation was insufficient, it was much easier to avoid hemorrhage by removing it completely than by cutting into it to leave a portion behind. If both lobes caused deformity, their removal might result in total excision of the gland. This caused no concern since the objective was a safe and effective operation and the thyroid was not known to have any vital function. Several descriptive terms were used. "Strumectomy," "extirpation," "excision," and "ablation" referred to all operations for the removal of goiters, while lobectomy was applied to the removal of one lobe or both lobes. "Resection" was a different procedure, introduced later (p. T.47). Kocher referred to "thyroidectomy" until 1893, but then abandoned it in favor of "strumectomy" because it was "ambiguous and troublesome" (6ac), and the term did not reappear for several years (36a). rr.26)

28


In the third quarter of the century (about 1850-75), just before Billroth and Kocher came on the scene, four other surgeons, two of them Swiss, one German, and one Scottish, performed large numbers of operations with better results than any since those of Hedenus in 1821. Felix Heusser of Hombrechtikon, near Zurich, undertook thirty-five strumectomies with only one death between 1842 and 1859, and later another sixty-one operations, most of them for goiter, with only four deaths (2j). He operated in his own and patients' houses, thereby avoiding the septic hospital environment, his wife giving the anesthetics and his young son assisting him. Heusser did not publish his work, but left notes that were reported on (in 1878) after his death. His 5 percent operative mortality in a very large series was remarkable in pre-Listerian times. Viktor von Bruns of Tubingen, Germany, operated on twenty-eight patients, six (21 percent) of whom died from sepsis, between 1851 and 1876(6ad, 6ae). Most operations were for enucleation of cysts, but two (both fatal) were total excisions for carcinomas. He was the first surgeon for fifty years who is known to have dissected the isthmus from the trachea. He was also, perhaps, the first to control hemorrhage by ligating vessels as they presented with the help of an aneurysm needle (6ad, 6af). Georg Lucke, who preceded Kocher in Berne, enucleated ten solid goiters between 1865 and 1872, with only one death(6ag). Finally, Patrick Heron Watson (Fig. T.6) of Edinburgh undertook eight total thyroidectomies with one death between 1871 and 1875 (6g, 6ah, 36A). His incision was central, linear, and long, and the first patient lost much blood. He reduced hemorrhage thereafter by the rather crude method of palpating the four main arteries and ligating them blindly, together with the veins, within their fascial sheaths. The ligatures at first were unabsorbable and left long, but later they were made of catgut and cut short. The wound was closed with a large drain at the lower end. Seven patients survived, but the eighth died from aspiration of blood into a wounded trachea. Three of the patients had exophthalmos, which in one diminished markedly after operation. rr.27) During this same period surgeons in many countries were operating on the thyroid, but few reported more than one case. The greatest numbers came from central Europe but, in other areas, North America was catching up with France, Italy, and Britain. Kocher traced 146 extirpations worldwide between 1850 and 1877 and found that the operative mortality had fallen from 41 to 21 percent (6ac). rr.28) Billroth and Kocher Before settling in Vienna, Billroth held the Chair of Surgery in Zurich, from 1861 to 1867. There he undertook fifty-nine operations for goiter, including twenty extirpations, most of which were enucleations of solid nodules. Eight (40 percent) of his patients died, seven of them from sepsis.

The Thyroid (T) • 29 For this reason, when he moved to Vienna at the age of 38, he practically abandoned thyroid operations, except for asphyxia(2ac), and only performed sixteen with five deaths (31 percent), in the next ten years(6aj). He did not embark on elective thyroid surgery again until 1877, when he had been using antisepsis for two years. (T.29) Kocher, Billroth's junior by twelve years, was appointed to the Chair in Berne in 1872 at the age of 31. He employed antisepsis and engaged in thyroid surgery from the beginning. Greater advances were made in the surgery of simple goiter during the next decade in Central Europe than in any similar period anywhere, either before or since. Indeed, Halsted (writing in 1920) considered that thyroid operations had been "essentially perfected" by 1883 (6j). (T.30) Billroth and Kocher both employed iodine therapy, which was still in general use, and both injected goiters with iodine as a sclerotic, with some success. Lucke had used it in this way and preferred iodine injections to enucleation of solid goiters. Kocher found that only solid (parenchymatous) forms responded, but Billroth also obtained good results with cysts (6ak). (T.31) In his first two years Kocher undertook thirteen extirpations, six of them for the relief of dyspnea (6al). Through an incision along the anterior border of the sternomastoid or in the midline, he did nine enucleations, two " Ausschalung" procedures (scooping out nodules and suturing their incised capsules to the skin), and two total excisions. His antiseptic technique was clearly not yet perfect, for two patients (15 percent) died from infection. Kocher had previously undertaken research into blood clotting and hemostasis (34b), and no patient died from bleeding. He ligated the main arteries when he encountered them during removal of the lobes, not as a preliminary step, because he regarded the two procedures as essentially the same. He used aneurysm needles and artery forceps meticulously to ligate vessels before dividing them or to stop bleeding when it was unavoidable. He chose the very vascular plane between the true capsule and the goiter to "avoid floundering in the neck," and separated the posterior bands of vascular connective tissue into several portions before ligating and dividing each one individually. Like Desault, he dissected the isthmus from the trachea, if it separated easily. Otherwise, to avoid bleeding, he ligated it and left its stump attached, as Hedenus had done. rr.32) In 1877 Billroth embarked again on planned operations for goiter, and these were reported regularly by his assistant, Anton Wolfler (Fig. T.7)(6am). Conservative operations included arterial ligation, which he reintroduced(37a), division of the sternomastoid muscle (35b), and incision and drainage of cysts. Like Kocher, he achieved hemostasis with hemostatic forceps (37A), aneurysm needles, and an Indian vegetable styptic, punghawar djambi. In the first three years (1877-79) Billroth undertook

30 • History of Endocrine Surgery sixteen extirpations, which included twelve excisions of circumscribed nodules or lobectomies, and four total extirpations. Operations were now rr.33) usually performed for moderate dyspnea or for cosmetic reasons. The incision was made along the anterior border of the sternomastoid muscle, the strap muscles and omohyoid were divided transversely, and the external thyroid capsule was slit along a grooved director. A n attempt was then made to free the goiter bluntly, but if that failed, the superior thyroid artery was ligated with silk and the goiter was mobilized from above downwards. Obstructing bands were divided between artery forceps and ligated en masse to minimize the amount of ligature material in the wound, which sometimes delayed healing. Near the recurrent laryngeal nerve, however, smaller masses of tissue were clamped to avoid injury, and the inferior thyroid arteries were ligated carefully when they were encountered. The isthmus was dissected from the trachea. The incision was closed with drainage, and the wounds healed in one to five weeks. All sixteen patients survived, and Billroth was encouraged to operate more often and to attempt more difficult procedures. By 1881 he had performed forty-eight operations with antisepsis for benign lesions, including twenty-two total extirpations. Only four patients (8 percent) had died, and complicated procedures, involving tracheostomy, were responsible in three cases(6aj). (T.34) In this s a m e year (1881) Billroth performed t h e first successful gastrectomy in man and Wolfler the first gastroenterostomy(38). Gastric surgery was clearly uppermost in their minds, and Wolfler moved to the Chair of Surgery at Graz, Austria, in 1886. Perhaps for these reasons no further comprehensive analyses of Billroth's many thyroid operations were published. Wolfler, however, and other pupils (particularly Anton von Eiselsberg and Johann Mikulicz) made important contributions later, or.35) Kocher, on the other hand, following the example of his friend and mentor, Spencer Wells, who regularly reported the results of his ovariotomies (34c), recorded his own thyroid work at frequent intervals until his death in 1917. In 1883 he reported another 88 operations, 101 extirpations in all(6ac). His incision was usually midline and vertical, but he added an oblique extension to the anterior border of one sternomastoid ("Winkelschnitt") when he needed better access. He divided the strap muscles and omohyoid transversely, but then dissected outside the external capsule (pretracheal fascia) and isolated, ligated, and divided all the thyroid vessels with the help of his three-grooved director ("Kropfsonde")(6an). Starting with the superior vessels, he worked downwards, delivering the lower pole with a finger as soon as possible, a particularly important step with plunging goiters. When the whole gland was free, he split the external capsule, rolled the goiter medially, and ligated the inferior thyroid artery alone in continuity, close to the carotid artery, to avoid the recurrent laryngeal nerve. Finally, he dissected the isthmus from the trachea. Thirteen of the 101 patients died, none from bleeding or sepsis (6ac). At the same

The Thyroid (T) • 31 time (1883) Kocher collected reports of 268 operations since 1877 and found that the mortality for nonmalignant goiters had again fallen, to 12 percent, while that for malignant cases was 57 percent. Now that sepsis and hemorrhage had been overcome and many patients were surviving operation, other complications were recognized. (T.36) Recurrent Laryngeal Nerve Injury T h e danger of damage to the recurrent laryngeal nerves during operations on the neck had been recognized since antiquity. In 1820 Karl von Klein of Stuttgart, G e r m a n y , described a young man who suddenly became speechless during removal of a goiter. T h r e e weeks later he began to speak again, but "his voice had changed into a harmonious bass"(6ao). In Billroth's forty-eight patients (1877-81) the nerve was paralyzed on one side in eleven and on both sides in two(6aj). Wolfler, who used laryngoscopy routinely, recorded the clinical course following injury and noted that paralysis was sometimes present before operation (6ap). W h e n injury was unilateral the voice usually improved in four to six weeks as a result of compensation by the opposite vocal cord. Experiments in dogs had shown that section of the nerve trunk led to paralysis of the cord and the epiglottis. If, therefore, the cord only was paralyzed, Wolfler considered that branches of the nerve, and not the trunk, had been damaged. In 1881 Felix Semon of L o n d o n observed that the first sign of partial injury to the nerve was abductor paralysis of the cord(37b), and this came to be known as Semon's law. (T.37) Billroth, Kocher, and others took care to avoid the nerve while operating in its vicinity, for fear of clamping or dividing it, and all agreed that the inferior thyroid artery should be seen in a bloodless field, isolated, and ligated laterally. Kocher also left behind the posterior portion of the internal thyroid capsule(39). H e wrote that, although the nerve could be dissected

out beautifully, injury could be avoided with certainty without direct exposure(6aq). He observed hoarseness frequently in his early cases, but later found it to be exceptional. (T.38) Cachexia Strumipriva and Thyroid Function The function of the thyroid gland was discovered as a direct result of surgeons' observations of the effects of total thyroidectomy in man. This soon resulted in a reappraisal of the surgical approach to goiter and the preparation of an active thyroid extract for the relief of hypothyroidism. In 1867 Paul Sick (Fig. T.8) of Stuttgart, described a boy of 10 who had been "joyous and lively" and whose goiter had been totally extirpated by Wilhelm Hahn and Karl Bockshammer the previous year(6ar, 40). Ten months later the boy was quiet and dull. Sick suggested that either removal of the thyroid had disturbed the cerebral circulation or a chemical change in the blood had interfered with the brain's nutrution. His colleagues favored the latter view. The boy lived at least eighteen years as a cretinous dwarf (36b). No such

32 • History of Endocrine Surgery observation had been published before, perhaps because patients had not been observed for long enough after operation or, as Halsted suggested, because small amounts of the gland had been inadvertently left behind by previous operators. The significance of Sick's report was not appreciated at the time.

(T.39)

Kocher's first series of thirteen strumectomies included two total extirpations. One patient was Marie Bichsel, aged 11, who underwent operation on January 8, 1874, and whose behavior changed in a similar way. While previously "a spirited and joyous creature," she became "peevish and dull" and was reluctant to work. Kocher wrote at the time that he would learn from her further progress whether the altered mental state bore any relation to the operation. Later he heard from her physician that she had become "quite cretinoid"(5c, 41). In 1882 Jacques-Louis Reverdin of Geneva described several patients who became feeble and anemic two to three months after he had performed total ablation (42). Two of them also developed edema of the face and hands, and one looked "cretinoid." When Kocher learned of this he quickly contacted Marie Bichsel and was astonished at her appearance. Before the operation she and her younger sister had been taken for twins (Fig. T.9A). In the ensuing nine years the sister had blossomed into a very pretty young woman, while Marie had remained small and had an ugly, almost idiotic appearance (Fig. T.9B). He immediately requested all his goiter patients to return for examination. Thirty who had undergone partial excision attended, and twenty-eight of them were well. Those who had had total excisions were entirely different, for sixteen of the eighteen who came showed the features already described, and all did so eventually(6as). Patients of all ages were affected, but the sequelae were most obvious in children, whom Kocher again likened to cretins. Reporting these findings to the Congress of German Surgeons in Berlin in April 1883, he named the condition "cachexia strumipriva," but suggested that it was caused by injury to the trachea, which resulted in chronic asphyxia. Reverdin and Kocher ceased to perform total extirpation of the thyroid, and most surgeons soon followed suit(6as, 6at, 43). (T.40) Ten years earlier William Gull of London had described "a cretinoid condition supervening in adult life in women," later named "myxoedema" by William Ord, also of London(lg, 17d). In June 1883 Reverdin and his cousin, Auguste Reverdin, likened the condition of their adult patients to this disease and introduced the term "operative myxedema"(6au). Semon (Fig. T.10), an ENT surgeon, referred to this work at a meeting of the Clinical Society of London in November 1883, and mentioned that a patient operated on by Joseph Lister three years previously had developed the same condition. He proposed that cretinism, myxedema, and cachexia strumipriva were all associated with absence or degeneration of the thyroid. This assertion "was received with polite scepticism" (44), but was reported in the British Medical Journal the next week (45). Soon the society

The Thyroid (T) • 33 appointed a committee with Ord as chairman to investigate myxedema (46). (T.41) The committee analyzed 109 reports of myxedematous patients and studied the effects of thyroidectomy in animals. This operation had been performed by several workers, including Astley Cooper in the 1820s, usually with inconclusive results (lh). However, in the 1850s the physiologist Moritz Schiff of Berne had found that it caused fatal tetany in dogs and guinea pigs(43,47). In 1884, after cachexia strumipriva had been described, he (now in Geneva) repeated his experiments and found that death could be prevented by grafting the thyroid into the abdomen (lc). Victor Horsely of London, a member of Ord's committee, undertook thyroidectomy in monkeys the same year (43, 47, 48) and observed muscular twitchings and convulsions at first, and myxedema later. He concluded that the effects of thyroidectomy in man were due to arrest of thyroid function, fully endorsing Semon's view(47), and in 1888 the committee concurred(lg, 46). Although the parathyroids had been described in man in 1880, it was not until they were rediscovered and studied physiologically in the 1890s that the acute effects of thyroidectomy were recognized as due to their simultaneous, inadvertent removal (p. PT.3)(lj, 49). (T.42) T h e beneficial effects of thyroid transplantation, observed by Schiff, were confirmed by A n t o n v o n Eiselsberg, Billroth's first assistant, in 1890(lh, 50). T h e same year Horsley suggested that transplantation of thyroid tissue from apes or sheep might b e of benefit in m y x e d e m a (50), and this was soon tried by several surgeons in Portugal, G e r m a n y , and Britain with some early encouraging results(13b, 51). H o w e v e r , a simpler form of treatment was soon introduced. In 1891 G e o r g e Murray of Newcastle-upon-Tyne, a form e r pupil of Horsley, m a n a g e d to p r e p a r e an extract of sheep's thyroid in glycerine, which h e injected subcutaneously to Mrs. S., a 46-year-old lady with m y x e d e m a (p. E.12). T h e patient promptly improved a n d remained well for twenty-eight years(52, 53). T h e next year (1892) oral therapy proved equally effective(54, 55). E d w a r d Fox of Plymouth, England, administered "half a sheep's thyroid, lightly fried and taken with currant jelly once a w e e k " (56). In 1893 Kocher suggested that t h e thyroid gland might contain iodine, and in 1896 E u g e n B a u m a n n of Freiburg im Briesgau, G e r m a n y , found that the c o m p o u n d iodothyrin was a normal constituent (13c). (T.43) Thus, by the end of the nineteenth century there was clear evidence that a product of the thyroid was physiologically active, that its absence caused disease, and that its replacement brought relief. (T.44) Tetany Postoperative tetany was probably first described by Wolfler in 1879 in the first of Billroth's patients to survive total extirpation (6av, 37). She developed paralysis of the right vocal cord, then became very restless, and

34 • History of Endocrine Surgery finally suffered convulsions of the extremities. After three weeks she recovered; the attacks were attributed to hyperemia of the brain due to complete removal of the thyroid gland. One of Billroth's forty-eight patients reported in 1881 died from tetany (6aj). (T.45) In 1883 Nathan Weiss, Billroth's assistant, collected thirteen cases of tetany, eight from their own clinic and five from elsewhere (2ak, 6aw). All the patients were young females who had undergone total extirpation. Two had died, five had recovered, and one still had attacks three years after operation. Despite much speculation about vascular and nervous causes, the only firm conclusions were that tetany was not tetanus and that it was caused by the operation. Other surgeons also reported tetany after total extirpation, and some patients developed cachexia in addition(6ax). However, it is remarkable that Billroth's patients rarely became cachectic, while Kocher's hardly ever developed tetany and, when they did so, it was mild and transient in all but one. Halsted, who knew their work well, considered that the difference lay in their operative techniques (6ax). Kocher, neat and precise, operating in a relatively bloodless field, removed the thyroid only, although he was unaware of the parathyroids. Billroth, working more rapidly, clamping and ligating tissues en masse and with less concern for hemorrhage, could more easily remove the parathyroids or damage their blood supply, and at the same time leave fragments of the thyroid behind.

(T.46)

Further Progress with Simple Goiter The complications of total extirpation quickly caused surgeons to seek alternatives (6as, 6au), at least for benign lesions (6at, 43). Kocher preferred unilateral lobectomy and only once again removed both lobes (6as). Some British surgeons simply excised the isthmus between ligatures (36c). In 1886 Johann von Mikulicz-Radecki (Fig. T . l l ) of Krakow, Poland, formerly Billroth's assistant, reported a new operation(6ay, 57). In one patient he had been obliged to remove the second lobe to relieve tracheal obstruction and had incised the goiter, leaving a portion the size of a chestnut posteriorly. He had treated this "pedicle" as if it were that of an ovarian cyst, crushing, clamping, and ligating it in portions before dividing it. Bleeding was not a problem. He feared that the crushed tissue would slough, but the wound healed by first intention. Mikulicz repeated this maneuver, which he named "resection," in seven more patients, bilaterally in one of them, with the objects of avoiding total extirpation and injury to the recurrent laryngeal nerves in addition to preventing recurrence of the goiter. These and eighteen other operations for severe dyspnea were undertaken without mortality. (T.47) Kocher continued to modify his technique and improve his results and to investigate thyroid function, but others, like Mikulicz, began to take the

The Thyroid (T) • 35 initiative. By 1895 Kocher was performing many operations mainly for cosmetic reasons(39a). Ether anesthesia was usual, but he preferred Halsted's method of local infiltration with cocaine (58), or even light morphia narcosis alone, if there was severe dyspnea. He usually employed a collar incision, which had been introduced by Jules Boeckel of Strasbourg in 1880(6az), but still sometimes used an angular incision. Dissection now was mainly between the external and internal capsules, and the goiter was dislocated forward before ligation and division of the vessels. The posterior portion of the internal capsule was still left in situ. Enucleation of encapsulated nodules was described as simple and without risk of nerve injury, but much bloodier than excision. Kocher used it occasionally for multiple bilateral nodules, but preferred unilateral "enucleation-resection" for isolated lesions (6ba). This involved dislocation of the goiter, excision of the anterior capsule (composed of the internal thyroid capsule and a thin layer of thyroid tissue), enucleation of the nodule, and division (and ligation) of the isthmus (39a, 39b). The remaining (posterior) portion of the gland was left in situ. Kocher still employed unilateral excision for diffuse disease and regarded Mikulicz's resection as "especially difficult." At first, when he employed it, he applied numerous artery forceps to the vessels on the cut surface, but later (in nontoxic goiters) clamped and crushed the gland. When a nodule was soft and adherent to its surroundings, Kocher preferred "evidement," that is, incision of the capsule and evacuation of the contents by scraping and digital pressure (39b). The superficial muscles were removed together with the goiter for inflammatory and malignant disease. (T.48) The number of operations reported by Kocher increased steadily (6bb), and by 1898 his assistants, including Cesar Roux, Fritz de Quervain, and Albert Kocher (his son), had done 150 of them. In 1901,2,000 were performed and, by 1917, when Kocher died, 7,052 strumectomies had been undertaken in his clinic, three-quarters of them by him(34d). In 1884 Kocher's operative mortality, like that of other surgeons, was 14 or 15 percent(6bb), but fell progressively as his antiseptic (and later aseptic) technique was perfected. Within one year his death rate fell to 7 percent and in 1889 to 2.4 percent. Exclusion of the malignant and toxic cases reduced the figure to less than 1 percent (2/225) in a series that included seriously ill patients and very difficult operations. In 1898 only 1 of 556 patients with simple goiters died— from chloroform poisoning—a mortality of 0.18 percent. rr.49) By the turn of the century the surgical treatment of simple goiter was safe and the results were good, but left room for improvement. In 1909 Kocher was awarded the Nobel Prize for Medicine "for his works on the physiology, pathology and surgery of the thyroid gland" (59). Just before he died in 1917, aged 76, he added his weight to the view that the main hope of future progress lay in the prevention of goiter (2al). (T.SO)

36 • History of Endocrine Surgery THE TWENTIETH CENTURY General Developments Physiology Soon after the discovery of iodothyrin, iodine was found to be essential for normal thyroid function. An active component, containing 65 percent of iodine, was crystallized on December 25, 1914, by Edward Kendall and named thyroxin (later thyroxine) (Ik, 60). Thyroid extract and thyroxine were found to regulate the metabolism and growth of all tissues. Thyroxine was analyzed and synthesized in the middle 1920s by Charles Harington in London and proved to be tetraiodothyronine (T4), a derivative of tyrosine. Thyroid function was elucidated in the next three decades, knowledge being accelerated by the introduction of radioiodine in 1938 (61a). Iodide is trapped avidly by the thyroid acini, oxidized to iodine, combined with tyrosine to form T4, and linked to thyroglobulin, which is stored in the colloid. When required by the body, T4 is released into the blood, where most of it is bound with thyroid-binding protein (TBP) and delivered to the tissues. A thyroidstimulating hormone of pituitary origin (TSH) was identified in the 1920s (p. P.22) and recognized as a glycoprotein twenty years later. It is secreted when thyroid hormone is deficient, and stimulates the growth and activity of the acini. Its secretion is inhibited when sufficient hormone has been produced. In 1952 a second thyroid hormone, triiodothyronine (T3), which acts more rapidly and for a shorter time than T4, was discovered by Rosalind Pitt-Rivers and Jack Gross in London (13d). The two hormones together exert all the known effects of thyroid extract. rr.si) Pathology of Simple Goiter At the beginning of the nineteenth century Dupuytren recognized three types of goiter: hypertrophic, scirrhous, and cystic(21). Billroth regarded most goiters as "chronic endemic miasmatic tumors (adenomas or cystadenomas)" and the "local expressions of general infection" (14b, 61 A). In 1883 Wolfler, from Billroth's clinic, described congenital, hypertrophic, and adenomatous types of goiter and included in the third group a "fetal adenoma," which he represented as a solid tumor arising from embryonic cells, scattered among the adult follicles (62). In 1896 Halsted observed that partial thyroidectomy caused hyperplasia of the remaining gland (63a). At the turn of the century James Berry of London described eight principal types of goiter (36d): 1. Parenchymatous, usually in young people, in which both solid and colloid parts of the gland were enlarged uniformly; 2. Wolfler's fetal adenoma, usually single, small, solid, and encapsulated, with masses of undeveloped thyroid vesicles;

The Thyroid (T) • 37 3. Cystic adenoma, which was much commoner and formed from the coalescence of many large colloid-filled vesicles; 4. Fibrous; 5. Mixed; 6. Exophthalmic; 7. Malignant; and 8. Inflammatory. He did not propose any causes of goiter, but suggested that the change observed by Halsted after partial thyroidectomy was compensatory. The first three types came to be known as "simple goiter," which was either endemic, especially in mountainous areas, or sporadic. The great majority of thyroid operations were undertaken for these forms of goiter. (T.52) By about 1910 (63b, 64) t h r e e basic pathological changes w e r e recognized in simple goiter, namely, (1) hypertrophy, which usually progressed to (2) hyperplasia, b o t h of which might regress a n d b e followed by (3) involution, in which t h e vesicles stored colloid. Stimulation was often intermittent, so that these changes succeeded each other in a cyclical m a n n e r , a n d t h e response was n o t always uniform. Eventually t h e gland b e c a m e exhausted, partly atrophic or h e m o r r h a g i c , cystic, a n d fibrosed. T h e first t w o (active) changes were attributed to iodine deficiency by David M a r i n e of Cleveland, O h i o (65), a n d t o w a t e r - b o r n e bacterial infection by R o b e r t McCarrison of C o o n o o r , I n d i a ( 6 6 ) . W h e n t h e stimulus was r e m o v e d , activity ceased a n d involution or exhaustion supervened. Marine had found that iodine prevented the hyperplasia that followed partial thyroidectomy and that, in a large trial, it almost eliminated goiter in schoolgirls. McCarrison had caused goiters to recede under treatment with intestinal antiseptics (67a). Iodine deficiency was apparently the basic cause, but infection might be an aggravating factor. or.53) Clinically these pathological processes resulted in goiters of different types, which developed especially when thyroid h o r m o n e s were most n e e d e d , namely, during puberty, menstruation, pregnancy, a n d lactation. Goiters were generalized or localized a n d p a r e n c h y m a t o u s (cellular) or (T.54) colloid, in various combinations, according to the circumstances. Goitrous nodules were described as a d e n o m a s , which might b e single or multiple, variable in size, a n d sometimes cystic. Histologically they consisted either of well-differentiated tissue or, especially if single, of fetal-type cells. Both varieties were regarded as neoplastic, and the fetal adenomas were said to be prone to malignancy (63c). By the 1930s, however, they were recognized as different results of faulty (hyper-) involution (37c, 68). cr.55) By the 1940s, while iodine deficiency was accepted as the principal cause of endemic goiter, goitrogens, which had been identified in some foods (cabbage and soybean) and medicines (thiocyanates and thioureas), were

38 * History of Endocrine Surgery thought to be responsible for many sporadic cases (69a). In some regions chronic gastrointestinal infections might interfere with the absorption of iodine. Iodine deficiency and goitrogens prevented the synthesis of thyroid hormone, thereby removing the feedback brake on TSH (p. P.46), which was consequently secreted in large quantities. This in turn drove the thyroid to hypertrophy and hyperplasia, which resulted in goiter and might or might not preserve adequate thyroid function. Later more goitrogens were identified in foods and medicines, and congenital defects in thyroid hormone synthesis were recognized (61b). (T.56) Studies with radioiodine clarified t h e course of events in t h e thyroid in simple goiter(70). After studying autoradiographs of surgical specimens, Selwyn Taylor in L o n d o n described five stages in its evolution (71), namely: (1) diffuse hyperplasia, (2) focal hyperplasia, (3) focal h e m o r r h a g e a n d necrosis, causing disruption a n d encapsulation, (4) resolution, a n d (5) multinodular goiter, in which inactive a n d hyperfunctioning zones w e r e intermingled. Oliver C o p e in B o s t o n found that simple goiters rarely affected total thyroid function, a n d that all functioning tissue was sometimes concentrated in " h o t n o d u l e s , " t h e r e m a i n d e r of t h e gland being cold(72). T h e subjects were n o t always euthyroid, however. Rarely, if iodine was in a d e q u a t e or excess supply, hyperthyroidism might result, while in other rr.57) cases hypothyroidism followed. Investigation of Thyroid Disease X-rays, discovered in 1895, were soon employed for the investigation of thyroid disease, and in 1903 Kocher used them to display intrathoracic goiters(39b). Plain films, fluoroscopy, and stereoscopy were used routinely for all goiters (63d). Tracheal compression ("saber-sheath" or "scabbard" deformity) and deviation were recognized. Calcification was seen in some long-standing nodular goiters and in certain carcinomas. Contrast fluoroscopy during a barium swallow was often useful. Ultrasound, introduced in the 1970s, helped to distinguish cystic from solid nodules. (T.58) T h e first direct, t h o u g h relatively nonspecific, clinical m e a s u r e m e n t of thyroid function was the basal metabolic rate (BMR). Procedures for its estimation were developed in New York in the 1910s, and within a few years several methods were generally available(37d). The BMR was increased, sometimes greatly, by hyperthyroidism, but also by other normal and abnormal states. A low rate was almost diagnostic of hypothyroidism. The BMR remained the most reliable measurement of thyroid function for many years. The Goetsch test, in which the reaction of the body to adrenalin was assessed, was introduced in 1918 for the diagnosis of hyperthyroidism, but was nonspecific and did not last long (63k). (T.59) In t h e 1920s cholesterol levels w e r e found to vary inversely with thyroid function, a n d a high level strongly suggested hypothyroidism. In t h e 1930s m e a s u r e m e n t of creatine tolerance, which was reduced in thyrotoxicosis,

The Thyroid (T)

• 39

was sometimes used diagnostically(69b). In the 1940s measurement of protein-bound iodine in the blood (reflecting the thyroxine level) was beginning to prove similarly helpful (69b). The test was modified in various ways and replaced in the 1970s by measurement of T4 and T3 by radioimmunoassay ( R I A ) ( 7 3 a , 74). Muscle contractility is influenced by thyroid function, and m e a s u r e m e n t of the characteristics of the Achilles tendon reflex proved a useful accessory method for the diagnosis of hyper- and hypothyroidism (61c). (T.60) T h e introduction of radioactive iodine (1-131) in 1938 revolutionized the measurement of thyroid function (69c). In the first test a tracer dose was given by m o u t h , the amount excreted in the urine was measured, and the thyroid uptake was estimated indirectly. Many other measurements involving radioiodine were devised later, and other isotopes of iodine and technetium ("Tc m ) were introduced (75). Tests included direct measurement of iodine uptake by the thyroid and, of special help to surgeons, thyroid mapping to display hot and cold nodules(61d, 76a, 77a). (T.6i) Measurement of T S H by R I A was introduced in the 1960s. A high level usually indicated hypothyroidism or, very rarely, a TSH-secreting pituitary tumor (p. P.93). Dynamic tests of thyroid function, introduced in the 1970s, included suppression with T3 and stimulation with T S H . Both were largely replaced by stimulation with thyrotrophin-releasing h o r m o n e , which provided a sensitive test for the diagnosis of hyperthyroidism (73b). (T.62) Measurement of thyroid antibodies of three main types, first developed in the 1950s, proved particularly helpful in the diagnosis of auto-immuno thyroiditis (76b). rr.63) Surgical biopsy and excision biopsy of solitary nodules came into use many years ago, and in the 1950s needle biopsies of two types were employed in some centers. In one method a core of tissue was removed with a wide-bore needle (Vim-Silberman or Tru-cut) or a drill and examined histologically (78), while in the other fine needle aspiration ( F N A ) was used to obtain material for cytologic examination (Aspiration Biopsy Cytology— A B C ) ( 7 9 ) . Neither was adopted widely at first, but by the late 1970s, as cytologists gained experience, A B C was employed widely(80), often sparing patients with benign conditions unnecessary operations (81). (T.64) Treatment of Hypothyroidism Commercial preparations of dried thyroid extract and of throxine were introduced in the early 1900s for the treatment of hypothyroidism but, despite many successes, proved unsatisfactory for a long time(37j). Patients required close supervision, the doses needed periodic adjustment, and different batches of extract varied in potency. Thyroxine itself was more expensive and less potent, and often seemed ineffective by mouth. By the 1940s, however, dried extract had been reasonably standardized chemically and proved reliable. A decade later 1 -thyroxine sodium and T 3 , both of

40 • History of Endocrine Surgery which were stable and accurately standardized, were available, and t h e former, now inexpensive, was the best preparation for routine use. (T.65) Thyroid Grafting The unreliability of thyroid replacement therapy led surgeons to continue with attempts at thyroid grafting for some years. In 1914 Kocher described t h e transplantation of h u m a n toxic goiter tissue into the tibial b o n e m a r r o w , and in 1923 his son, Albert, reported results in 204 patients with congenital thyroid deficiency, treated in B e r n e (82). H e claimed that one-quarter were cured a n d that most (86 percent) were improved, although a few (5 percent) required two or more grafts. O t h e r workers attributed any t e m p o r a r y improvement that they observed to t h e absorption of thyroxine from the grafts. Little m o r e was heard of grafting, although it was mentioned in textbooks for another twenty years (37w, 83). (T.66) Thyroiditis A c u t e inflammation of the thyroid, sometimes forming an abscess, occasionally complicated injection of t h e gland. It was also seen rarely with general infections (36e). In 1932 Cecil Joll of L o n d o n reported abscesses in 2 of 2,000 patients with goiter(37e). A c u t e thyroiditis later became very rare(84), and suppuration was usually prevented by t h e use of antibiotics, where they were available (74, 76c). In t h e middle of the nineteenth century pathologists stated that t h e presence of a goiter was proof that t h e subject did not have tuberculosis (85). By 1900, however, tuberculous and syphilitic thyroiditis were relatively c o m m o n but rarely required treatment (36e). Tuberculous lesions were reported in 0.4 percent of goiters removed surgically at A n n A r b o r , Michigan, in t h e 1920s(85), but both these forms of thyroiditis practically disappeared in places where the diseases came under control.

(T.67)

T h r e e other specific forms of nonacute thyroiditis were described by surgeons and n a m e d after t h e m . (T.68) RiedeVs Disease Fibrous goiters had been described before 1896, when Bernhard Riedel of Jena reported an iron-hard ("eisenhart") inflammatory tumor of the thyroid (37f, 86). He mistook the lesion for malignant disease at first, owing to involvement of the surrounding parts, and abandoned the operation. To his surprise the patient recovered, and he subsequently described several similar cases. This clinical and pathological entity came to be known by several names, but usually as Riedel's disease. Although rare, it was later described in about 0.5 percent of goiters treated surgically in both Britain and the United States, two-thirds of the patients being women(87). The cause was unknown. The thyroids were large, extremely hard, and invaded by fibrous

The Thyroid (T)

• 41

tissue, which infiltrated the surrounding structures also, eventually fixing and replacing the glands and causing pressure symptoms. Fibrosis sometimes affected the mediastinum, liver, and retroperitoneal tissues also. Thyroid cancer could not be excluded for certain without a generous biopsy. Surgical relief of dyspnea was sometimes needed, and wedge resection of the isthmus, which might be difficult, was very effective. Surprisingly, hypothyroidism developed only occasionally (61e, 69d, 74). (T.69) De Quervains Thyroiditis In 1902 and 1904 de Quervain described subacute nonbacterial inflammation of the thyroid(32, 88, 89) and in 1936 gave a fuller account. A goiter, often painful and with symptoms and signs of subacute inflammation, usually developed and resolved after some weeks or months. The cell walls disintegrated and the nuclei formed clumps, resembling tuberculous giant cells. Hyperthyroidism occurred occasionally at the onset; subsequent hypothyroidism was rare unless radical surgery had been undertaken (61f, 74).

(T.70)

The disease was reported more often in some places than in others, especially in Minnesota, Ohio, and Toronto, but was recognized generally. Its cause was unknown, but it was sometimes associated with outbreaks of viral infection. Subacute thyroiditis was sometimes mistaken for acute or chronic thyroiditis or even cancer. No specific diagnostic tests were available, and biopsy was needed occasionally, especially if cancer was suspected. Corticosteroid therapy was very effective for relieving pain, but rarely necessary. The relief of pain was, however, of diagnostic value. Very rarely thyroidectomy was needed for obstruction. rr.7i) Hashimoto's Disease In 1912 Hakaru Hashimoto (Fig. T.12), working at Kyushu University, Japan, described the clinical and pathological features of four patients with struma lymphomatosa, a condition that came to bear his name(90). The patients had goiters that were diffusely infiltrated with lymphocytes and plasma cells and that showed small follicles and fibrosis. Hashimoto's paper was published in Germany and was not noticed in Japan for many years. Very few patients were recognized elsewhere at first, but in 1929 the condition was named lymphadenoid goiter (91). Joll (in 1932) advised against operation, except for severe dyspnea, and then recommended preserving as much thyroid tissue as possible because of the risk of myxedema (37g). By 1948 Howard Means of Boston, an internist, had collected reports of thirty-eight patients, incuding twelve of his own, all but one of whom were women. The goiters were smooth and firm, and signs of inflammation and pressure were common (69e). One of his patients developed myxedema, which he was by then able to treat effectively with thyroid

42 • History of Endocrine Surgery extract, and he did not hesitate to recommend subtotal thyroidectomy. Seven of these patients then became myxedematous but, with replacement therapy, were cured. rr.72) Nothing was known of the cause of Hashimoto's disease until 1956, when Deborah Doniach and her colleagues in London found that the sera of patients often contained thyroid autoantibodies(92). This observation led to the recognition of autoimmune thyroiditis as a pathological process, of which this disease was one manifestation(61g, 74). Other forms described were primary adult myxedema without goiter formation, a fibrous variant with histologic features similar to those of Riedel's thyroiditis, and lymphocytic thyroiditis, with exophthalmic goiter (Hashimoto toxicosis). Some unknown agent damaged the thryoid cells and caused the release of thyroglobulin and the formation of autoantibodies. Thyroid tissue was then destroyed, the production of thyroid hormones was diminished, TSH production was increased, and goiter often resulted. The diagnosis could usually be made immunologically and the condition treated effectively with thyroxine, which inhibited TSH production as in simple goiter. Biopsy was still needed sometimes, especially to exclude cancer. Surgical treatment was rarely required to relieve pressure, especially from retrosternal goiters, and when carcinoma could not be excluded. (T.73) Treatment of Simple Goiter Many medical and surgical methods were employed for the treatment of simple goiter at the turn of the century (36f). Removal of patients from goitrous to nongoitrous districts sometimes caused a diminution in size, and the administration of iodine, whose popularity had waxed and waned, was often effective. Thyroid extract (thyroidin) was employed also, and sometimes succeeded when iodine had failed. The reverse was also true. The effect of thyroid extract on goiter was first reported in 1895(93), and the next year Paul Bruns of Tubingen described its use in over 300 patients. The goiters disappeared in 8 percent, decreased in size in another two-thirds, and failed to respond in one-quarter(94). Purification of drinking water, local application of iodine or mercury, and exposure of the neck to the sun's rays, said to be curative in India, were not recommended elsewhere. Tapping of cysts usually failed, but injection of cystic and parenchymatous goiters, especially with iodine, was still sometimes used with benefit. Arterial ligation was sometimes beneficial. Exothyropexy, a new operation introduced by Mathieu Jaboulay in 1892 in Lyon, involved dislocation and exteriorization of the goiter. It was employed for toxic goiters also, but the results were bad and the operation fell into disrepute (36g, 37h). Division or resection of the thyroid isthmus for the relief of dyspnea was sometimes helpful. The definitive operation, however, was thyroidectomy, a term that had now

The Thyroid (T) • 43 come back into use. Enucleation of solid and cystic lesions was practiced by August Socin in Basle and by several others. Unilateral lobectomy, as perfected by Kocher, sometimes combined with partial resection of the other lobe, and enucleation-resection were, however, the commonest operations. Total thyroidectomy was now recommended only for some malignant goiters. rr.74) The surgical treatment of simple goiter was generally safe, but there were occasional complications, some of them alarming(36h, 37k). Immediate accidents included sudden death, air embolism, and hemorrhage. Many structures had been damaged at operation, including the recurrent laryngeal and hypoglossal nerves, the cervical sympathetic chain and vagus, the pleura, pharynx, and esophagus, and the trachea. Sometimes postoperative respiratory obstruction, attributed to tracheal collapse after prolonged pressure, required tracheostomy. Most cases were probably due to laryngeal edema. Later complications included secondary and recurrent hemorrhage, sepsis, tachycardia, and restlessness (perhaps in patients with unrecognized toxic goiters), tetany, and compression of the recurrent laryngeal nerves by scar tissue. Cachexia strumipriva still followed total thyroidectomy, but was now often controllable with thyroidin. According to J.-L. Reverdin's statistics for the last twenty years of the nineteenth century, 91 of 3,254 (2.8 percent) patients had died after partial thyroidectomy for simple goiter (36i). The commonest causes of death were pneumonia, sepsis, and bleeding, in that order. Experienced thyroid surgeons, especially Kocher, achieved the best results (0.18 percent mortality for simple goiter), while others, who treated fewer patients, had more complications and tended to use simpler procedures. Often, as in other branches of surgery, these were less effective and sometimes (as with exothyropexy) more dangerous, cr.75) In the 1890s three American surgeons who had visited Europe began to operate on goiters by the methods that they had seen there, and reported large numbers of patients in the early 1900s. These were William Halsted (Fig. T.13) of Baltimore, Charles Mayo (Fig. T.14) of Rochester ("Father of American Thyroid Surgery"[95]), and George Crile (Fig. T.15) of Cleveland, Ohio. They and their colleagues took much of the initiative in advancing thyroid surgery. (T.76) Now that operations were relatively safe, surgeons concentrated on t h e cosmetic and r e m o t e effects, including recurrence of the goiter. T h e prevention of complications, particularly malignancy and hyperthyroidism, was now recognized as an indication for operation(96). M a n y nodules, thought to b e single, were found at operation to be simply the largest lesions in bilateral, multinodular goiters. Small nodules left behind at operation frequently enlarged, a n d n e w nodules often developed later(39b). Unilateral lobectomy sometimes resulted in shrinkage of the remaining lobe for a time. Often, however, it enlarged later, b e c a m e unsightly, and sometimes caused

44 • History of Endocrine Surgery dyspnea. The isthmus, pyramidal lobes, and both upper and lower poles of the glands, if not removed, might develop into unsightly swellings. According to Kocher some eighteen percent of goiters recurred ("struma recidiva"), most of them after enucleation, so that second operations, which were difficult and dangerous, were required (39b). Many surgeons therefore followed Mikulicz and undertook bilateral resections except when a nodule was seen at operation to be clearly single. In 1914 Donald Balfour reported bilateral operations in more than half the patients at the Mayo Clinic (96), and by 1922 George Crile described the procedure as routine (63e). A margin of thyroid tissue, sometimes including the upper poles of a colloid goiter, was left at the postero-medial border of each lobe, from the upper to the lower margin of the gland, and a thin layer of connective tissue was left covering the trachea(371). The remnant, estimated to have the same functional capacity as the normal thyroid, was preserved. With simple goiters this was larger than a normal gland (10-20 g on each side), while with toxic ones it was smaller (3-5 g). (T.77) General and local anesthesia were both used, local being preferred when dyspnea was a problem. The collar incision was employed by most surgeons. Opinion was divided about the best way to avoid injury to the recurrent laryngeal nerves. Some surgeons used local anesthesia to provide early warning. The patient was encouraged to talk and, if the voice changed suddenly, forceps that had just been applied could be removed. Intracapsular thyroidectomy, which had been used by Kocher in 1872 and then abandoned, was revived in 1934 (without ligation of the main vessels) by Oleg Nicolaiev in Moscow and used successfully by him and his students in many thousands of operations (97). It does not appear to have been practiced much elsewhere. (T.78) Single solid nodules, which had been treated by enucleation or enucleation-resection for many years, were found to be malignant in 10 to 25 percent of cases. When this was recognized preoperatively by aspiration biopsy, the nodule was treated as a carcinoma (p. T.130). Otherwise, resection by partial lobectomy, followed by histological examination, was practiced for some time(61h). If a carcinoma was found, total lobectomy, which was then often required, could be difficut and dangerous. For these reasons total lobectomy, together with removal of the isthmus and pyramidal lobe, came to be preferred by many as the best method of surgical biopsy (74, 98, 99).

(T.7 9 )

Intrathoracic goiters often went unrecognized, but were especially liable to cause death from suffocation, and all required operation(39b). Kocher employed local anesthesia and a low incision, with free division of muscles for access. He controlled all the vessels, especially the veins, and then tried three maneuvers in turn to deliver the goiter: first, extraction with long toothed forceps; second, enucleation with a blunt elevator; and, third, incision and evacuation of cystic goiters or exenteration (morcellement) of

The Thyroid (T) • 45 solid lesions. After delivery and excision, hemostasis was again secured. H e operated on seventy-seven patients, only one of whom died, and Berry on forty, also with only o n e d e a t h ( 3 7 m ) . Kocher's method stood the test of time. T h o m a s Dunhill, however, split t h e sternum to improve access (100), a method employed later by others for very large, difficult goiters(74). Positive pressure anesthesia, which came into general use in the 1940s, rendered the whole operation much simpler. roo) The roles of iodine and thyroxine in the prophylaxis and treatment of simple goiters became clear in t h e course of time (61 j). Endemic goiters and many sporadic ones could be prevented almost entirely by the administration of iodine from infancy, and slight thyroid enlargement could be reversed by iodine, which was m o r e effective in endemic than in sporadic cases. Larger goiters often shrank when, in addition, T S H production was inhibited by thyroxine. Results were best with diffuse goiters, and any shrinkage of nodular ones was said to affect the nonnodular parts only (74). Operations were designed to remove all unhealthy tissue (74) and, if the whole gland was diseased, total thyroidectomy was sometimes advised (99). Half the patients w h o underwent bilateral partial resection for simple lesions became hypothyroid in time, and half developed significant recurrence of their goiters in seven or eight years (74). For these reasons most surgeons prescribed thyroxine after operation with the object of preventing both these complications (61 j), and most now continue its use indefinitely (74, 76d). (T.8i) The Morbidity of Thyroidectomy After alternative forms of therapy for thyrotoxicosis came into use in the 1940s, the complications of thyroidectomy in general came under scrutiny, notably by Hilary Wade in Cardiff (101) and Oliver Beahrs at the Mayo Clinic(102). The operative mortality was acceptably low, and virtually nil in many centers, but the postoperative morbidity was greater than that of most other procedures of similar magnitude (101). In addition to hypothyroidism and recurrence of disease, two other sequelae, which had been recognized since Billroth's and Kocher's time, were particularly troublesome, namely, laryngeal nerve injuries and tetany. (T.82) Laryngeal Nerve Injuries All surgeons tried to avoid injuring the nerves. Most, including Billroth, Kocher, and Joll, avoided them(36m, 37u, 63j), while some, notably August Bier (in 1911) of Berlin (103), preferred to expose them deliberately. Charles Mayo in 1913 estimated that 5 percent of patients had permanent paralysis of one nerve after operation (104). In 1938 Frank Lahey of Boston advocated routine dissection and demonstration of the nerves, and reported injury in 0.3 percent of patients in whom this had been

46 • History of Endocrine Surgery practiced(105, 106). Some considered dissection itself to be dangerous, owing to the consequent edema and possible hemorrhage, and one surgeon even stated that "a nerve if seen is injured" (107). rr.83) Protagonists of nerve identification pointed out that when pre- and postoperative laryngoscopy had been carried out routinely, the published incidence of nerve injury was much the same—2.8 to 5.6 percent of nerves at risk—whether the nerves had been identified or not. The difference was that when the nerves had been identified, the paralysis was nearly always transient, while when they had not, one in three of those injured was permanently paralyzed (103, 108). Most surgeons agreed that paralysis was commoner after operations for diffuse toxic goiters and large nodular glands than for other forms (109), and that operations for recurrent goiters carried the greatest risk(110). Although William Michie of Aberdeen, a very good thyroid surgeon who did not identify nerves, reported paralysis in less than 0.5 p e r c e n t ( l l l ) , the practice of identification has become almost universal among thyroid surgeons. rr.83a) The external branch of the superior laryngeal nerve, which runs medial to the superior thyroid artery and supplies the cricothyroid muscle, was occasionally damaged during ligation of the vessel, with consequent impairment of the voice. The opera singer Amelita Galla Curci is said to have suffered this injury (77b). Thyroid surgeons became familiar with the position of the nerve and were usually able to avoid it(112, 113). However, as with the recurrent nerve some years ago, the practice of identification is growing (113 A ) . (T.84) Hypoparathyroidism When the cause of tetany after thyroidectomy was appreciated, surgeons tried to avoid the parathyroid glands at operation. Mikulicz's thyroid resection provided fortuitous protection against their inadvertent injury, and dissection inside the thyroid capsule posteriorly, as practiced by Kocher, Halsted, and Mayo, had the same effect. The surgical anatomy and blood supply of the parathyroids were studied and described by Halsted in 1907 (114) and later by many others(115). Despite this knowledge, surgeons often found great difficulty in identifying parathyroids in the presence of a goiter (101). However, they took great care to preserve tissue resembling the glands, particularly when it lay at sites where they were commonly found (99, 101). cos) A few patients, however, suffered hypoparathyroidism, which was presumed to be due to inadvertent removal of parathyroid tissue at operation (113). Surgeons at the Mayo Clinic reported in 1956 that 3 percent of patients developed tetany permanently (102). Most of these, however, had undergone secondary thyroidectomy for recurrent Graves' disease, and only 0.3 percent of patients were affected after primary operations(110).

The Thyroid (T)

• 47

Some 5 percent had transient tetany and hypocalcemia, which lasted from days to months, and it was generally accepted that patients nearly always recovered from parathyroid insufficiency (116, 117). rr.86) The extent of parathyroid injury was investigated closely in the 1960s. In some series 2 to 3 percent of patients were found to suffer permanent insufficiency (101,118), especially after operations on toxic goiters(119). In many "transient" cases frank hypoparathyroidism could be provoked by tests that challenged the parathyroid reserve, suggesting that complete recovery was unlikely in 70 percent of patients who had transient symptoms and hypocalcemia after operation (116, 117). In one series a quarter of the patients who had undergone thyroidectomy were found to have reduced parathyroid reserve which, it was suggested, might cause chronic ill health (120). Hypoparathyroidism could not be accounted for entirely by inadvertent removal of parathyroid tissue, and it was proposed that damage to the vascular pedicle of the gland was a common cause (101,119). Another suggestion was that in thyrotoxic patients postoperative hypocalcemia was due to the hunger of osteoporotic bones for calcium (121). These studies focused attention on the risk of damage to the parathyroid glands during thyroid operations and made surgeons more conscious of the danger. When hypoparathyroidism was recognized, it could be treated effectively with calcium and vitamin D . (T.86a) THYROTOXICOSIS The nature of thyrotoxicosis remained in doubt for many years. Graves ascribed the thyroid enlargement to overaction of the heart (18). Some attributed the disease to derangement of the central nervous system, neurosis, or irritation of the cervical sympathetic chain (11, 36j, 122). Others implicated glandular dysfunction associated with enlargement of the thymus, insufficiency of the adrenal cortex, or overactivity of the adrenal medulla (11, 63f). rr.87) A role for the thyroid itself was strongly suggested by the effects of surgical operations. In the nineteenth century several patients who clearly had unrecognized toxic goiters were treated with setons (p. T.17), by thyroid artery ligation (p. T.19), and by partial or total thyroidectomy (p. T.27)(6az). The operations had been performed to relieve the local effects of goiter, but toxic features, including exopthalmos, were relieved in some. The significance of these observations was not appreciated until 1884, when Ludwig (Louis) Rehn (Fig. T.16), of Frankfurt-am-Main reported three patients with Basedow's disease, who were cured incidentally when their goiters were removed for the relief of dyspnea. H e proposed that overactivity of the thyroid was responsible for the condition (123). Toxic symptoms also subsided after resection in one of Mikulicz's patients (57). Paul Mobius

48 • History of Endocrine Surgery of Leipzig made the same suggestion as Rehn two years later, and in 1893 William Greenfield of Edinburgh described hyperplasia of the thyroid in this condition (lm). rr.88) It was soon observed that the wasting of thyrotoxic patients was associated with excessive loss of nitrogen, even when they were eating well, and that their metabolic rates were increased (In). These findings supported Rehn's hypothesis, and in 1907 Charles Mayo introduced the term "hyperthyroidism" (124). The concept was accepted eventually, but the precise nature of the thyroid secretion and the cause of the overactivity remained obscure.

(T.89)

Hyperthyroidism w a s usually characterized by diffuse ( n o n n o d u l a r ) goiter, exophthalmos, nervous symptoms, and tachycardia, developing at about the same time, mainly in young adults. Another form of the disease had, however, been described by Parry in 1825, and by several others later (37n). Parry did not differentiate between the two types, but various names were later given to the second variety. The patients were older, often had long-standing nodular goiters, were not exophthalmic, and were prone to cardiac complications. In 1912 Henry Plummer (Fig. T.17), Mayo's medical colleague, drew attention to this condition, describing it first as "toxic nonexophthalmic goiter" and later as "toxic adenoma." Other names included "secondary thyrotoxicosis," "secondary toxic goiter," and "Plummer's disease ." The commoner disease, which was the only form described by Graves and Basedow, was known as "primary" or "exophthalmic" goiter. Although many found it convenient to use the terms "primary" and "secondary" toxic goiter, there were so many similarities between them and so many intermediate forms that most people maintained that there was but one disease with numerous variations in its severity and manifestations (37n, 73c). (T.90) Typically in primary exophthalmic goiter the thyroid was diffusely hyperplastic, while in the secondary form it was multinodular, with areas of intense hyperplasia in a preexisting endemic or sporadic goiter. In another rare form of the disease a single "hot nodule" was present in an otherwise inactive gland (72). (T.9i) Berry in 1901 had suggested that the thyroid secretion in toxic goiter was altered in quantity and quality, and others attributed the disease to a specific thyroid toxin (125). Plummer had observed that administration of thyroid extract or thyroxine in excess caused all the features of hyperthyroidism, but not exophthalmos. He now proposed that secondary thyrotoxicosis resulted from excessive secretion of thyroxine by the gland and that the primary disease was caused by this, together with a hypothetical abnormal product, perhaps an incompletely iodized compound, which was responsible for the eye signs (126). It was later confirmed that thyroxine (T4) and triiodothyronine (T3) were secreted in excess, but no abnormal product of thyroid origin has yet been found. rr.92)

The Thyroid (T) • 49 When TSH was described in about 1930, it was proposed that its excessive secretion might be the cause of hyperthyroidism(11). When, thirty years later, TSH could be measured reliably by RIA, low blood levels were found in thyrotoxic patients and high levels in those with hypothyroidism (127). Very rarely high readings accompanied TSH-secreting pituitary tumors (p. P.93).

(T.93)

A thyroid-stimulating factor was, however, discovered in the sera of patients with toxic goiter by Duncan Adams and Herbert Purves of Dunedin in 1956(128). While performing a bioassay for TSH, they unexpectedly found prolonged stimulation of thyroid function by sera from three patients with thyrotoxicosis and one with severe exophthalmos alone. They later named the responsible agent "long-acting thyroid stimulator" or "LATS." This proved to be an immunoglobulin (IgG), produced by lymphocytes, with the properties of a thyroid-stimulating autoantibody(73d). It was found in the sera of about 80 percent of patients with primary Graves' disease and in some with secondary hyperthyroidism, but not in those with autonomous toxic nodules. Other related thyroid-stimulating antibodies (TSAbs), specific to the human thyroid, were found in the sera of some patients with Graves' disease in whom LATS was absent, judged by bioassay. Similar, but nonstimulating, TSAbs were present in the sera of patients with Hashimoto's disease and in some with thyroid cancer and with Graves' disease itself. The stimulus to LATS and other TSAb production is unknown, but most varieties of toxic goiter are now thought to be due to stimulating autoantibodies. rr.94) Treatment Medical Therapy Rest, diet, ventilation, ice-packs, and sedatives were used from early times(37o). Serotherapy in the form of milk, serum, and blood from thyroidectomized animals was advocated and abandoned early this century. Thyroid extract had been advocated, but was found to aggravate the condition. Good results were reported from medication with thymus gland (given in mistake for thyroid) and adrenal extract. Digitalis and quinidine were employed for cardiac complications. (T.95) Moving patients t o high altitudes was r e c o m m e n d e d sometimes. C o p e , w h o h a d observed this practice in t h e Bavarian Alps in t h e 1920s, pointed out that its value lay in depriving t h e patient of iodine (129). rr.95a) Intraglandular Injections Boiling water, alcohol, u r e a , quinine hydrochloride, carbolic acid, a n d glycerine were all injected. Iodine, which was used for simple goiter,

50 • History of Endocrine Surgery apparently was not employed. Boiling water, introduced by Miles Porter of Fort Wayne, Indiana, in 1913, was probably the most popular(129A) and gave good results in selected cases(37p, 130). rr.96) Radiotherapy Irradiation of the thyroid with an external x-ray beam was employed in Boston in 1902, and by 1908 benefit was reported in over 80 percent of patients (lp, 37q, 63g). Radiotherapy was safer than thyroidectomy and was therefore sometimes preferred; in 1926 two-thirds of 300 consecutive patients were regarded as cured after about twenty treatments. Some physicians advocated operation only when radiotherapy failed. Some surgeons found that it altered the tissues of the neck so that thyroidectomy became difficult, while others saw no difference even after prolonged treatment. As the results of thyroidectomy improved, interest in this form of radiotherapy waned. Treatment with interstitial radium, used intermittently from 1905, proved less effective. Good results were reported in 1915 from irradiation of the thymus after unsuccessful thyroidectomy and, in 1934, from irradiation of the pituitary. rr.97) Operations Not Involving the Thyroid Cervical sympathectomy was practiced for over thirty years in the belief that thyroid secretion was controlled by the sympathetic nervous system and that sympathetic overactivity caused exophthalmic goiter (37r). Jaboulay first performed this operation in 1896, and results in thirty-one patients were reported fifteen years later (37r, 131). Six died postoperatively and three were considered cured. Several other surgeons, including Kocher, undertook the operation, but without benefit(132). Charles Mayo used it for a time for exophthalmos (130). Working on the thesis that "hyperthyroidism and adrenalism coexist, each augmenting the other," Crile treated many selected hyperthyroid patients by adrenal denervation and a few by unilateral adrenalectomy, and claimed that all were improved or cured (p. H.2). Thymectomy and irradiation of the thymus were based on the premise that this gland was often enlarged in patients with primary thyrotoxicosis and in some way caused or aggravated the disease. Between 1910 and 1923 several surgeons advocated and practiced thymectomy either alone or together with thyroidectomy, but the results were unimpressive. Surgical removal of septic foci had also been reported as beneficial (36k) and was even advocated by McCarrison in preference to thyroidectomy (67b). ros) Thyroidectomy After Rehn's paper in 1884 many more thyrotoxic patients underwent thyroidectomy, and slowly toxicity itself, rather than goiter, became an indication for operation (132). Kocher operated on five patients within three years and by 1907 had done 315 operations in 254 patients, with nine

The Thyroid (T) • 51 deaths (3 percent of operations and 3.5 percent of patients) (132). Others followed his example, and in the same year, Halsted, who began in about 1898, had operated on ninety patients with two deaths (2 percent) and Mayo on 176 with nine deaths (5 percent) (132). To improve his results Kocher had turned to preliminary ligation of three thyroid arteries, sometimes one at a time, to reduce thyroid function, and found improvement so marked that he could later excise the goiter safely or leave it alone. Mayo likewise undertook staged procedures from 1908 and within four years had reduced the operative mortality to 3 percent (95, 130, 133, 134). (T.99) The usual form of thyroidectomy, like that for simple goiter, was removal of one lobe and the isthmus. When, as frequently happened, this failed to control toxicity, one or more arteries were then ligated on the other side. By 1910, 40 percent of Mayo's thyroid operations were for arterial ligation, a procedure that caused patients to gain an average of 9 kg in four months. He was relieving hyperthyroidism in 70 percent of patients (134). Kocher reported relief in 73 percent with primary exophthalmic goiter and in 92 percent of those with secondary disease (132). Surgeons were reluctant to remove more tissue for fear of hypothyroidism (135), even though the remaining lobe was bigger than the whole normal gland. (T.IOO) In 1905, h o w e v e r , F r a n k Hartley of N e w Y o r k approached the p r o b l e m in a n e w way, proposing that cure of Graves' disease d e p e n d e d on sufficient removal of thyroid tissue. H e reported twenty-one operations, in five of which h e h a d r e m o v e d all of o n e lobe a n d varying amounts of the second at the same time, and claimed that nineteen patients (91 percent) were relieved(136). Hartley had been a colleague of Halsted and, like him, was a victim of cocaine(135). He died before he could contribute more, and his paper was largely ignored. Kocher had previously done more extensive resections at one operation, but, finding them dangerous, had abandoned them (132). Two years later, however (1907), Halsted mentioned that it might be necessary to remove part of the other lobe at a subsequent operation (114, 132), and William Mayo stated that "failure to cure the disease was due to failure to remove enough of the gland." However, the surgeon who adopted this policy and did most to exploit it was Thomas Dunhill (Fig. T.18), working independently in Melbourne and, after the Great War, in London. His massive contribution is appreciated fully in Australia and Britain, but is hardly known elsewhere. He had read Hartley's paper and in this same year (1907) reported seven operations for patients with severe toxic goiter (137). He removed one lobe and the isthmus from all and ligated the superior vessels on the other side in one. Although the operations were effective at first, the initial improvement was not maintained, and in six he operated again, removing part of the second lobe instead of ligating its arteries(138). Hoping to avoid a second operation, Dunhill then undertook a bilateral procedure in one stage, but the first patient in whom he attempted this—his thirteenth—died in thyroid crisis.

52 • History of Endocrine Surgery This experience persuaded him that staged operations were safer, but by 1909, when he had operated eighty-eight times without further mortality, he sometimes removed half or more of the second lobe at the first operation(139, 140). In 1910 he reported operations in 200 patients, with three deaths (141). Two years later (1912) he considered removal of the larger lobe, together with the isthmus and any middle lobe, sufficient for young patients with mild disease, but resected part of the other also for those who were older or very ill (142). The lobectomy was total and included the capsule posteriorly. In resecting the opposite lobe Dunhill left the superior pole with its vessels intact, but took away all the inferior pole, apart from a thin portion posteriorly (143). He continued to use this method of thyroidectomy for the rest of his career (68). He rarely had to operate more than once, but had occasionally done so twice and, on three occasions (in 380 operations), three times. There were four operative deaths (1.05 percent). Later he reverted to more staged operations for very ill patients (68,143). Hyperthyroidism was relieved in all patients by these methods, at least for a time. (T.IOI) In 1911 and 1912 Dunhill visited the UK and the United States, where he met Berry, Halsted, and Mayo(142). His claims—1.05 percent mortality and all survivors virtually cured—were scarcely credited (135, 144). In 1912 Kocher wrote that "the degree to which health may be restored" was "proportional to the amount of gland removed" (145). The next year (1913) Halsted stated that ligation of two, three, or four arteries did not cure Graves' disease and that, since 1902, he had excised the greater parts of both lobes for relapse in thirty-nine patients at two or more operations (146). Nevertheless, he continued to perform many arterial ligations, preferring to tie the inferior vessels. Mayo also began to report resection of part of the second lobe for relapse (104) or as the initial procedure (96,135). By 1913 he removed up to four-fifths of the second lobe, leaving a piece the size of the normal gland (96,104). The mortality rate was 1 percent and the cure rate 75 percent. By 1918 Mayo removed the larger lobe completely and part of the other at one operation (147), and by 1920 had changed to bilateral resection of the Mikulicz type (135). Crile followed Mayo in general surgical policy and technique, and by 1922 also undertook bilateral resections(63e). Both, however, still often operated in stages. Mayo and Crile now removed the same proportion of tissue as Dunhill, but in a different way, and all three aimed to restore normal thyroid function. Most other surgeons were slower to accept the need for radical subtotal thyroidectomy as the initial procedure. (T.102) Kocher, Halsted, and Dunhill(137) used local anesthesia, while Mayo preferred ether. Crile was much influenced by seeing patients die from fear without operation and from postoperative crises, and stressed the importance of nervous influences in toxic goiter (148). Consequently he introduced his method of "stealing" the thyroid and "anociassociation." This involved

The Thyroid (T) • 53 premedication with scopolamine and morphia, surreptitious induction with ether followed by gas and oxygen, and local infiltration with novocaine. In later years Dunhill and others came to use combinations of light general anesthesia, rectal narcosis, and a local anesthetic. All regarded chloroform as dangerous and responsible for some deaths(68). Dunhill and Crile, especially, emphasized the need to handle tissues gently and to operate fast. Dunhill excelled at dissection with the finger and Crile with the knife (95). Thyroid crisis was attributed to absorption of toxic material expressed from the goiter at operation or exuding from its cut surface afterwards. For this reason Dunhill would not clamp or crush the gland, and removed one lobe completely to avoid putting forceps on it and to minimize the size of the raw area(140). Drainage allowed the "toxin," as well as blood, to escape. If a bilateral operation was planned, all surgeons were prepared to stop after doing the first side if the patient's condition, especially the pulse, deteriorated. (T.103) T h e r e was disagreement about the indications for operation. All insisted that the surgeon should be called in early and not as a last resort. Kocher and Mayo(104, 132) did not operate in the presence of auricular fibrillation or cardiac failure, but two of Dunhill's first seven patients had these problems, and he regarded fibrillation as a strong indication for operation. Later he gave details of thirty-two patients in whom fibrillation disappeared after operation, either spontaneously or with quinidine(148A). M a y o , in 1913, still advocated medical therapy for patients with severe disease and injection of boiling water if they did not improve (104). (T.HM) Precise statistics are hard to find. Different methods of presentation were used by different surgeons and by the same surgeons on different occasions. It is often unclear whether figures referred to numbers of patients or of operations and which operations had been used. However, the "surgical mortality" overall at the Mayo Clinic by 1921(126) was about 3.5 percent, and the death rate for toxic a d e n o m a was greater than that for exophthalmic goiter. Crile's figures were probably similar(63h). The different types of patient operated on also m a d e comparisons between series difficult. Dunhill's overall operative mortality increased to about 2.7 percent for many years(68, 149), but this figure included seventeen deaths in 240 patients with auricular fibrillation (7 percent). H e accepted almost all risks and probably had m o r e patients with very severe disease than most other surgeons (68, 142, 143). H e did not publish separate figures for uncompli-

cated patients.

rr.ios)

Iodine Therapy Iodine, when used to treat simple goiter, had soon been found to cause features suggesting hyperthyroidism if it was given in large doses (37s). Nevertheless, its use continued. Basedow employed mineral water, rich in iodine, with great benefit(19), and, also in the nineteenth century, Armand

54 • History of Endocrine Surgery Trousseau in Paris and Walter Cheadle in London reported favorably on the use of iodine itself. Berry found that it aggravated toxic symptoms (361). Kocher also employed iodine in the early 1900s, but abandoned it around 1910 owing to unfavorable results reported by other Swiss observers (39c). They appear to have given it in excessive doses for adenomatous goiter, so that toxicity was induced or aggravated. This form of the disease, initiated by iodine, Kocher named "Jodbasedow" (G Jod = iodine). In 1914 Ewan Waller of Birmingham, England, found, to his surprise, that tincture of iodine controlled the symptoms of thyrotoxicosis better than any other drug(150). The pulse rate fell from 160 to 80 or even 60 per minute, diarrhea and vomiting ceased, patients gained weight, and the glands increased in size and hardness. Relapse commonly followed if the iodine was stopped suddenly. Waller maintained that iodine caused the vesicles to retain colloid. The beneficial effects were soon confirmed by others. Then, in 1923, Henry Plummer and Walter Boothby, at the Mayo Clinic, published their observations on 600 patients whom they had treated preoperatively with Lugol's iodine and in whom they had also measured the BMR (151). Plummer thought that iodine might complete the iodization of the postulated abnormal thyroid secretion (126). The BMR often fell from+40 or +60 percent almost to normal. Two-thirds of the patients benefited greatly and one-quarter slightly, while about 5 percent were unaffected. None was made worse. The number of patients who died in hospital without operation was reduced from fifteen to five per year, the operative mortality after thyroidectomy fell from 3.5 percent to 1 percent, and thyroid artery ligation ("with all the attendant suffering, morbidity and expense") was almost abandoned as a separate operation (126). Preoperative iodine therapy was soon adopted worldwide. Plummer and some others found iodine effective in primary exophthalmic goiter, but not in the secondary disease, while Joll and others found it beneficial in all types. The effects of iodine were maximal within ten to fourteen days, after which, if treatment was continued, symptoms recurred or even became worse. The increase in size and hardness occasionally caused dyspnea. For all these reasons physicians and surgeons experienced in thyroid surgery used iodine only in preparation for operation. Many, however, tended to prescribe it indiscriminately and for long periods, so that patients who relapsed came to operation late and fared badly. Several histological studies showed that iodine caused nonuniform involution of the goiter. (T Subtotal

Thyroidectomy

In the 1930s bilateral subtotal resection slowly became the accepted operation for patients who failed to respond to medical treatment. The operation required more skill and experience than were generally available, and most results were not nearly so good as those of the masters. Physicians were naturally reluctant to refer their patients to surgeons with poor

The Thyroid (T) • 55 records(129). Nevertheless, increasing numbers of surgeons acquired the necessary expertise. Notable among these were Cecil Joll and James Walton in London and Frank Lahey in Boston. The long-term results of operation for secondary thyrotoxicosis were almost uniformly good, while those for the primary disease were more variable. Between 85 and 90 percent of them were cured, although 4 to 5 percent needed further thyroidectomy (37t, 83). (T.107) Before the introduction of iodine therapy Osier considered that if the patient was not better after three months' treatment, partial thyroidectomy offered the best hope of cure (152). In 1936 Humphrey Rolleston of Cambridge wrote that operation was advisable when medical treatment had not produced well-marked improvement in six months and when auricular fibrillation or congestive heart failure had supervened (lp). The thyroid change was generally thought to be secondary to an undetermined stimulus, so that the rationale of thyroidectomy was questionable. It had to be used, however, until equal or better therapy was available. Thyroid surgeons would have preferred to receive patients within six months and would have employed radical subtotal thyroidectomy as soon as the patient had been adequately prepared. Iodine remained the only effective medication for toxic goiter until the 1940s. Then, despite World War II, two major therapeutic advances provided alternatives and adjuncts to operation, and improved still further the prospects for thyrotoxic patients. (T.IOS) Radioiodine In 1942, four years after the introduction of radioiodine for the investigation of thyroid function, two groups of workers in the United States began to use it therapeutically. It seemed ideal for this purpose because external radiotherapy was often effective, iodine was taken up rapidly and selectively by the thyroid cells, and the particles emitted by the isotope penetrated the tissues for a few millimeters only. Saul Hertz and Arthur Roberts of Boston reported the successful use of 1-130 (half-life 12 h) in ten patients with Graves' disease (153). At the same time Joseph Hamilton and John Lawrence of Berkeley, California, reported the use of 1-131 (half-life 8 d) effectively in three patients(154). The Boston work advanced rapidly, and twenty-eight patients were treated within four years (155). The doses administered to the later patients were 0.5 to 1.0 mCi per estimated gram of thyroid tissue. Of those who received radioiodine, two-thirds responded well to one dose, while the other third required two or three. About 20 percent developed hypothyroidism, and 10 percent remained slightly hyperthyroid. One-quarter had radiation sickness, but no other obvious ill effects. Biopsy of two glands showed fibrosis. Seven of the patients had previously failed to respond to thyroidectomy and three to radiotherapy, and one was sensitive to drugs. The Boston workers gradually changed from 1-130 to 1-131 and obtained almost identical results in their first sixty-five patients

56 • History of Endocrine Surgery followed up to four years (69f). The response to radioiodine was slower than that to iodine, the BMR usually taking about three or four months to return to normal. (T.109) Radioiodine was soon employed widely in the United States, and these early results were amply confirmed. It was also used effectively for thyroid cancer (p. T.130). The exigencies of war prevented its use elsewhere for some time. Twenty years later, however, when many thousands of patients had been treated, about 60 percent became euthyroid after one dose, while 25 percent required two or more doses (61k). The goiter usually shrank, and minor degrees of tracheal compression or deviation were corrected. Permanent hypothyroidism developed in about one-third within the first year, especially in patients with small glands, or in those who had undergone previous thyroidectomy. Thereafter, a further 2 percent became hypothyroid each year and then required permanent replacement therapy (156). For this reason it became common practice to prescribe thyroxine routinely as a prophylactic measure. The safety of radioiodine was questioned because of the possible risks of thyroid cancer and leukemia and of gonadal and fetal damage. It was therefore used mainly at first in patients aged 45 or over, and never in pregnant women. Workers in the UK tended to be more cautious than those in the United States and Scandinavia, and preferred thyroidectomy for most patients. ouio) As time passed these fears proved ill-founded (76e). Leukemia did tend to follow the large doses given for thyroid cancer, but not those used for hyperthyroidism. (T.IID Antithyroid Drugs The second great advance was the introduction of antithyroid drugs in 1943 by Edwin Astwood of Boston (157). Thiourea and thiouracil had been found in animals to inhibit the synthesis of thyroid hormones, thereby causing hypothyroidism and compensatory hyperplasia, mediated by TSH. When Astwood treated three hyperthyroid patients with these drugs their symptoms were relieved, and the serum cholesterol levels and basal metabolic rates returned to normal in two to three weeks. Remissions lasted for several weeks or months, while treatment was given, but hyperthyroidism returned when it was stopped. One patient developed a rash and another suffered agranulocytosis, from which they recovered when the drugs were stopped. One possibly had some enlargement of the goiter. Similar results were soon reported elsewhere(158, 159). Toxic reactions, especially agranulocytosis, were not uncommon, and many other compounds were tested. Methyl and propyl thiouracil and methimazole and carbimazole proved effective and safer. Potassium perchlorate, which prevents the uptake of iodine by the thyroid, was also effective, but its action was inhibited by iodides, and it sometimes caused aplastic anemia. (T.112)

The Thyroid (T) • 57 A few patients had lasting remissions after courses of treatment, but many relapsed and some required thyroidectomy. In one case, reported by Harold Himsworth in London in October 1943, tracheal compression required relief (158). "Thiourea alone was given and proved a satisfactory preoperative preparation." Other workers were already using these drugs to prepare patients for operation, and the next year Francis Moore, Oliver Cope, Howard Means, and colleagues from Boston reported thirty-five cases, the first patient having undergone operation on June 24, 1943(160). They used thiouracil alone preoperatively in three-quarters of cases and found it superior to iodine as preparation for thyroidectomy. They observed intensification of thyroid hyperplasia, sometimes associated with increased vascularity and friability, which made the gland difficult to handle and rendered hemostasis arduous. This was especially so in glands that had been operated on previously. Preliminary or concomitant administration of iodine delayed the response to thiouracil, but iodine therapy after thiouracil possibly reduced the bleeding. (T.113) Antithyroid drugs usually increased the size of the goiter, especially if it was large originally, and dosage had to be regulated carefully to ensure control of the disease without causing hypothyroidism. Both these complications were largely prevented by giving thyroid extract (161) or thyroxine (162) in replacement dosage simultaneously. With this regimen onethird of the glands became smaller, while only one in ten enlarged, (T.IH) By about 1960, carbimazole emerged as the best antithyroid drug, causing major and minor toxic reactions in about 0.5 and 1.5 percent of patients, respectively (611). Methimazole was a close second. Less than 50 percent of patients obtained prolonged remissions after one course, but some others did so after a second. Young patients (up to 40 years) with small diffuse goiters and mild or moderate disease fared best, about three-quarters being relieved permanently. Only about one-third of older ones with nodular glands and very few with large glands obtained lasting benefit. rr.iis) Therapeutic Policy Three effective forms of treatment were now available—subtotal thyroidectomy, antithyroid drugs, and radioiodine—and they were used sometimes alone and sometimes in combination. Their relative merits were summarized in 1963 (61m) (Table T.l). Physicians and surgeons differed in their therapeutic policies, and the practice in one center (Belfast, Northern Ireland) was outlined in the same year (61n) (Table T.2). rr.ii6) Thyroidectomy By 1960 subtotal thyroidectomy was the standard operation, except for solitary toxic adenomas, which were removed by unilateral partial thyroidectomy. Patients were prepared for operation with iodine alone when

Table T.l.

Relative merits of Therapeutic Procedures for Toxic Goiter (1963)

Antithyroid Drugs

Subtotal Thyroidectomy

Radioactive Iodine

Mortality

Less than 0.05%

Less than 1%

Nil

Speed of control

2-4 months, followed by treatment for 18 months

Few weeks

3-6 months

Remission rate

60% of all cases. 75% of those with small smooth goiters below 40 years of age

95% after first operation (50% after second operation)

95% or better after one or more treatments

Goiter

Remains and may enlarge. Regression may accompany remission

Removed (scar remains)

Reduced or disappears

Hypothyroidism

Occasional but temporary only, reverting when drug therapy is reduced or withdrawn

5% after first operation (10% after second operation)

30%

Ocular changes

Usually improved

Usually improved. Rarely aggravated seriously

Usually improved

In-patient treatment

Not usually necessary

Essential

2-3 days only, but not essential

Discomfort

Nil

Severe for 1-2 days

Very rare

Tetany

Nil

Transient 3 % , permanent less than 1%

Nil

Cord palsy

Nil

2% or more

Nil

Drug reactions

2-3% with carbimazole or perchlorate

Only if patient receives antithyroid drug also

Only if patient receives antithyroid drug also

Source: Montgomery, D.A.D, and Welbourn, R.B. Clinical endocrinology for surgeons. London: Arnold, 1963: 275. 58

Table T.2.

Therapeutic Policy for Toxic Goiter (1963) Treatment Recommended

Type of Goiter and Clinical Features I. Diffuse goiter 1. Under 45 years (a) Small gland and mild or moderate toxicity (b) Large gland and moderate or severe toxicity 2. Over 45 years II. Nodular goiter 1. Under 45 years 2. Over 45 years (a) Small gland without obstruction (b) Large gland with obstruction III. Recurrent thyrotoxicosis 1. After antithyroid drugs (a) Under 45 (b) Over 45 years 2. After operation (a) Under 45 years (b) Over 45 years (c) Large obstructive goiter at any age 3. After radioactive iodine IV. Special circumstances 1. Childhood 2. Pregnancy

Antithyroid drugs Subtotal thyroidectomy Radioactive iodine

Subtotal thyroidectomy Radioactive iodine Subtotal thyroidectomy

Subtotal thyroidectomy Radioactive iodine Antithyroid drugs Radioactive iodine Subtotal thyroidectomy Radioactive iodine

Antithyroid drugs Antithyroid drugs or subtotal thyroidectomy Radioactive iodine

3. Infirmity (heart failure, old age, inter-current disease, etc.) 4. Hyperophthalmopathic Graves' disease 5. Solitary toxic adenoma 6. Thyrotoxic crisis

Antithyroid drugs until eyes stabilized and special measures Partial thyroidectomy Special measures

Source: Montgomery, D.A.D, and Welbourn, R.B. Clinical endocrinology for surgeons. London: Arnold, 1963: 276.

59

60 • History of Endocrine Surgery the toxicity was mild or moderate, and with an antithyroid drug when it was severe. The drug was given with thyroxine up to the time of thyroidectomy, and iodine was administered also for the last two or three weeks. If the antithyroid drug, especially potassium perchlorate, was stopped earlier, the disease sometimes recrudesced and became uncontrollable. Although "occasional thyroidectomists" probably lost many patients, the operative mortality had fallen to below 1 percent in the hands of exerienced thyroid surgeons, and was as low as 0.1 to 0.2 percent in some very large series (163). Two factors were responsible. First, surgeons were operating on euthyroid patients and, second, anesthesia had advanced greatly. In particular, muscle relaxants and endotracheal intubation enabled surgeons to obtain complete hemostasis and to identify important structures in the operative field. Thyroidectomy had become precision surgery. (Tin) The outcome of thyroidectomy was less predictable in children than in adults, and operation was reserved for those whose glands enlarged during treatment, who were unable to cooperate, who relapsed, or who developed toxic reactions. Pregnancy was no contraindication to thyroidectomy, if performed in the middle trimester when the risk of abortion was small, but special care was needed with antithyroid drugs. Radioiodine was never used in children or in pregnant women. (T.IIS) Other matters being equal, the choice between medical and surgical treatment might depend on the patient's temperament or social circumstances or both (156). For example, he or she might prefer a few days in hospital for an operation with a 90 percent chance of cure to years of visits to the doctor for tests and tablets. And an operation might be much cheaper. (T.119) Permanent relief of hyperthyroidism was achieved in 85 to 95 percent of patients after one operation in most series. In the remainder the toxicity either persisted or recurred, usually within months, but sometimes many years later. In these the goiter usually recurred also. A second operation cured only one-half of these patients, and the risk of complications was higher. Hypothyroidism developed in about 10 percent of patients within a year of operation and in some 30 percent eventually. The cause of the hypothyroidism seemed to be related to the size of the remnant, the dietary intake of iodine, and the presence of thyroid antibodies in the blood, associated with lymphocytic infiltration in the gland. er.120) Beta-Adrenergic Blockade Treatment with sympatholytic drugs, which diminish the clinical features of thyrotoxicosis without affecting thyroid function, was introduced in 1957 and proved valuable but not revolutionary. Reserpine(164, 165), guanethidine(166, 167), and a-methyldopa(168), drugs that deplete the stores of catecholamines, were of limited value. The first beta blocker, nethalide(169), was unsatisfactory, but the second, propranolol, was very

The Thyroid (T) • 61 effective (170, 171). It consistently relieved tachycardia, tremor, restlessness, and anxiety within twenty-four hours, and sometimes reduced other symptoms also(76f). It could be used alone in mild hyperthyroidism or together with antithyroid drugs or radioiodine. It also reduced the time needed to prepare patients for thyroidectomy, gave greater flexibility in planning the date of operation, and counteracted the adverse effects of antithyroid drugs on the gland (111, 172). It was also the most effective remedy for thyrotoxic crises. cr.m) Progressive (Malignant) Exopthalmos "Malignant" exophthalmos was described in 1840 in association with untreated goiter by Basedow, one of whose patients had corneal ulcers and lost both his eyes(19). This very rare, severe form of the disease usually followed thyroidectomy and therefore received little attention until the present century, when it was reported mostly by ophthalmologists(173). The disease was usually self-limiting, but blindness sometimes resulted, either from increased intraorbital pressure or from exposure and inflammation. Infection sometimes proved fatal. cr.122) Exophthalmos was attributed variously to an excess of edematous orbital fat, venous congestion, or sympathetic over activity with stimulation of Muller's muscle. Attempts to relieve it surgically were based on these theories. An operation to decompress the orbit was performed in October 1910 by Julius Dollinger of Budapest, who employed Kronlein's lateral orbitotomy(174, 175). In 1914 Charles Mayo undertook cervical sympathectomy (130), which caused ptosis of the upper lid, miosis, and "relaxation of the eyeball," but did not reduce the protrusion(178). Later /3-blocking drugs were found to have similar effects (74, 76f). or.123) Several minor palliative operations were employed also. Lateral tarsorrhaphy, to protect the cornea, had some value on its own and remains as an adjunct to other procedures. Lateral canthotomy, to relieve tension, was ineffective. In 1920 Foster Moore of London attempted to relieve pressure by removing orbital fat through an incision within the lower eyelid (176). In 1929 Oscar Hirsch (Fig. P.8) of Vienna (p. P. 12) attempted surgical decompression of the orbit by removing its bony floor through the maxillary antrum, which he entered via the canine fossa, as in the Caldwell-Luc operation. He described the procedure in two German papers, which passed unnoticed in the English-speaking world, where thyroid surgery was then advancing most rapidly(173, 177). In the next year (1930), however, Howard Naffziger (Fig. T.19) of San Francisco attracted worldwide attention when he described a transcranial operation to decompress the orbit by removing its bony roof (178). At the same time he observed that the extraocular muscles were greatly enlarged. After operation the exopthalmos receded and the patient, who had been nearly blind, was able to read. At her

62 • History of Endocrine Surgery insistence he treated the second eye in the same way with similar success. Naffziger reported five more patients the next year, treating both eyes together(179), and others took up the operation. The pathological lesions were similar in all, and one surgeon even mistook the recti for a four-lobed tumor (175). Fifty years later this gross enlargement was shown clearly by CT scans. Histologically the muscles were edematous and infiltrated with round cells and fibrous tissue. All Naffziger's patients improved markedly without complications, the only minor drawback being that pulsation was transmitted from the brain to the orbits. One other approach was described by Edward Sewall, also of San Francisco, in 1936(180). He suggested removal of the medial wall and parts of the superior and inferior walls of the orbit, allowing its contents to crowd into the sinuses. The procedure was undertaken in 1939 by Frank Kistner of Portland, Oregon(181). Others described variants of the superior and lateral operations at about the same time (175, 182). Naffziger's operation, however, was adopted widely when sight or life was threatened by progressive exophthalmos. After modification by himself and others, it became the most popular procedure, and by 1950 he had treated forty patients with progressive disease (183). Complications were minimal, but one patient, already nearly blind, lost both eyes. Muscular imbalance (ophthalmoplegia) often caused diplopia, which sometimes persisted after decompression, and could then be corrected by operations on the extraocular muscles (184). (T.124) These observations stimulated much work on the pathology and pathogenesis of exopthalmos (183, 185). The fibrofatty tissue of the orbits was found to be affected in the same way as the extraocular muscles, but not so severely (186). Progressive exophthalmos tended to follow not only thyroidectomy, but also treatment with antithyroid drugs and radioiodine. Sometimes "endocrine" exophthalmos developed without any sign of thyroid disease(183). As in thyrotoxicosis itself, a cause for exophthalmos was sought in the pituitary. TSH was long suspected, and in 1952 an exophthalmos-producing substance (EPS) was found (187). Neither substance, however, was confirmed as being active in man. Attempts to treat progressive exophthalmos by reducing pituitary function were continued for years. Administration of thyroid extract (93), thyroxine (185), and sex hormones were ineffective (188). Irradiation of the pituitary was thought to bring relief at first (189), but not when care was taken to exclude the orbits from the field(188). Surgical hypophysectomy, however, was employed successfully in a few patients(187,188), and Jules Hardy of Montreal cured one by selective removal of a small pituitary adenoma of unspecified type (190).

(T.125)

The lymphocytic infiltration of the orbits suggested an immunological process. Steroids and ACTH were used without benefit until 1966, when Sidney Werner of New York reported the successful treatment of two

The Thyroid (T) • 63 patients, regarded as hopeless, with very large doses of prednisone (120-140 mg/day). Irradiation of the orbits alone (without the pituitary) was also found to be effective and to cause rapid dispersal of lymphocytic infiltration and edema(191). Immunosuppressive drugs, such as azathioprine, and plasmapheresis have been used therapeutically, but their roles are not yet established (192). Exophthalmos and Graves' disease are now seen as closely related, but separate, organ-specific autoimmune diseases, which usually coexist, but which sometimes develop independently(193). It was suggested in 1963 that there was a close relationship between thyroid cells, LATS, and progression of exophthalmopathy. Consequently Boris Catz and Samuel Perzik of Los Angeles have employed total thyroid ablation, by operation or with radioiodine, with replacement therapy, and have reported good results(194, 195). Others, however, have been less successful(192). Untreated hypothyroidism is generally thought to aggravate the disease (113). (T.126) In 1950 Hirsch, who had moved to Boston, (p. E.31), described his operation of antral decompression in an American journal (173), and others began to use it. In the next thirty years it was adopted widely, with minor modifications (including the use of the operating microscope), and largely replaced other surgical procedures. Operations on hundreds of patients were reported, with satisfactory results, and the indications for operating were broadened to include cosmetic and social considerations (196, 197). Muscle operations for persisting diplopia were also commonly employed. (T.127) SIMPLE THYROID TUMORS When most so-called thyroid adenomas were recognized as involutional nodules, a few lesions remained, which appeared to be true benign tumors. In 1932 Joll described three varieties—papillomas, dermoid cysts, and fibromas—all of which were rare(37v). In 1948 Means listed four types of adenoma, but described their nomenclature as chaotic(69g). By 1963 the situation was clearer and the adenomas were classed as follicular or papillary (61o). Both types were rare, and the follicular, which were the commoner, were subdivided into five groups: embryonal, fetal, simple, colloid, and Hurthle cell. They presented usually as solitary nodules in otherwise normal glands and were sometimes complicated by degenerative changes, toxicity, or malignancy. Clinical diagnosis was impossible, and excision biopsy by partial lobectomy was usual. Later, when scanning and needle biopsy came into general use, adenomas still couldmot be distinguished from carcinomas without surgical excision(80). Even then, many that had been regarded as benign, particularly the papillary lesions, later recurred or metastasized(198, 199), so that all papillary tumors were then regarded as

64 • History of Endocrine Surgery carcinomas. Thus, total lobectomy became the preferred method of treatment (98, 99). (T.128) One tumor, described by Theodor Langhans in Germany in 1907, consisted mainly of large eosinophilic cells, which resembled some normal interfollicular cells described by Cresswell Baber in England in 1877 and later (in 1894) by Karl Hurthle in Germany(199, 200). They came to be known as Hurthle cell tumors and were described in both benign and malignant forms. Both, however, probably represented variants of ordinary epithelial tumors. Later it became clear that the diagnosis of Hurthle cell adenoma was at best tenuous and that many such lesions eventually behaved as carcinomas(201). Norman Thompson of Ann Arbor, Michigan, recommended in 1974 that they should be treated as such(98). (T.129) THYROID CANCER Coauthored by I.D.A. Johnston Early Problems Thyroid cancer was well known by the nineteenth century. In 1811 Allan Burns of Glasgow gave a long account, mentioning the slow enlargement, irregular surface, stony hardness, and lancinating pain, and distinguishing it from "the terrible affliction denominated by Mr. [John] Abernethy [of London] as medullary sarcoma" of the thyroid(lq). Most series of operations for goiter at that time included cases of cancer, which were listed separately (6u) (p. T.49), and in 1887 Henry Butlin of London reviewed fifty cases(36n). The results were bad, thirty patients (60 percent) dying soon after operation, only one surviving four years, and none being cured, CT.DO) Berry gave a full account of the disease in 1901 (36n). It usually developed after the age of 40, but had been described in children. The sexes were affected equally, and most patients had goiters already. Cancer could not be recognized for certain while confined to the thyroid capsule, but was strongly suspected when a hard, noninflammatory tumor increased rapidly in size. Later an irregular and bossy surface, dysphagia, pain, paralysis of a vocal chord, penetration of the trachea and esophagus, and attachment to great vessels were diagnostic. Berry stressed that the skin was seldom involved unless the growth had been punctured or incised. Lymph nodes were often enlarged, but were usually deep and impalpable at first. Distant metastases appeared, especially in the bones and the lungs. Few patients survived for more than eighteen months, suffocation being the commonest cause of death. The only hope of cure lay in "free removal of the whole of the disease," but this was rarely possible, because it was disgnosed so late. By 1901 the operative mortality had fallen to 34 percent, but the long-term results in the survivors were little better than before. (T.131)

The Thyroid (T) • 65 Kocher, who had the greatest experience, dissected outside the thyroid capsule, removing adherent muscles and sometimes resecting portions of the trachea and esophagus, great vessels, and important nerves(36n, 39b). The wounds failed to heal in one-third of the patients, but he considered this a small price to pay for relief from the great distress caused by dyspnea and dysphagia. One of his patients lived for eleven years after operation. Incision or partial removal of the growth, insufficient to relieve obstruction, did more harm than good because a fungating wound added to the patient's problems(36n). When an effective operation was not possible, dyspnea could be relieved by tracheostomy, if necessary through the growth, and a long endotracheal tube. Papilliferous growths stood apart from the ordinary types as being much less malignant, and Berry mentioned one patient in whom such a tumor had been growing for eight years before operation. She then lived for ten more years. One case of great interest was reported by von Eiselsberg in 1894. The patient, in whom Billroth had undertaken total thyroidectomy, developed myxedema, which remitted when a secondary deposit appeared in the sternum, only to return when this was removed (202). (T. 132) The Twentieth Century In the early part of this century Charles Mayo and his colleagues, as well as Crile and Dunhill, all published series. From the Mayo Clinic William Herbst (in 1924) and John P e m b e r t o n (in 1928) each reported between 200 and 300 patients, of whom one-third survived between three and eighteen years after operation(37x). All those with sarcomas died within three years, while half or more of those with papillary growths fared well. The outlook was much better for patients whose growths were apparently encapsulated at the time of operation than for those with infiltrating lesions. Lloyd Craver from New York "advocated systematic removal of all nodular goiters with a view to avoiding the risks of malignant degeneration" (37x). Crile found that about 2 percent of his patients undergoing thyroidectomy had malignant goiters. In advanced cases, when the tumor could not be removed, he had provided temporary relief from obstruction by division of the preglandular muscles. In one such case subsequent radiotherapy caused complete regression and myxedema. rr.133) Pathologists introduced complicated classifications, and as many as twenty-three varieties of thyroid cancer were described, including some with contradictory n a m e s , such as "metastasizing a d e n o m a " (203). Allan G r a h a m of Cleveland, O h i o , simplified matters greatly in 1925 when, on analysis of sixty-five tumors, he reduced the number of types to three. (1) Malignant a d e n o m a s (carcinomas) (85 percent) were highly malignant solid tumors, which invaded blood vessels and spread via the bloodstream

66 • History of Endocrine Surgery while still contained within their capsules. (2) Papillary (or papilliferous) adenocarcinomas (12 percent) were often cystic, less malignant, and spread chiefly to the local lymph nodes. (This was Berry's papilliferous growth.) (3) Scirrhous carcinomas (3 percent), so named by Billroth in 1888, were solid tumors, which invaded tissue locally and also spread to the lymphatics. Most were diagnosed late and were incurable. The first two varieties usually developed in simple goiters. Graham's nomenclature was adopted widely, but for many years pathologists held different views about whether individual tumors were benign or malignant and about the categories to which they should be assigned. From this time on, however, the pathology and the surgery of thyroid cancer became progressively interdependent. (T.134) Dunhill used this classification in 1931 in a clinico-pathological review of thirty-eight patients (198). He found the three varieties in similar proportions to Graham, but made some other points concerning the nomenclature and pathology. By "malignant adenoma" he implied that the tumor had arisen in an existing nodule or "adenoma," especially of the so-called fetal type (p. T.52). He described some of them, which were undifferentiated, as "medullary." The "papilliferous" adenocarcinomas arose de novo in the thyroid and were extremely rare in Switzerland, where goiters were endemic. Despite this, he regarded them as similar to compensatory hyperplastic goiter. Scirrhous carcinoma was also named "carcinoma simplex." Dunhill did not consider that advanced cases were hopeless, and performed radical excisions, in some cases splitting the sternum to obtain access to deep thoracic masses. There were no postoperative deaths. In the last ten years he had used radiotherapy after operation in fourteen patients, with both malignant adenomas and papilliferous tumors, and had obtained some "surprisingly good" results. Ten patients were still alive, two of them having survived seven years, but three had not responded. He used radium needles in two patients. One of these had an unresectable scirrhous growth, which was insensitive to x-rays, but responded for a short time to radium, cr.135) Dunhill's views about the nature of papilliferous growths led him to use thyroid extract therapeutically in two young patients (68). It had been employed effectively for many years to inhibit pituitary TSH and reduce the size of simple goiters (p. T.74). The patients, aged 13 and 24, had had advanced, recurrent cancer for five and nineteen years, respectively. The tumors disappeared and had not returned when he reported them in 1937(68). The first was still alive twenty-five years later (204). (T.136) One clinical type of thyroid cancer, much discussed at this time(68, 69), had been known for at least 100 years and was referred to as a "lateral aberrant thyroid tumor." About fifty cases had been described. The growth was distinct from the thyroid, often multiple, and of the papillary adenocarcinomatous variety. Thyroid and lymphatic tissue often appeared together and were thought to develop from the ultimobranchial body, forming combined thyroid-lymphoid rests. In 1942, however, William King

The Thyroid (T) • 67 and John P e m b e r t o n of the Mayo Clinic discovered, as some h a d suspected before, that they were nearly always metastases from minute thyroid tumors, sometimes only 1 m m in diameter, and r e c o m m e n d e d that they should b e treated by hemithyroidectomy and block dissection (205). (T.137) T h e classification of thyroid cancer soon underwent further modification (206). In 1947 Alexander D r e n n a n of Edinburgh described 23 percent of a large series (144 patients from a nongoitrous region of Scotland) as adenocarcinomas ( G r a h a m ' s malignant a d e n o m a ) and 16 percent as papillary adenocarcinomas. H o w e v e r , h e recognized a new large group of "undifferentiated carcinomas," which h a d previously been included with the others or regarded as sarcomas, and which now accounted for 61 percent. H e described a "scirrhous reaction" as rare and did not include a separate scirrhous group. (T.138) These patients were unselected and h a d been referred to Edinburgh during World W a r II. Their clinical features and m a n a g e m e n t were reported by James G r a h a m and R o b e r t McWhirter. Owing to the wartime conditions, many came late, and m o r e than half h a d such advanced disease that curative treatment was not attempted. However, radical operations were undertaken when possible, and radiotherapy was employed in many patients. T h e five-year survival rates were as follows: Whole series Adenocarcinoma Papillary adenocarcinoma Undifferentiated

24 percent 46 percent 40 percent 15 percent

Half the undifferentiated tumors were radiosensitive, while all t h e differentiated ones were resistant. (T.139) Taking Stock Around 1950 Once thyroid surgery had become safe in the 1880s, surgeons tried to recognize thyroid cancer at an early stage in the hope that they could operate with some prospect of curing the disease. By 1950 conditions had become stabilized, some important advances had been made, and it was time to take stock (207). The disease was more prevalent in goitrous areas than elsewhere. Contrary to Berry's earlier finding, it was three to four times commoner in women than in men, while simple goiter was about nine times commoner (206). Goiters in men were therefore more prone to undergo malignant change than those in women. Single nontoxic nodules, which had been excised surgically, were found to be malignant much more frequently than multinodular goiters, the proportions being about 20 and 10 percent, respectively, in three centers in North America(207, 208, 209). Cancer was found in only about 1 percent of resected toxic goiters. Clearly the single

68


nontoxic nodule was the one to be feared most. A clinical pointer to the diagnosis of cancer was the presence of enlarged "Delphian" nodes on the trachea, above the thyroid isthmus (208), and scanning with radioiodine, which had been in use for about ten years, was sometimes helpful (p. T.61).

(T.140)

Many patients were now being treated at a relatively early stage (207). Papillary growths could often be removed by total lobectomy with excision of adjacent lymph nodes. Sometimes removal of more thyroid tissue and block dissection were used. The nonpapillary adenocarcinomas, being more malignant, were treated by total extended thyroidectomy, when this was possible and safe, sometimes with tracheostomy also. Block dissection on one or both sides was sometimes undertaken. Surgeons disagreed then and for many more years to come about the optimal extent of operations on the thyroid and on the lymph nodes. Radiotherapy, which had advanced greatly, was used in many centers and, as Graham and McWhirter had found, was most effective for undifferentiated carcinomas, which were often unsuitable for operations(206). (T.WI) Radioiodine therapy, introduced in 1942, had been used in the United States for some years and had just (after the war) become available in Britain(207). Very few thyroid cancer cells take up iodine, but some—less than 50 percent—can be induced to do so after removal of the thyroid. The tumor in von Eiselsberg's patient must have done so much more avidly than most, but such cases are extremely rare, and few have been described (210). The following therapeutic policy was developed. Total thyroidectomy was undertaken first in an attempt to eradicate the tumor, to reveal its extent in the neck, and to provide tissue for histological examination. If the patient was unfit for operation, or if the normal thyroid tissue could not be removed, radioiodine was used to destroy it. Both methods of ablation render the patient myxedematous. The capacity of metastases to take up iodine could then be assessed by administering a tracer dose and measuring its distribution by scanning the whole body and by counting the radioactivity of surgical biopsies. Metastases were then stimulated to activity by injections of TSH or by the prolonged administration of methylthiouracil until two or three days before the iodine was given. Many patients so treated obtained symptomtic relief, but none was cured. (T.142) Surgery and Pathology Advance Together A new variety of thyroid cancer with a "distinctive histological appearance" was described by Robert Horn of Philadelphia in 1951 and assumed great importance later (211). In 1953 Shields Warren and William Meissner of Boston gave the name "follicular" to the differentiated form of cancer, previously described as malignant adenoma or adenocarcinoma (204). At the same time they recognized several rarer types, including

The Thyroid (T) • 69 Hurthle cell tumors (p. T. 129). The proportion varied in different series, but the average percentages published in the next few years were(61o): Differentiated: papillary follicular Undifferentiated: anaplastic Miscellaneous Total

46 percent 28 percent 23 percent 3 percent 100 percent

The distinction between the first two types was somewhat arbitrary, because there were often papillary and follicular elements in both. However, one pattern usually predominated and determined the designation. This classification, together with clinical factors, was found to provide a good guide to the most appropriate form of therapy to employ in each patient, and it came into general use. (T.143) In 1959 John Hazard and colleagues from Cleveland, Ohio, reported more examples of the tumor described by Horn in 1951 and named it "medullary (solid) carcinoma" (212). (The term "medullary" had been used for at least two types of thyroid cancer previously.) The tumors were solid, but nonfollicular, had amyloid in the stroma, and often metastasized to the lymph nodes. They were quite distinct from other solid cacinomas, being much less malignant than anaplastic lesions, but more aggressive than papillary growths. Medullary carcinoma was now included as a separate group in the classification of thyroid carcinoma(213, 214, 215). (T.144) In the 1960s Oliver Beahrs (Fig. T.20), Marden Black, and colleagues reported their experience of over 1,100 patients treated at the Mayo Clinic from 1926 to 1960 (i.e. after those reported in the 1920s[213, 214]). Medullary growths accounted for 6 percent, and papillary, follicular, and anaplastic for 62, 18, and 14 percent, respectively. They were rather conservative in their treatment of papillary lesions, only occasionally undertaking total thyroidectomy or radical neck dissection. Follicular lesions were treated by total thyroidectomy when distant metastases were known to be present or were suspected, after which radioiodine was given. Medullary carcinoma, being more aggressive, was treated by total thyroidectomy and radical neck dissection. Six patients died postoperatively in the first fifteen years, but thereafter there were no deaths attributable to operation. rr.i45) In each of the differentiated varieties one group of patients was identified whose life expectancy after treatment was normal. These were: (1) patients with papillary growths whose lesions were confined to the gland, (2) those with follicular tumors with equivocal or slight capsular invasion, and (3) patients with medullary lesions, whose lymph nodes were negative. The prognosis for patients in whom these criteria were not met varied with the histological type. About 50 percent of those with papillary and 40 percent with follicular or medullary growths survived ten years. In the papillary group the prognosis was better for patients under the age of 40 than for older

70


ones. Anaplastic tumors were "uniformly fatal," however they were treated. Hurthle cell tumors, which others regarded as important (98), were not recognized as a separate group (p. T.129). (T.146) Thyroid cancer in children and young people is rare. In 1950, however, twenty-eight cases were reported in children, ten of whom had received radiotherapy to the thymus in infancy (216). By 1961 it was reported that 75 percent of children with thyroid cancer worldwide h a d been irradiated for a variety of nonmalignant conditions(217), especially in the United States, where this practice was fashionable (218). Other children had been subjected to radioactive fallout (221). By the 1970s it was generally accepted that the radiation caused the cancer (219). T h e tumors were nearly all papillary carcinomas, affected males m o r e often than other types of thyroid cancer, and usually developed after a latent period of ten to twenty years after exposure. Actively growing glands were apparently m o r e susceptible than adult organs. T h e clinical features and prognosis after treatment were similar to those of other forms of papillary cancer(217, 218). (T.147) Thyroid hormone therapy, first reported in 1937 by Dunhill for papilliferous lesions (68), was also employed successfully by others (220). George Crile, J r . , of Cleveland, O h i o , described its use in thirty-nine patients with advanced cancer (221). T h e best results were obtained with large (full replacement) doses of thyroid extract in seventeen patients aged from 5 to 66 with papillary lesions. T h e tumors stopped growing or actually regressed in all. Growths were also arrested in a few patients with other differentiated t u m o r s , but most of them and all with undifferentiated lesions failed to respond. Crile considered that hypothyroidism stimulated t h e growth of thyroid cancer and treated all patients with thyroid extract after operation. Many surgeons follow this practice(215), but the prognosis for papillary carcinoma is so good without it that its prophylactic value is not known. (T.i48) Chemotherapy was used in the early 1970s to treat a few patients who were unsuitable for conventional treatment or who had failed to respond. Adriamycin was the most effective drug, but produced only partial response in about one-third of patients, with all types of lesion(222). rr.i49) Calcitonin and Medullary Carcinoma The parafollicular cells, described by Baber in 1877 and by Hurthle in 1894 (p. T.129), were so named by Jose Nonidez of New York in 1932(223). He noticed their granular cytoplasm and suggested that they had an endocrine function, but his work was received with scepticism at the time. In 1962 Douglas Copp and colleagues in Vancouver described calcitonin as a new hormone from the parathyroids that lowered the blood calcium. Two years later, however, Iain Maclntyre and colleagues in London found that it originated in the thyroid(223) and, together with their colleague Everson

The Thyroid (T)

• 71

Pearse, found that it was secreted by the parafollicular cells(223). Pearse renamed them C cells and found them to be members of the A P U D series, originating in the neural crest and reaching the thyroid via the ultimobranchial body (224). rr.iso) A t the same time (1966) Dillwyn Williams, another colleague, reviewed the slides of all Selwyn Taylor's thyroid cancers and found seventeen (6.8 percent) that he recognized as medullary (225). Most of these had been regarded as anaplastic originally, but the patients had survived much longer than expected. Williams suggested that the C cells, formerly thought to be the source of Hurthle cell tumors (p. T.129), were the origin of medullary carcinoma, which might well secrete calcitonin in large quantities (226). By good fortune Maclntyre and Williams then (in 1968) learned that the coauthor, Ivan Johnston, was about to operate on such a patient in Newcastle-upon-Tyne(226). A combined effort resulted in (1) detection of calcitonin by bioassay in the blood (not detectable in normal subjects), (2) an increase in concentration during infusion of calcium, (3) higher levels in a thyroid vein than at the periphery, (4) total thyroidectomy, revealing bilateral medullary tumors surrounded by normal thyroid tissue, (5) disappearance of calcitonin from the blood after operation, (6) very great quantities of calcitonin in the tumor, (7) the isolation, analysis, and synthesis of h u m a n calcitonin and, finally, (8) the development (in 1969) of an R I A for it. T h e patient recovered from the operation, but had other features of the syndrome, which that same year was named "multiple endocrine neoplasia ( M E N ) , type 2" (p. M.8). (T.ISI) Other similar patients were soon studied, and it became clear that this tumor had a distinct marker in the form of a raised blood calcitonin level, found by R I A . W h e n the disease was sporadic the diagnosis was not considered until a mass was found in the neck, and the prognosis was unchanged(227). In many cases, however, the tumor was familial, whether part of the M E N 2 syndrome or not (228) (p. M.8), and could be detected, if sought, at a preclinical stage. T h e prognosis was then excellent. (T.152) A common symptom caused by medullary carcinoma—diarrhea—was noticed by Williams in 1966(225). It was possibly caused by prostaglandins secreted by the tumor, and was relieved by total excision. In 1969 Kalman Kovacs, Ilona Szijj, and colleagues from Szeged, Hungary, reported an ACTH-secreting medullary carcinoma, and referred to it as an " a p u d o m a " — t h e first time this term had been used (p. E.38). rr.153) Calcitonin was found to be a single chain peptide, composed of thirty-two amino acids. It is produced mainly by thyroid C cells, and its rate of secretion is related directly to the blood calcium level. Its influence on calcium metabolism is largely antagonistic to that of parathyroid h o r m o n e (p. P.T4), namely, inhibition of bone resorption, promotion of renal excretion of calcium, and inhibition of its absorption from the gut(76g). These actions are not strong enough to cause hypocalcemia when calcitonin is secreted in

72


excess by medullary carcinoma (76h), but they render it effective therapeutically in reducing the hypercalcemia of acute hyperparathyroidism (76j) (p. PT.3) and in the relief of pain in Paget's disease of bone (76k). cr.154) Solitary Thyroid Nodules

The management of nontoxic solitary nodules has been controversial since it was realized in about 1950 that many of them were carcinomas (229). Malignancy proved to be most likely at the extremes of life(217). Some advocated early operation for all, while others investigated the patients thoroughly and operated reluctantly. Needle biopsies had been used safely and effectively in some centers since the 1950s (p. T.64)(78, 79, 204), but had not gained general acceptance because of the fear (which proved to be groundless) of implanting tumor cells in the needle tracks (81). In the 1970s, however, fine needle aspiration and cytological examination, which had been pioneered particularly by Per-Ola Granberg and his colleagues in Stockholm, assumed great importance (80). Ultrasonography was also introduced for the investigation of thyroid nodules (p. T.58), and the value of simple needle aspiration of cysts was appreciated (229). The results of these procedures were that malignancy could often be excluded with confidence and that many patients were spared unnecessary operations. Despite this, thyroidectomy for single nodules became the commonest operation performed on the thyroid in the United States. At the same time, and as a result of good selection, the proportion of excised nodules that were found to be malignant was increased, especially in youths and in old people, reaching 50 percent by 1980 in one series (81). When an operation was required, the minimal acceptable procedure for a solitary nodule was total lobectomy (p. T.79) with immediate histological assessment of the tissue(81, 229). If, unexpectedly, multiple nodules were found, bilateral thyroid resection was undertaken (217). (T.155) In the 1980s the main requirements for thyroid surgery in general were the prevention of endemic goiter, with all its attendant complications and sequelae, by the general provision of iodine, the proper use of existing methods for the diagnosis of thyroid disease, and the widespread application of medical and surgical skills, which were already available in the best centers. Further advances awaited new discoveries and ideas. rr.i56)

GENERAL SOURCES Berry, 1901. See Ref. 36. Halsted, 1920. See Ref. 6. Crile, 1922. See Ref. 63.

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Mayo & Plummer, 1926. See Ref. 126. M l , 1932. See Ref. 37. Means, 1948. See Ref. 69. Moran et al., 1972. See Ref. 175. Vellar, 1974. See Ref. 135. Merke, 1984. See Ref. 2. Clark, 1985. See Ref. 77.

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134. Mayo, C H . Ligation and partial thyroidectomy for hyperthyroidism. Surg Gynecol Obstet 1910; 11: 562-65. 135. Vellar, I.D.A. Thomas Peel Dunhill, the forgotten man of thyroid surgery. Med Hist 1974; 18: 22-50. 136. Hartley, F. Thyroidectomy for exophthalmic goitre. Ann Surg 1905; 42: 33-48. 137. Dunhill, T.P. Exophthalmic goitre—partial thyroidectomy under local anaesthesia. Intercolonial Med J Aust 1907; 12: 569-72. 138. Dunhill, T.P. Surgical treatment of exophthalmic goitre. Ibid. 1908; 13: 29399. 139. Dunhill, T.P.Surgical treatment of exophthalmic goitre. Aust Med Congress, 8th session, Melbourne 1908; 1: 365-72. 140. Dunhill, T.P. Partial thyroidectomy. Br Med J 1909; 1: 1222-25. 141. Dunhill, T.P. Surgical treatment of Graves' disease. Med J Aust 1910; 15: 625-36. 142. Dunhill, T.P. Partial thyroidectomy under local anaesthesia, . . . exophthalmic goitre. Lancet 1912; 1: 422-24. 143. Dunhill, T.P. Operation for exophthalmic goitre. Br J Surg 1919; 7:195-210. 144. Keynes, G. The gates of memory. Oxford: Clarendon Press, 1981: 193-94. 145. Kocher, T. Basedow's disease. Ann Surg 1912; 55: 142-43. 146. Halsted, W. S. Excision of both lobes of thyroid gland for . . . Graves' disease. Ann Surg 1913; 58: 178-82. 147. Mayo, C H . Principles of thyroid surgery. JAMA 1918; 71: 710-12. 148. Crile, G.W. Graves' disease. Ibid. 1911; 56: 637-41. 148A. Dunhill, T.P. Surgical treatment of exophthalmic goitre. Br Med J 1926; 1: 557-60. 149. Dunhill, T.P. Toxic goitre. Br J Surg 1929-30; 17: 424-50. 150. Waller, H.E. Iodine, taken internally, in Graves' disease. Prescriber 1914; 8: 153-55. 151. Plummer, H.S., and Boothby, W.M. Value of iodin in exophthalmic goiter. Collected Papers Mayo Clin 1923; 15: 565-76. 152. Osier, W. Principles and practice of medicine. 5th ed. London: Appleton, 1905: 839. 153. Hertz, S., and Roberts, A. Application of radioactive iodine in therapy of Graves' disease. J Clin Invest 1942; 21: 624. 154. Hamilton, J.G., and Lawrence, J.H. Recent developments in therapeutic application of radio-phosphorus and radio-iodine. Ibid. 1942; 21: 624. 155. Chapman, E.M., and Evans, R.D. Treatment of hyperthyroidism with radioactive iodine. JAMA 1946; 131: 86-91. 156. Taylor, S. Surgical treatment of thyroid disease in modern perspective. Ann R Coll Surg Engl 1979; 61: 132-37. 157. Astwood, E.B. Treatment of hyperthyroidism with thiourea and thiouracil. JAMA 1943; 122: 78-81. 158. Himsworth, H.P. Thyrotoxicosis treated with thiourea. Lancet 1943; 2: 46566. 159. Astwood, E.B. Treatment of hyperthyroidism with antithyroid compounds. In: Dock, W., and Snapper, I., eds. Advances in internal medicine. New York: Interscience Publishers, 1949; 3: 237-74. 160. Moore, F.D., Cope, O., Means, J.H., et al. Use of thiouracil in preparation

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of patients with hyperthyroidism for thyroidectomy. Ann Surg 1944; 120: 152-69. 161. Danowski, T.S., Man, E.B., and Winkler, A.W. Additive effects of iodine and thiourea in treatment of hyperthyroidism. J Clin Invest 1946; 25: 597-604. 162. Fraser, R., and Wilkinson, M. Simplified method of drug treatment for thyrotoxicosis. Br Med J 1953; 1: 481-84. 163. Bartels, E . C Hyperthyroidism . . . treatment with antithyroid drugs followed by subtotal thyroidectomy. Ann Intern Med 1952; 37: 1123-34. 164. Canary, J.J., et al. Effects of oral and intramuscular reserpine in thyrotoxicosis. N Engl J Med 1957; 257: 435-42. 165. Buchanan, J., et al. Use of reserpine in treatment of thyrotoxicosis. Scott Med J 1959; 4: 486-90. 166. Lee, W.Y., Bronsky, D., and Waldstein, S.S. Thyroid and sympathetic . . . interrelationships. Effects of guanethidine. J Clin Endocrinol 1962; 22: 879-85. 167. Waldstein, S.S., West, G.H., Lee, W.Y., and Bronsky, D. Guanethidine in hyperthyroidism. JAMA 1964; 189: 609-12. 168. Theilen, E.O., Wilson, W.R., and Tutunji, F.J. Acute hemodynamic effects of alpha-methyldopa in thyrotoxic patients. Metabolism 1963; 12: 625-30. 169. Wilson, W.R., Theilen, E.O., and Fletcher, F.W. Pharmacodynamic effects of beta-adrenergic receptor blockade in hyperthyroidism. J Clin Invest 1964; 43: 1697-1703. 170. Turner, P., Granville-Grossman, K.L., and Smart, J. V. Effect of adrenergic receptor blockade on the tachycardia of thyrotoxicosis. Lancet 1965; 2: 1316-18. 171. Vinik, A.L, Pimstone, B.L., and Hoffenberg, R. Sympathetic nervous system blocking in hyperthyroidism. J Clin Endocrinol 1968; 28: 725-27. 172. Michie, W., et al. Beta-blockade and partial thyroidectomy for thyrotoxicosis. Lancet 1974; 1: 1009-11. 173. Hirsch, O. Surgical decompression of malignant exophthalmos. Arch Otolaryngol 1950; 51: 325-34. 174. Dollinger, J. Die Druckentlastung der Augenhohle durch Entfernung der ausseren Orbitalwand bei hochgradizem Exophthalmus. Dtsch Med Wochenschr 1911; 37: 1888-90. 175. Moran, R.E., et al. Surgical correction of exophthalmos. Plast Reconstr Surg 1972; 49: 595-608. 176. Moore, R.F. Exophthalmos and limitation of eye movements of Graves' disease. Lancet 1920; 2: 701. 177. Hirsch, O., and Urbanek. Behandlung eines excessiven Exophthalmus durch Entfernung von Orbitalfett von der Kieferhohle aus. (a) Mschr Ohrenheilk 1930; 64: 212-13; (b) Zbl Hals Nas Ohrenheilk 1931; 16: 59—both cited by Hirsch, O., 1950, Ref. 173. 178. Naffziger, H . C Progressive exophthalmos following thyroidectomy. Ann Surg 1931; 94: 582-86. 179. Naffziger, H . C , and Jones, O.W. Surgical treatment of progressive exophthalmos following thyroidectomy. JAMA 1932; 99: 638-42. 180. Sewall, E.C. Operative control of progressive exophthalmos. Arch Otolaryngol 1936; 24: 621-24. 181. Kistner, F.B. Decompression for exophthalmos. JAMA 1939; 112: 37-38. 182. Swift, G.W. Malignant exophthalmos and operative approach. West J Surg Obstet Gynecol 1935; 43: 119-26.

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183. Naffziger, H . C Progressive exophthalmos. Ann R Coll Surg Engl 1954; 15: 1-24. 184. McCullagh, E.P. Comments on exophthalmos of Graves' disease. J Clin Endocrinol 1953; 13: 818-24. 185. Means, J.H. Hyperophthalmopathic Graves' disease. Ann Intern Med 1945; 23: 779-89. 186. Campbell, R.J. Pathology of Graves' ophthalmopathy. In: Gorman, C.A., et al., eds. The eye and orbit in thyroid disease. New York: Raven Press, 1984: 25-31. 187. Dobyns, B.M., Wright, A., and Wilson, L. Assay of exophthalmos-producing substance in . . . patients. J Clin Endocrinol 1961; 21: 648-62. 188. McCullagh, E.P., et al. Exophthalmos of Graves' disease. Ann Intern Med 1958; 48: 445-70. 189. Beierwaltes, W.H. Irradiation of the pituitary in . . . malignant exophthalmos. J Clin Endocrinol 1951; 11: 512-30. 190. Hardy, J. Transsphenoidal surgery of hypersecreting pituitary tumors. In: Kohler, P.O., and Ross, G.T., eds. Diagnosis and treatment of pituitary tumors. Amsterdam: Excerpta Medica, 1973: 179-94. 191. Covington, E.E., et al. Radiation therapy for exophthalmos. Radiology 1977; 122: 797-99. 192. McConahey, W.M. Medical therapy. In: Gorman, C.A., et al., eds. Ref. 186: 317-24. 193. Havard, C W . H . Progress in endocrine exophthalmos. Br Med J 1979; 1: 1001-4. 194. Catz, B., and Perzik, S.L. Subtotal vs. total surgical ablation of the thyroid. In: Cassano, C , and Andreoli, M., eds. Current trends in thyroid research. New York: Academic Press, 1965: 1183-99. 195. Bauer, F.K., and Catz, B. Radioactive iodine therapy for progressive malignant exophthalmos. Acta Endocrinol (Copenh) 1966; 51: 15-22. 196. Ogura, J.H., and Thawley, S.E. Orbital decompression for exophthalmos. Otol Clin North Am 1980; 13(1): 29-38. 197. De Santo, L.W. Transantral orbital decompression. In: Gorman, C.A., et al.,eds. Ref. 186:231-51. 198. Dunhill, T.P. Carcinoma of the thyroid gland. Br J Surg 1931; 19: 83-113. 199. Hurthle, K. Beitrage zur Kenntniss des Secretionsvorgaugs in der Schilddriise. Arch fur Geschichte Physiol (Pfluger's) 1894; 56: 1-44. 200. Willis, R.A. Pathology of tumours. London: Butterworth, 1948: 606-8. 201. Horn, R . C Hurthle-cell tumors of the thyroid. Cancer 1954; 7: 234-44. 202. Eiselsberg, A. Freiherr von. Ueber physiologische Function einer im Sternum zur Entwicklung gekommen, krebsigen Schilddriisen-Metastase. Arch Klin Chir 1894; 48: 489-501. 203. Graham, A. Malignant tumors of the thyroid. Ann Surg 1925; 82: 30-41. 204. Burn, J.I., and Taylor, S.F. Natural history of thyroid cancer. Br Med J1962; 2: 1218-23. 205. King, W.L.M., and Pemberton, J. de J. So called lateral aberrant thyroid tumors. Surg Gynecol Obstet 1942; 74: 991-1001. 206. Graham, J.M., and McWhirter, R. Carcinoma of the thyroid. Proc R Soc Med 1947; 40: 669-80.

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207. Taylor, S. Carcinoma of the thyroid. Postgrad Med J 1950; 27: 1-11. 208. Cope, O., Dobyns, B.M., Hamlin, E., and Hopkirk, J. What thyroid nodules are to be feared? J Clin Endocrinol 1949; 9: 1012-22. 209. Cope, O. Diseases of the thyroid gland. N Engl J Med 1952; 246: 451-57. 210. Seidlin, S.M., Marinelli, L.D., and Oshry, E. Radioactive iodine therapy. JAMA 1946; 132: 838-47. 211. Horn, R . C Carcinoma of the thyroid. Cancer 1951; 4: 697-707. 212. Hazard, J.B., Hawk, W.A., and Crile, G. Medullary (solid) carcinoma of the thyroid. J Clin Endocrinol 1959; 19: 152-61. 213. Woolner, L.B., Beahrs, O.H., Black, B.M., McConahey, W.M., and Keating, F.R. Classification and prognosis of thyroid carcinoma. Am J Surg 1961; 102: 354-87. 214. Beahrs, O.H., and Pasternak, B.M. Cancer of the thyroid gland. Curr Probl Surg 1969; December: 1-38. 215. Taylor, S. Carcinoma of the thyroid gland. J R Coll Surg Engl 1969; 14: 18392. 216. Duffy, B.J., and Fitzgerald, P.J. Thyroid cancer in childhood and adolescence. Cancer 1950; 3:1018-32. 217. Thompson, N. W., Nishiyama, R.H., and Harness, J.K. Thyroid carcinoma. Curr Probl Surg 1978; 15, November: 1-67. 218. Richardson, J.E., Beaugie, J.M., Brown, C.C., and Doniach, I. Thyroid cancer in young patients. Br J Surg 1974; 61: 85-89. 219. Dolphin, G.W. Radiation carcinogenesis of the thyroid. Proc R Soc Med 1974; 67: 63-64. 220. Balme, H. W. Metastatic carcinoma of the thyroid successfully treated with thyroxine. Lancet 1954; 1: 812-13. 221. Crile, G., Jr. Endocrine dependency of certain thyroid cancers. Cancer 1957; 10:1119-37. 222. Gottlieb, J.A., and Hill, C S . Chemotherapy of thyroid cancer with adriamycin. N Engl J Med 1974; 90: 193-97. 223. Foster, G.V. Calcitonin. Ibid. 1979; 279: 349-60. 224. Pearse, A.G.E., and Polak, J.M. Neural crest origin of mammalian ultimobranchial C cells. Histochemie 1971; 27: 96-102. 225. Taylor, S. Thyroid medullary carcinoma. Ann R Coll Surg Engl 1977; 59: 374-81. 226. Cunliffe, W.J., Hall, R., Johnston, I.D.A., Williams, E.D., Joplin, G.F., Maclntyre, I., et al. A calcitonin-secreting thyroid carcinoma. Lancet 1968; 2: 63-66. 227. Rossi, R.L., Cady, B., Meissner, W.A., Sedgwick, C.E., et al. Non-familial medullary thyroid carcinoma. Am J Surg 1980; 139: 554-60. 228. Hillyard, C.J., Evans, I.M.A., Hill, P. A., and Taylor, S. Familial medullary thyroid carcinoma. Lancet 1978; 1: 1009-11. 229. Wheeler, M.H. Management of the solitary thyroid nodule. J R Soc Med 1988;81:437-38.

T.l.

T.2.

T.3.

T.4.

T.l. Pierre-Joseph Desault. Courtesy of L. M. Zimmermann and I. Veith, Great Ideas in the History of Surgery, © 1961, The Williams & Wilkins Co., Baltimore, p. 364. T.2. Johann A. W. Hedenus. Courtesy of Staatliche Kunstsammlungen, Dresden, East Germany. T.3. William Blizard, by John Opie. Courtesy of the President and Council of the Royal College of Surgeons of England. T.4. Nikolai Ivanovich Pirogoff. Courtesy of N. Kanneff, M.D., Institute of Endocrinology, Sofia.

T.5.

T.6.

T.7.

T.8.

T.5. Christian Albert Theodor Billroth. Courtesy of D. F. Roses, Surg Gynecol Obstet 1986; 163: 386. By Permission of SURGERY, GYNECOLOGY & OBSTETRICS. T.6 Patrick Heron Watson. Courtesy of the Royal College of Surgeons of Edinburgh. T.7. Anton Wolfler. Courtesy of the Institut fiir Geschichte d. Medizin der Universitat Wien. T.8. Paul v. Sick. Courtesy of Professor Dr. D. Lorenz, Diakonissenkrankenhaus, Stuttgart. 84

T.9. (a)

(b)

T.10.

T.ll.

T.9. Kocher's patients—the Bichsel sisters: (a) before operation (Marie on right); (b) after operation (Marie on left). From T. Kocher, Ueber Kropfextirpation und ihre Folgen. Arch klin Chir 1883; 29: 254-337. T.10 Felix Semon. From The Autobiography of Sir Felix Semon. London: Jarrolds, 1926. T.ll. Johannes v. Mikulicz-Radecki. Courtesy of P.D. Dr. v. Mikulicz-Radecki, Karlsruhe. 85

T.12.

T.13.

T.14.

T.l 5.

T.12. Hakaru Hashimoto. Courtesy of Dr. Hachinen Akita, Fukuoka-shi, 810, Japan. T.13. William Stewart Halsted. By permission of the President and Council of the Royal College of Surgeons of England. T.14. Charles Horace Mayo. Courtesy of Mayo Clinic. T.15. George Crile. Courtesy of George Crile, Jr., M.D. 86

T.16.

T.17.

T.18.

T.l 9.

T.16. Ludwig (Louis) Rehn. Courtesy of Professor Hans-Dietrich Roeher, M.D., Dusseldorf. T.17. Henry Stanley Plummer. Courtesy of Mayo Clinic. T.18. Thomas Peel Dunhill, by James Gunn. Courtesy of St. Bartholomew's Hospital, London. T.19. Howard Naffziger, Courtesy of the late Mrs. Elizabeth Naffziger Stern, Los Angeles.

87

T.20.

T.20. Oliver H. Beahrs. Courtesy of Mayo Clinic.

3

(P)

The Pituitary

During most of the last century the pituitary gland was regarded as a vestigial organ (1), its tumors were viewed as pathological curiosities, and no surgeon had ventured far enough into the skull to explore it. In 1886, however, acromegaly was described, and three years later, when the surgery of the thyroid was already well established, surgeons started to operate to relieve pressure from pituitary tumors. Removal of adenomas for endocrinological reasons came much later. (p.i) Galen (second century) and Vesalius (1543) recognized the pituitary, and both stated that it discharged mucus into the nose (p. E.2). Thomas Wharton (1656) wrote that it drained moisture from the brain (p. E.2), while Richard Lower of London (1670) speculated that whatever passed from the brain into the pituitary returned to the blood (2a). The gland was named "hypophysis cerebri" ("outgrowth under the brain") by Samuel von Soemmering of Germany in 1778 (2b). The origin of the anterior lobe or adenohypophysis from a diverticulum of the foregut was described by Martin Rathke of Konigsberg (1838)(3), and the posterior lobe or neurohypophysis was recognized as an extension of the floor of the brain. Chromophil (acidophil and basophil) and chromophobe cells were described in the anterior lobe in the 1880s and 1890s (4), but their functions were unknown. (p.2) Disease states, not then attributed to pituitary dysfunction, have been known from ancient times. Giants and dwarfs attracted attention, and acromegalic faces were depicted in art (5). In recent times studies of the skeletons of giants and acromegalics have confirmed the nature of their

90 • History of Endocrine Surgery diseases, and several have been found to have enlarged pituitary fossae (2c, 6). Pathological enlargement of the pituitary was recognized in the seventeenth century, and the pressure effects on adjacent structures, particularly blindness, were reported in the eighteenth and nineteenth centuries (2d). (P.3)

PITUITARY TUMORS In 1886 Pierre Marie of Paris wrote an account of "deux cas d'acromegalie" and found reports of five similar cases (7, 8a). One had a large pituitary tumor, and one of Marie's own patients was found, two years after death, to have a large sella(9). Other reports soon followed, but the relationship between acromegaly and the pituitary remained speculative for twenty years (2c). The general view was that acromegaly resulted from pituitary insufficiency, although it did not follow hypophysectomy in animals (10). Some, however, suggested that pituitary hyperfunction (4) caused the disease, and this idea received support later when chromophil hyperplasia of the pituitary was found in some patients (11) and when partial removal of tumors relieved the endocrine features(12, 13, 14). Another important suggestion at this time (1895-1903) was that the pituitary provided a growth center for the whole body. Hyperfunction caused gigantism before puberty and acromegaly in adult life. This view was eventually accepted and received experimental support in the 1920s (2e). (p.4) T w o young patients with pituitary t u m o r s a n d distinctive clinical features (but not those of acromegaly) were r e p o r t e d independently, the first in 1900 by Joseph Babinski of Paris (15), and the other in 1901 by Alfred Frohlich of V i e n n a ( 8 b , 16, 17). B o t h patients were obese and sexually infantile, a n d neither author suggested hypopituitarism. T h e new syndrome came to b e k n o w n (in 1908) as dystrophia adiposogenitalis or, later, Frolich's synd r o m e (2f). Soon patients were reported with the additional features of retarded growth and polyuria, while obesity was seen only with lesions in or near the infundibulum. Impaired sexual development and retarded growth were regarded as manifestations of partial anterior pituitary failure (17) and polyuria as the result of total posterior lobe deficiency (18a). (p.5) In 1909 Harvey Cushing (Fig. E . 6 ) ( l ) of Baltimore, w h o , in the next thirty years, contributed greatly to many aspects of pituitary science and surgery (19), introduced the terms "hyperpituitarism" and "hypopituitarism," indicating increased and decreased activity, respectively, of the anterior lobe. H e attributed the first to oversecretion of a h o r m o n e by a tumorous or hypertrophied gland, and the second either to pressure by a tumor on the normal gland or to atrophy. H e recognized that hypopituitarism caused loss of secondary sexual features in adults, and later described the combination of hyper- and hypopituitarism as "dyspituitarism" (18b).

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Cushing regarded total absence or destruction of the anterior lobe—"apituitarism"—as incompatible with life, a view that long remained controversial. Little was then known of the pathology of pituitary tumors, and many terms, including struma, were used, in addition to adenoma, to describe them. In 1900 Carl Benda of Berlin made a major discovery when he found cells with chromophil granules in the pituitary lesions (11). (p.6 In 1901, soon after t h e discovery of x-rays, H e r r m a n n O p p e n h e i m of Berlin observed enlargement of t h e sella in a patient with a pituitary t u m o r (20), a n d in 1905 an x-ray of the skull of Frohlich's dystrophic patient showed an a b n o r m a l sella (17). A b o o k o n x-ray diagnosis published in 1912 by A r t h u r Schiiller of Vienna described t h e sellar changes caused by pituitary t u m o r s a n d t h e skeletal disturbances of acromegaly (21). By this time Cushing was advocating t h e use of stereoscopic films (18c), a n d surgeons were consulting x-rays during pituitary operations. (pj) Early Operations on the Pituitary Surgeons soon turned their attention to treating pituitary tumors, usually trying out operations on animals and cadavers before applying them to patients. There were no specialist neurosurgeons, but some general surgeons were pioneering intracranial operations, and in 1889 the foremost of these, Victor Horsley (Fig. P.l) of London, performed the first known operation. He had already undertaken hypophysectomy and thyroidectomy (p. T.42) in animals. He published his work on pituitary surgery with tantalizing brevity in 1906(22, 23), and Howard Tooth of London described four of his patients in 1913(24). Horsley had undertaken ten craniotomies for patients with pituitary tumors, some of them probably acromegalic. He used chloroform anesthesia and operated in two stages, first raising a bone flap and then opening the dura and completing the operation. He employed a frontal approach at first, but found it unsatisfactory, and later used the temporal route instead (Fig. P.2). He stated that the surgeon's duties were to relieve mechanical pressure, to avert blindness, and to remove the tumor "to prevent a fatal result." All the patients described by Tooth had visual field defects, three suffered headaches, and one had hypopituitarism. The tumors were removed largely or completely from two, but small parts only were taken from others. One patient died after six hours, and the other three had serious complications. Three patients survived between nine months and eight years after operation. Horsley died on war service in 1916 at the age of 59. An earlier report of an operation for pituitary disease (and probably the first to be undertaken for acromegaly) was published in 1893 by Richard Caton and Frank Paul in Liverpool (25, 26). The patient had severe headaches, failing vision, and facial pain. Horsley advised operation, and Paul did a right temporal decompression. Pain was relieved, but the patient lost her sight and died after three months. (p.s)

92 • History of Endocrine Surgery Extracranial (Transsphenoidal) Operations By 1906, when Horsley's work was published, no one else had treated pituitary tumors successfully, and radiotherapy was not tried until the next year. (Schloffer [28] mentions, without details, two earlier palliative operations performed in 1898 and 1899 [by Dogen, and by Thomas and Syme, respectively].) General surgeons and ear, nose, and throat (ENT) surgeons, however, were devising ingenious extracranial operations (Fig. P.3) and neurosurgeons soon followed. Despite the fact that many patients had visual defects, no ophthalmic surgeons seem to have attempted hypophysectomy(27a). There were three main problems: first, to discover the best route to the pituitary, which must inevitably pass through the sphenoidal sinuses; second, to avoid serious infection, which was difficult when the meninges were exposed to the nasal cavity; and third, to prevent disfigurement after the removal of facial and nasal bones. In this same year (1906) Herman Schloffer (Fig. P.4) of Innsbruck, Austria, reviewed the methods that had been proposed and tried previously(28), and the next year, on March 16, performed the first known extracranial operation on a patient with severe pressure effects and a large fossa. He mobilized the nose on a pedicle (Fig. P.5), removed much bone and mucuous membrane, laid the pituitary fossa open to the whole bared nasal cavity, and then excised much of the tumor piecemeal. The patient was greatly improved and lost his headaches, but did not recover sight, and lived for ten weeks(29, 30). (p.9) Other surgeons introduced modifications. Anton von Eiselsberg (Fig. P.6) of Vienna used a similar approach to operate on Frolich's patient, who had already received some benefit from thyroid extract (17, 31). He drained a cyst and biopsied the wall, which may have been part of a craniopharyngioma. The young man improved greatly and remained well six years later. Eiselsberg reported six operations in 1910 and sixteen in 1912(31, 32); he modified the incision and managed to reduce the facial deformity. Herrmann Preysing of Koln (Cologne), Germany, used a transpalatal approach (33) and illustrated three anatomical forms of the sphenoid bone, including the conchal type, which for long precluded the use of the transsphenoidal approach in a few patients. Eiselsberg, however, had the greatest experience and the best results (34). Of his first six patients, three with hypopituitarism were cured, two with acromegaly died, and one with mixed features was improved(31). Of the first sixteen patients, five developed meningitis and four of them died. Others suffered persisting nasal infection, which produced an offensive odor(32, 34). (p.io) These operations provided a new route to the pituitary, but were unacceptably crude. However, several important refinements were introduced in 1909, which was to prove a seminal year for surgery of the pituitary. First, on January 9, Theodor Kocher (Fig. E.l) of Berne, using a large incision, resected the nasal septum submucosally, separated the two layers of

The Pituitary (P)

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mucosa, and reached the pituitary by the midline, thereby avoiding a wide opening into the nasal cavity (35). Next, Allen Kanavel of Chicago devised in cadavers an infranasal approach in which the nose was reflected upwards (36). Before he had used this operation his colleague, Albert Halstead, employed it on a patient on July 21(37), but made a gingival incision concealed behind the upper lip. Finally, on December 27, Samuel Mixter of Boston employed the Kanavel approach but, like Kocher, resected the septum submucosally (38). Mixter's colleague, Alex Quackenboss, was an opthalmologist. Kanavel then performed his own original operation in patients, but did not employ submucous resection until 1913, after one of them had died from meningitis (39). Cushing undertook his first transsphenoidal operation on the pituitary in 1909, using a modification of Schloffer's method (13). The patient, an acromegalic, improved greatly and lived for twenty-one years after partial hypophysectomy (40). The next year, on June 4, 1910, by combining the two main modifications of the infranasal operation—an oral incision and submucous resection of the septum—Cushing established an operation that he and others used successfully and virtually unchanged for fifty years (Fig. P.7)(18d). In 1912 Cushing published his classic monograph, The Pituitary Body and Its Disorders (IS), left Baltimore, and moved to Boston. He dominated the field of pituitary surgery and of neurosurgery as a whole until the time of his retirement in 1933 and after, until his death in 1939. (p.ii) At the same time Oscar Hirsch (Fig. P.8) of Vienna, an ENT surgeon, was developing a slightly different approach. First, in two or three stages, he resected the middle turbinate bones and the nasal septum, creating a large single cavity through which he reached the pituitary. He first operated thus on March 8, 1910(41, 42), but soon modified the procedure, making a midline incision between the nares and adopting Kocher's submucous septal resection. He first used this method on June 4, the same day as Cushing's definitive operation. Their main differences in technique were the sites of the incisions and the fact that Hirsch resected the middle turbinates (creating a large raw area), while Cushing crushed them. (p.12) One other operation, devised about this time, was the paranasal, transethmosphenoidal approach of Ottokar Chiari, another ENT surgeon in Vienna (Fig. P.9). Chiari performed the operation twice in 1911, with excellent results(43). Others, incuding Otto Kahler of Freiburg im Breisgau, then adopted it(44); although fifteen procedures had been performed by 1917 with only two deaths (34, 35), little attention was paid to the method at the time. Felix Nager in Zurich soon adopted the operation, which was used very effectively in Switzerland and Scandinavia for many years (46). (p.13) Anesthesia for these operations proved difficult at first. Most surgeons employed morphia and chloroform or ether, although Hirsch used cocaine, which was rather unsatisfactory (34). The anesthetic was often administered

94


via a temporary tracheostomy, especially in acromegalics, but Cushing's anesthetist in Baltimore, Samuel Davis, used a metal tube, attached to a combined mouth gag and tongue depressor, for the delivery of ether into the pharynx (18e). (p.14) In 1909 Cushing had written that "surgeons could not afford to enter this new field too precipitously," but within a year he and others had found an effective and safe route to the gland(13). In 1912, after operating on fortythree patients, he concluded that the "services of surgical therapy" were relief of neighborhood symptoms, palliation of raised intracranial pressure, and partial extirpation of the gland in hyperpituitarism(18f). The lesion could be dealt with by removal of an infrasellar tumor derived from a hypophyseal rest in the nasopharynx (47) (an exceptionally rare occurr e n c e ^ ] ) , sellar decompression, which "promised much for the future," evacuation of an intrapituitary cyst, and fragmentary extirpation of the gland or tumor. Cushing did not mention, as Horsley had done, removal of the whole tumor, presumably because it would cause fatal apituitarism. (Pis) Analysis of all operations published by 1913 showed that twenty-four of sixty-four transsphenoidal procedures had been fatal (37.5 percent), mostly as a result of meningitis in patients with tumors extending well outside the sella. In those who survived, visual disturbance and headache were relieved or improved in about 60 percent and 40 percent, respectively, while acromegalic features and adiposity diminished in about 30 percent and 20 percent. In many patients the beneficial effects of operation persisted for at least two years, and few had been followed for longer(34, 49, 50). By 1916 Cushing had done 106 operations with 8 operative deaths (7.5 percent), and Hirsch 26 with 4 deaths (15 percent). Their operations and Chiari's established transsphenoidal hypophysectomy as a relatively safe and effective procedure. Cushing's was adopted widely, while Hirsch continued, almost alone, to use his technique successfully in Vienna and later in Boston, and followed his patients for nearly fifty years (51, 52). Chiari's operation achieved prominence later (p. P.70) (p i6) Transcranial Operations The transsphenoidal route to the pituitary was now advancing more rapidly than the transcranial, but it was unsuitable for the removal of tumors with large suprasellar extensions. In the early 1900s, however, a few other surgeons, including Fedor Krause (Fig. P. 10) of Berlin, were exploring a transcranial approach(4) (Fig. P.2). In 1900 Krause removed a bullet from the region of the optic foramen by a frontal approach in a young man who had attempted suicide when disappointed in love. He found that he had an excellent view of the sella, and that year demonstrated the approach, which was largely extradural, in a cadaver to the Berlin Medical Association(53, 54). Later he and others tried it unsuccessfully in patients (55). In 1909,

The Pituitary (P)

• 95

however (the seminal year again), Krause operated successfully on an acromegalic patient. It was regarded as hazardous to breach the dura mater, and the operation was done in two stages, the dura being opened at the second operation, and a large tumor was removed. The patient experienced thirst and polyuria, but obtained great relief for at least twenty-one months (54). After Horsley's operation in 1889, this was the first known procedure on the pituitary by the frontal route. Two others were performed soon, one in 1911 by N.F. Bogoiavlensky in Vladimir, Russia(14), the other in 1912 by Lewis McArthur in Chicago. The second, done in one stage, involved removal of the orbital roof and an extradural approach until the sella was reached (56). Cushing had used Horsley's temporal approach successfully in dogs, but found it very difficult in man(13, 57). He attributed any relief that it conferred to cranial decompression, and later (like Paul in 1893) used the procedure for palliation. By 1914 he had also operated on five patients by the frontal route with very unsatisfactory results (57). (p.n) In 1912, however, Charles Frazier (Fig. P. 11) of Philadelphia, who was mainly responsible for developing transcranial hypophysectomy at this time (4), devised another transfrontal approach to the pituitary and within a year had performed four operations successfully (49, 50). His original procedure was a modification of McArthur's and included a right frontal osteoplastic flap. The supraorbital ridge was removed and replaced as a free graft at the end of the operation. Frazier regarded the two approaches to the pituitary as complementary, recommending the extracranial where the sella had a narrow orifice, or when the tumor invaded the sphenoid bone, and the transcranial when the fossa had a wide opening. For the next two decades the transcranial route gained in popularity among neurosurgeons in the United States and Europe (34). The immediate problems were safety, access to the pituitary, and the cosmetic result. Frazier, George Heuer of Cincinnati, Charles Elsberg of New York, and others introduced many modifications (58, 59, 60, 61). Frazier changed the skin incision twice, preserved the bone at the base of the skull, fashioned a low temporal bone flap, which avoided the frontal sinus and reached the pituitary along the greater wing of the sphenoid bone (4, 62, 63). His later approaches and minor modifications of them were used by many others (64). The extradural dissections were extensive and quite often caused hematomas, which were sometimes fatal(40, 65). Some surgeons advised a right-handed surgeon to approach the pituitary from the right, and others advocated this side for a righthanded patient (4). Some operated on the side with the smaller frontal sinus and others on that with the worse vision, in case they damaged the optic nerve. In 1919 Frazier began to open the dura before mobilizing the brain, and to approach the pituitary directly, and most surgeons did so eventually, with improved results (61). After Cushing's own early disappointments with the transcranial approach (and his success with the transsphenoidal), he did not employ it again until the early 1920s (40, 66). Frazier's management of

96


the pituitary lesion evolved over the years. At first he evacuated cysts and removed portions of "strumas." In 1931 he opened and emptied the capsule, separated it from the optic nerves and chiasm, and then removed it, except for the portion lying on the floor of the fossa (63). The surgical techniques employed were those that had been devised for intracranial operations in general. Cushing(40) and many others(64) preferred sedation and local anesthesia for all intracranial operations, but still used general anesthesia for transsphenoidal hypophysectomy. (p.is) The results of the transfrontal procedures improved steadily as surgeons learned how to operate on the brain. The mortality, at first 70 to 80 percent, fell to about 30 percent by the early 1920s (61,62). Ten years later Cushing had lost only 7 percent (7/107) of patients in twenty years (1913-32), and fewer still in the last ten years (40). Frazier similarly lost only 3 percent at this time(63). Many of the deaths were associated with large tumors, and a few (2 percent) with hematomas. (p.19) Eclipse of Transsphenoidal Operations During this same period Cushing lost only 5 percent of patients after transsphenoidal hypophysectomy (12/227), half the deaths being associated with large intracranial extensions of tumor and a few with meningitis. Vision was restored more effectively by intracranial operations, because suprasellar extensions of tumor could be removed more effectively (27a). However, in about 10 percent of patients with chromophobe adenomas the optic chiasm was prefixed, the tumor was inaccessible from above, and the transsphenoidal operation gave superior results (40). The restoration of vision depended on the state of the optic nerves. If they were intact, vision might return at once, while if atrophy was advanced, it could not improve(27, 63). Analysis of the long-term results in 338 patients, whom Cushing had treated in Boston (1913-32), was published in 1939, the year of his death, by his former pupil, William Henderson of Leeds, England(40). Longer periods of remission followed the transfrontal operation than the transsphenoidal, and patients who had received radiotherapy also fared best after both operations (p. P.29). Many remained in remission for ten to twenty years, but nearly all those who suffered recurrence did so within five years. The follow-up was extended later to include the patients treated in Baltimore (1905-12) and was updated by twenty-five years (67). (p.20) During the 1920s "the struggle for survival of the transsphenoidal operation began" (4), and progressively more neurosurgeons adopted the transfrontal route for most patients. Cushing was influenced by lesions, mainly suprasellar craniopharyngiomas(27b, 57), meningiomas(68), and large chromophobe adenomas, which caused neighborhood effects but could not be distinguished before operation, and for which the transsphenoidal approach was inadequate(27a). He changed abruptly in 1929 and 1930,

The Pituitary (P) • 97 when he performed his last transsphenoidal operation for a chromophobe adenoma (66). Meanwhile other developments were also influencing surgical practice. (p.21) PARALLEL DEVELOPMENTS Physiology By the middle 1930s the anterior pituitary, "the leader in the endocrine orchestra," was known to secrete at least six humoral agents that controlled the structure and functions of tissues and other endocrine glands (2g). 1. Growth hormone, formed by eosinophilic cells, controlled tissue growth. Excess caused gigantism and acromegaly, while deficiency resulted in dwarfism. 2. Thyroid-stimulating hormone controlled the thyroid. Hypothyroidism was a fea ture of hypopituitarism, and thyroid extract was beneficial. 3. & 4. Gonadotrophins were of two types: Prolan A (follicle-stimulating) and Prolan B (luteinizing). Hypopituitarism impaired gonadal function. 5. An adrenocorticotrophic hormone, possibly formed by basophil cells, controlle the two inner zones of the adrenal cortex. 6. A mammotrophic hormone or prolactin, concerned with mammary growth in pregnancy and with lactation, was first used effectively to stimulate lactation in 1934. 7. Several other pituitary secretions had been proposed but not confirme d. (p The role of the posterior pituitary was still unclear. Diabetes insipidus (DI), which had been distinguished from diabetes mellitus at the end of the eighteenth century (2h), was found with lesions of the hypothalamus, the posterior pituitary, or both. Experimentally it was caused by damage to the supraoptic nuclei and neurohypophysis by occlusion of the pituitary stalk, and by removal of all the posterior lobe, together with part of the anterior. DI was thought to be due either to deficiency of an antidiuretic hormone or to excessive secretion of a diuretic factor. It had been observed after hypophysectomy in man(18g, 54). Pitressin, a posterior lobe extract, provided effective relief by injection or by inhalation. (p.23) Whether or not the pituitary was essential to life was still undecided, and the evidence was "absolutely contradictory"(49, 50). Some investigators, including Horsley, had found total hypophysectomy in animals compatible with life (at least for a time), but others, including Cushing, had not. Bernardo Houssay of Buenos Aires had observed in 1930 that hypophysectomy in dogs, previously made diabetic by pancreatectomy, ameliorated their state (the Houssay phenomenon) (69). (p.24) Total hypophysectomy had rarely been attempted in man, although Alfred Adson of the Mayo Clinic reported one case with an excellent result,

98 • History of Endocrine Surgery when total clearance of the sella was followed by therapy with pituitary extract(60). Hypopituitarism from any cause, when involving all aspects of pituitary function, was called "Simmonds' disease" (2i, 70) and was compatible with long survival, albeit with very poor health. The more severely the pituitary was damaged, however, the more likely was the subject to succumb to stress, often dying in an Addisonian-like crisis. (p.25) Pathology

The pathology of pituitary tumors was studied in lesions removed at operation, and correlated with the clinical features. In 1922 Cushing(68) had already simplified the classification. In a review of over 700 intracranial tumors he reported that 21 percent were "adenomas (chiefly pituitary)," 4 percent "suprasellar tumors (mainly of pharyngeal pouch origin)," and 1 percent "suprasellar meningiomas." (There were many more meningiomas elsewhere.) In 1925 two of Cushing's pupils, Norman Dott of Edinburgh and Percival Bailey of Chicago, studied 162 of his patients with pituitary adenomas and described five types(71): 1. Chromophobe adenomas (66 percent) were associated with hypopituitarism. The cells were arranged either in a relatively normal columnar pattern, or in an unorganized mass with little connective tissue (previously called "struma"). 2. Eosinophil adenomas (24 percent), accompanied by acromegaly or gigantism, contained alpha granules in the cells. Some tumors had a "strumatous" arrangement. 3. Mixed adenomas (8 percent) caused dyspituitarism. There were three types of cell: (a) resembling eosinophils but with few granules, (b) like chromophobes, but with peripheral rings of alpha cells, and (c) like chromophobes, but with faint alpha granules. 4. "Malignant adenoma" or adenocarcinoma (2 percent) was very rare and had no specific clinical features. The cells contained many mitoses and invaded surrounding tissues. One tumor had metastasized to the liver. Some benign tumors extended very widely but were noninvasive. 5. Basophil adenoma (nil). Such tumors, none of which were seen in this series, were rare, formed minute intraglandular nodules, and were regarded as clinically insignificant. (p.26)

Other types of tumor in the neighborhood of the pituitary were reviewed by Cushing in 1932. Of 2,000 intracranial tumors, 360 (18 percent) were pituitary adenomas, while 95 (5 percent) were "congenital" tumors close to, or within, the pituitary fossa. The great majority were craniopharyngiomas, also known as adamantinomas(72). One-third presented in the second decade of life, whereas pituitary adenomas were rare before the age of 20(71). Clinical features included hypopituitarism, visual field defects, headache, hypothalamic disturbances, DI, and hydrocephalus. (p.27)

The Pituitary (P)

• 99

Radiodiagnosis Plain and stereoscopic x-rays were of limited help in the diagnosis of pituitary tumors and in transsphenoidal operations(27a, 71), but the introduction of cerebral pneumography (ventriculography) by Walter Dandy of Baltimore, in 1919, opened up new possibilities(40, 73, 74). Cerebral angiography, introduced in Portugal in the late 1920s, although not free from complications, revealed aneurysms clearly (73). (p.28) Radiotherapy Radiotherapy, then in its infancy, was probably first used for a pituitary tumor by A. Gramegna of Turin, Italy, in 1907(75), the same year as Schloffer's first operation. The patient had acromegaly and was irradiated through the mouth twice weekly for four weeks. Headaches were relieved rapidly, and vision improved for a short time. The next year, in France, Antoine Beclere treated a girl of 16 with a large pituitary tumor, using a "cross-fire" technique at four or five sites, weekly for ten weeks. She was so much improved that the planned operation was abandoned, and her mother said that she was "d'une sante parfaite" thirteen years later (76, 77). The early machines yielded only 50 kV, and the required dosage and effects of irradiation were discovered empirically. Nevertheless, the outcome was surprisingly good, and radiotherapy assumed a lasting place in the treatment of pituitary tumors. Others, including Cushing, had encouraging results also(18h). In 1912 he considered that the main indication for radiotherapy was a rapidly expanding tumor with distortion of neighboring structures but minimal alteration of glandular function, and was cautiously optimistic about the possibilities. After the Great War, Beclere increased the energy of his machine to 200 kV ("high voltage") and established the radiotherapy of pituitary tumors on a firm basis (71, 77). By 1925 over fifty of Cushing's patients had been treated (78). The growth of the tumor was usually retarded, and its size was sometimes reduced, but occasionally there was temporary aggravation of symptoms. Patients without severe visual impairment were followed carefully, and operations were undertaken immediately if vision deteriorated. Radiotherapy was continued postoperatively. In a collective review of over seventy patients from Kiev in 1926(79), the results were good and lasting in two-thirds of the acromegalics and in one-third of those with dystrophia adiposogenitalis. In about half the patients with other types of pituitary tumor, eye signs improved and intracranial pressure was lowered. However, those with severe intracranial hypertension required surgical decompression before being irradiated. By 1930 radiotherapy in general had advanced further, high-voltage machines were available in many centers, and doses were being expressed in roentgen (r) units. Some of the early optimism was waning, and Frazier had seen only one patient with lasting benefit (62, 63). Cushing(27a) suggested that, while chromophil

100 • History of Endocrine Surgery tumors responded to radiotherapy, it would be discarded for chromophobe adenomas as neurosurgeons perfected their techniques, and that irradiation was only advocated routinely in clinics where the surgical results were poor. Craniopharyngiomas and adenocarcinomas were considered quite unresponsive (80, 81, 82). In 1935 Carl Rand and Raymond Taylor of Los Angeles, who employed doses up to 3,000 or 4,000 r, concluded that radiotherapy might render surgical intervention unnecessary in some cases, but emphasized again that operations should not be delayed if vision deteriorated (81). Many surgeons continued to irradiate patients postoperatively (80, 83), but the benefits of doing so did not become apparent until Henderson's analysis of Cushing's patients in 1939(40). The proportions who were symptom-free after five years were as follows:

Operation only Operation and radiotherapy

Transsphenoidal 33% 65%

Transfrontal 57% 87%

The series was uncontrolled, but the results reveal definite benefit from irradiation after both the transfrontal and the transsphenoidal operations. Clearly radiotherapy was an adjunct to surgical operations, not a substitute for them (81). (p.29) In 1911 Hirsch began to apply radium to the remnants of pituitary tumors after their partial removal and, after ten years, was able "to achieve lasting results" (51). Indeed, by 1937 he had used radium after hypophysectomy in nearly 300 patients, with 5 percent mortality. After five or more years vision was preserved or showed lasting improvement in two-thirds. Cushing's experience was quite different. He employed radium in the same way as Hirsch in a few patients, implanted it into tumors without excision in others, and also used it for recurrences after operation. He saw no benefit and found that necrosis of bone and meningitis were frequent and distressing (40, 71). Arnold Henry of Dublin was one of the few other surgeons to use radium at this time(84), but other radioactive materials, applied locally, were used effectively later. (p. 30) PROGRESS WITH PITUITARY TUMORS (1932-60) Pituitary Basophilism Until 1932 acromegaly and gigantism were the only known syndromes of hyperpituitarism, both associated with eosinophilic tumors and attributed to excessive secretion of the growth hormone. In 1912 Cushing(18i) had described Miss M.G. (Case XLV) as suffering from a "polyglandular (or pluriglandular) syndrome" (Fig. A5). She was a Russian of 23 with painful obesity, hypertrichosis, amenorrhea, hydrocephalus, and increased intracranial tension. The pituitary fossa was normal, but Cushing was uncertain

The Pituitary (P) • 101 whether the causative lesion was in the pituitary, the adrenals, the pineal, or the ovaries. He found reports of six similar patients, all of whom had had adrenocortical tumors or hyperplasia, and he suggested that they might exhibit a hitherto unrecognized syndrome of hyperadrenalism. (p.3i) Basophil adenomas were known, but regarded as insignificant (71). However, in 1932 Cushing proposed that they did have important clinical manifestations. In a classic paper(85) he referred again to Miss M.G. and described eleven other patients, six female and five male, and later that year added four more(86, 87). Miss M.G. had undergone subtemporal decompression, with relief of headache, and adrenal exploration had been considered, but not undertaken. She was still in reasonable health twentynine years after the onset of amenorrhea. Ten of the sixteen patients were examined post mortem, and small basophil adenomas were found in six. Some had adrenal hyperplasia, and one had a small adrenal nodule, but none had a large tumor. Cushing postulated that this clinical syndrome might be due to a basophil adenoma of the pituitary with secondary hyperplasia of the adrenal cortex, and named the condition "pituitary basophilism." This was a bold hypothesis to make when the function of the basophils was unknown and only one third of the patients were known to have basophil tumors. However, the name was adopted and the condition came to be known also as "Cushing's disease." (p.32) Widespread Adoption of Transcranial Operations By the mid-1930s, half a century after Marie's description of acromegaly, pituitary surgery was well established, but still had far to go. The transfrontal operation, begun in Europe, had been developed mainly in the United States and was now used worldwide—by Clovis Vincent in Paris (88), Geoffrey Jefferson in Manchester (89), Hugh Trumble in Melbourne (90), and many others (91). Most neurosurgeons abandoned the transsphenoidal operation (92); some began to operate mainly for endocrinological reasons (63, 93, 94); some preferred general, and others local, anesthesia (64). (P.33) Three scalp incisions, usually on the right (Fig. P.2) and involving small osteoplastic flaps, were in common use (64, 92). Tumors were evacuated, but the intrasellar parts of the capsules were not removed because of the danger and the risk of removing all the normal gland (92, 95). Tumors that extended outside the sella presented special dangers (40, 90, 91, 96), and Jefferson(89, 97) distinguished between (a) the majority, which were benign tumors spreading widely, but without invasion, (b) the malignant or locally invasive "adenomas" (carcinomas), and (c) the exceptionally rare metastasizing carcinomas (71). The operative mortality for intrasellar tumors in general was now about 2 to 5 percent, while that for extrasellar lesions was nearer 33 percent, and Jefferson warned surgeons against accepting such great operative risks too readily. (p.34)

102 • History of Endocrine Surgery Surgical treatment of craniopharyngiomas was unsatisfactory (98). The operative mortality from radical operations was high(99, 100, 101), and for this reason some surgeons simply evacuated cysts, with or without removing parts of their walls, and sometimes used radiotherapy also. The mortality from these limited procedures was low (102), and some patients obtained relief for years. Total removal, although attempted at this time, especially by Edgar Kahn of Ann Arbor, Michigan, was associated with a high mortality, which he attributed to hypothalamic injury (98, 101). This problem was soon to be overcome (p. P.45 & P.128-32)). (p.35) DI, which had hardly been mentioned since 1912(18g), was encountered in Herbert Olivecrona's series in Stockholm at three different periods (91): (1) on presentation, probably due to pressure on the hypothalamus, and usually relieved by operation; (2) temporarily after operation and controlled by posterior lobe extract; and (3) at a later stage, usually signifying recurrence of tumor. By 1961 DI was reported in some 33 percent of patients who had undergone operations for sellar or adjacent lesions(103). (p.36) In 1950 Francis Grant of Philadelphia expressed most surgeons' feelings when he wrote that "the removal of a tumor adjacent to the sella without injury to optic nerves, carotid branches or hypothalamus, leaving a patient without his tumor, but more important, without severe neurologic deficit, requires surgical deftness and courage plus a large slice of luck" (82). (p.37 Advances in Radiotherapy By 1957,250-kV machines were generally available, while those producing conventional rays of much greater energy and proton emitters were in use in some centers. Tumor dosage was increased, and .Gilbert Horrax of Boston found that 4,000 r in four weeks was optimal(104). At Ann Arbor the proportions of patients who responded satisfactorily rose from less than half with 2,000 r to nearly 80 percent with 4,000 r(105). At the Lahey Clinic, Boston, Horrax found that the proportion of patients receiving radiotherapy as initial treatment who subsequently required operation fell from 60 percent to 12 percent(104). Nevertheless, many surgeons continued to plead that operation should not be postponed when vision failed to improve. Postoperative radiotherapy was still usually employed. The results of radiotherapy alone for craniopharyngiomas were very poor, but Frazier was impressed by its capacity to prevent the reaccumulation of fluid after aspiration of cysts (106). (p.38) Preservation of Transsphenoidal Operations Transsphenoidal operations were still used in several neurosurgical clinics, especially in Europe. Norman Dott (Fig. P. 12) of Edinburgh wrote in 1936 that they had "fallen into rather undeserved neglect" (74), and

The Pituitary (P) • 103 Cushing, in 1939, thought that they would probably return(107). Dott continued to develop the operation (Fig. P.3), combining it with radiotherapy and, like Hirsch, with radium implants. By 1956, when he was visited by Gerard Guiot (Fig. P. 13) from Paris, he had done eighty consecutive operations without a death(66). Guiot, who had used the transcranial route previously, adopted Dott's method the next year, but introduced radiological control with an image intensifier during the operation, and soon reported good results (108,109). Jules Hardy from Montreal learned the transsphenoidal operation while working with Guiot in Paris, introduced it to Canada in 1962(110), and made many important contributions. During operations for tumors he used radiofluoroscopy (which he attributed to Guiot) at first (111) and televised fluoroscopy with spinal pneumoencephalography (which was replacing ventriculography) later (112). He operated transsphenoidally to remove normal glands and tumors that remained within the sella, had expanded into the sphenoid, or that had slight or moderate suprasellar extensions. He employed a transcranial approach for tumors with large suprasellar extensions, and either route for those that had expanded the sellae and spread superiorly. He aspirated craniopharyngiomas, but did not attempt their radical removal transsphenoidally. In 1965 he reported hypophysectomy in twenty patients with tumors and in forty with normal glands (112). (p.39) Hirsch used his endonasal procedure for more than fifty years, often combining it with radium, and by the outbreak of World War II he had operated on nearly 400 patients (113). Hirsch moved from Vienna to Boston in 1938 and co-operated with Hannibal Hamlin in New England. He reported "life-long cures and improvements after transsphenoidal operation" in thirty-three patients followed for at least twenty years in 1959 (52), and Hamlin described a combined series of 110 patients with two operative deaths in 1962(114). The endonasal approach was then used little, if at all, by others. (p.40) In Zurich Nager employed Chiari's operation and, in 1940, reported a series of forty-three operations with one death (46). This procedure was used by others in Switzerland and Austria for the removal of pituitary tumors (115) and was employed later for removal of the normal pituitary (p. P.70). In 1955 Carl-Axel Hamberger of Stockholm and Goteborg, Sweden, devised a transantrosphenoidal approach, with a gingival incision(116,117), which he employed in over eighty patients with pituitary tumors (118) and which was adopted and modified in the United States (119, 120). The transethmoidal and transantral operations provided direct access to the sella, albeit from one side, and were used for all types of pituitary tumor. The advocates of the transseptal approach found that keeping to the midline facilitated identification of the pituitary, and therefore preferred it(121), despite the long, narrow, tunnel-like route to the gland. All agreed that gross nasal sepsis precluded operation. Some still regarded the conchal type

104 • History of Endocrine Surgery of sphenoid as a contraindication (122), but others had overcome the difficulties in various ways (123). Other major advances in transsphenoidal surgery were under way in the late 1950s, but were not published or adopted widely until the next decade. (p.4i) GENERAL DEVELOPMENTS (1935-65) The surgical advances of the war (p. E.32), including developments in anesthesia and blood transfusion, made pituitary operations simpler and safer (64, 103, 124). Infection, which had bedevilled transsphenoidal operations from the outset, had been affected little by the sulphonamides in the 1940s, but was reduced greatly by antibiotics. They were life-saving when meningitis developed after hypophysectomy, and were soon used prophylactically. Hirsch found that they reduced his operative mortality from 6 to 1.5 percent and that transsphenoidal operations became safer than transcranial procedures (51). (p.42) Supportive measures, found to be valuable during operations, included drainage of cerebrospinal fluid, systemic hypothermia and hypotension (125), the intravenous administration of urea or mannitol, hyperventilation, and a positive-negative phased ventilatory cycle(103). (p.43) Hypopituitarism and apituitarism were clarified by Harold Sheehan of Glasgow, Scotland, who identified necrosis of the anterior lobe, usually as a result of postpartum hemorrhage, as the commonest cause (Sheehan's syndrome) (126). Many other lesions had the same effects when at least three-quarters of the gland was destroyed (127). (p.44) Cortisone Cortisone was first used therapeutically in 1949 with immediate and dramatic effects (p. E.34, A.42). The lives of patients with hypo- and apituitarism were transformed by its administration, especially when combined with thyroid extract (128). The use of cortisone and ACTH rendered operations for pituitary tumors much safer than formerly and made total hypophysectomy feasible(129). Kahn, who had previously reported a high operative mortality after attempted total removal of craniopharyngiomas, now (in 1955) found that all who received cortisone recovered uneventfully (101). At the Mayo Clinic the hospital mortality after operations on or near the pituitary fell from 17 to 6 percent after the introduction of cortisone (130). Despite these observations, surgeons were reluctant to operate early for pituitary tumors or to undertake radical operations (116). (p.45) Normal Structure and Function By 1960 four varieties of chromophil cells and their probable secretions had been recognized (131a):

The Pituitary (P) Anterior Pituitary Cells

• 105

Possible Hormone Secretion

Chromophil Acidophil (Eosinophil)

a

Basophil

/3 y d

Chromophobe

Growth hormone (GH) ? Prolactin Corticotrophin (ACTH) Thyroid-stimulating hormone (TSH) ? active forms of f3 and d Gonadotrophins (FSH & LH) Resting phase

Some of the chromophobes were regarded as chromophil cells in a resting phase. The hypothalamus controlled the function of the anterior pituitary by means of neurohumors carried in the hypophyseal portal system, and was itself under the influence of higher centers. The homones of the target glands regulated, by feedback mechanisms, the secretions of both the hypothalamus and the pituitary. (p.46) The six main humoral agents were now designated hormones, although the structure of only one, corticotrophin (ACTH) was known (see table above). The gonadotrophins were named follicle-stimulating (FSH) and luteinizing hormones (LH), respectively, and were identical in the two sexes. Human chorionic gonadotrophin (HCG) was used for treating cryptorchidism. ACTH, a polypeptide, controlled the secretion of the adrenal steroids, other than aldosterone, and cortisone (or cortisol) operated its feedback. It had some melanocyte-stimulating activity. ACTH, which was made available clinically at about the same time as cortisone, was used by intramuscular injection for testing pituitary and adrenal function, and was also used to treat pituitary and adrenal insufficiency before hydrocortisone was prepared for intravenous use (p. A.55). Other possible hormones included hemopoietin and exophthalmos-producing substance (EPS), which was found in some patients with exophthalmic goiter (p. T.125). A small intermediate lobe of the pituitary was thought to secrete melanocytestimulating hormone (MSH), responsible for pigmentation in Addison's disease. Its secretion, like that of ACTH, was controlled by the concentration of cortisol. (p.47) The neurohypophysis secreted two active peptides. Vasopressin (antidiuretic hormone, ADH) regulated the reabsorption of water from the distal renal tubules, and its partial or complete absence in the presence of cortisol and thyroid hormones was found to cause DI. The development of DI in pituitary and hypothalamic disease, and after surgical hypophysectomy (91, 132), depended on two factors: (1) the relative degrees of destruction or removal of the neurohypophysis and the anterior lobe, and (2) the substitution therapy provided. It was readily controlled by ADH, injected or given as snuff. Oxytocin, the other neurohypophyseal secretion, was responsible for uterine contractions and for the ejection of milk. (p.48)

106 • History of Endocrine Surgery Diagnosis of Pituitary Disease Previously the diagnosis of pituitary tumors had been made mainly on clinical and radiological grounds, including measurement of the visual fields. In the 1950s urinary gonadotrophins (FSH and LH) were measured routinely by bioassay, and were low in hypopituitarism and high in patients with primary gonadal deficiency. Bioassays for other hormones and a radioimmunoassay (RIA) for GH were used for research. The functions of the target glands provided indirect evidence of pituitary activity. In hypopituitarism the secretions of the thyroid, adrenal cortex, and gonads were reduced (133), and in pituitary basophilism adrenal function was often increased. (p.49) By 1960 radiographic measurements of the sella aided the recognition of minor degrees of enlargement (134), and tomography, first used in the 1930s in Europe, was being employed(117, 135). Spinal pneumoencephalography, instead of ventriculography, was employed to delineate pituitary tumors(lll, 136), and cerebral angiography was now used confidently both to exclude aneurysms and to delineate the configuration of vessels adjacent to the sella(112,136). Electroencephalography (98) also came into frequent use (112). (p.50) ABLATION OF THE NORMAL PITUITARY The idea that removal or destruction of the pituitary might benefit patients with general disease was current long before cortisone made it practicable. In 1934, four years after Houssay's observation, Pierre Puech in Paris undertook transcranial hypophysectomy in a diabetic (137). The patient improved temporarily, but died five months later. The next year W.P. van Wagenen in Rochester, New York, on tenuous grounds, used electrocoagulation to destroy the pituitary in an epileptic. The patient did not improve, but developed severe hypopituitarism and died seven years later. About 10 percent of the pituitary was found at autopsy (138, 139, 140). Hypophysectomy was also performed for prostatic cancer in 1948 (p. C.8). (P.51) In the 1950s and 1960s, many surgeons and others devised methods of ablating the gland by old and new techniques. The experience that they gained from treating many patients with common diseases helped them to manage those with the comparatively rare pituitary tumors. The first known hypophysectomy for cancer in man (a metastatic melanoma) after the advent of cortisone was performed by Edwin Boldrey of San Francisco (following unsuccessful attempts by Howard Naffziger) on January 25, 1951. The patient received cortisone for only six days after operation, then developed hypopituitarism and died after two months without any effect on the tumor. A small nest of pituitary cells was found post mortem (141, 142a). On November 29 that year Jacques le Beau in Paris undertook the same operation in a woman with advanced breast cancer (p. C.8). (p.52)

The Pituitary (P) • 107 The use of cortisone during operation, and for replacement afterwards, had an explosive effect. Olivecrona undertook a series of pituitary ablations in twenty-three patients with normal glands, first with electrocoagulation and then with surgical hypophysectomy, and reported them with Rolf Luft in 1952 (p. C.8) (143,144). They concluded that advanced carcinoma of the breast and possibly of the prostrate, and also chorionepithelioma, offered a "promising field for hypophysectomy," but that malignant hypertension and diabetes were not suitable for operation. It was soon found that the best results were indeed achieved in mammary and prostatic cancer and that hypophysectomy was of no value in hypertension (unless caused by a pituitary tumor). However, severe diabetics did often derive benefit, but patients with other forms of cancer were helped little, if at all. Malignant exophthalmos was also treated by pituitary ablation with some benefit (p. T.125). Larger series of hypophysectomies soon followed. (p.53). Complete ablation was regarded as essential for an optimal result. The objectives(131b) were to eliminate gonadotrophins, ACTH, prolactin and GH for cancer, GH for diabetes, and possibly EPS for malignant exophthalmos. Replacement of adrenal and thyroid hormones (and vasopressin) maintained health without conflicting with these aims. Pituitary deficiency did not appear until most of the anterior lobe was destroyed (127, 145), but it was not possible to distinguish between subtotal and total destruction during life (124,145,146,147). In some series the pituitary fossa and target glands were examined at autopsy (148, 149). (p.54) Procedures for the removal of normal pituitaries differed from those for tumors because the glands are confined within normal fossae and are less accessible, and the operations were designed to remove the glands totally. At first most operations were performed transcranially, usually through a small frontal flap, and various maneuvers were employed to provide access(124, 125, 144, 150). The pituitary stalk was divided, the gland removed, and the sella curetted. Gelatine sponge was sometimes needed for hemostasis. (p.55) Extracranial hypophysectomy was employed very little at this time for removal of the normal pituitary, but Franz Escher of Berne (151) used the transethmosphenoidal and Hamberger the transantrosphenoidal approaches (117). (P.56) Complete surgical removal of the pituitary proved very difficult. It was assumed that tissue left behind would regenerate, and surgeons tried to destroy everything within the fossa by swabbing with a corrosive (124, 125, 144), or by introducing radioactive gold (Au-198)(124) or yttrium (Y-90)(152, 153). Some found that a transcranial, transsphenoidal approach facilitated removal of the whole gland, intact(154). After death many sellae contained up to 10 percent of normal pituitary tissue (124), sometimes with new vascular connections to the hypothalamus (149). Anatomical factors also rendered total hypophysectomy difficult. A variable amount of glandular tissue extends up the pituitary stalk, and high section,

108 • History of Endocrine Surgery especially if combined with diathermy or clipping, increases the risk of DI. Consequently most surgeons divided the stalk low with a clean cut(124, 125), thus leaving glandular tissue behind in some patients. Finally, the pharyngeal pituitary, whose cells normally appear quiescent, shows activity after sellar hypophysectomy (48) (p.57) Replacement therapy included cortisone, the maintenance dose being about 50 mg daily, but mineralocorticoid was not required. Thyroid extract was given after a few weeks, sometimes being withheld until hypothyroidism appeared. ADH was administered when necessary. (p.58) The operative mortality was influenced by the serious illness of most of the patients. In those with breast cancer about 6 percent died from transcranial operations and the same number from their disease within one or two months(124, 125). Most patients with diabetic retinopathy and malignant hypertension died from operation (144). A few patients required early reoperation for bleeding or hematoma. Other complications were damage to the optic tract (in 10-20 percent) with some loss of vision(124, 125), anosmia, and transient hemiparesis or convulsions. DI varied in its incidence, time of onset, severity, and duration, and was readily controlled, (p.59) Alternatives to Hypophysectomy Many alternatives to surgical hypophysectomy were introduced to provide simpler and safer methods of ablating the normal gland and of treating tumors. (p.60) Electrocoagulation and Ultrasound Electrocoagulation of tumors with a needle, introduced transethmoidally and controlled with an image intensifier, was employed by Karl Bauer of Heidelberg, with good results in three-quarters of his patients, between 1948 and 1957(155). He also treated patients with normal glands for advanced breast cancer, without mortality, but later changed to implanting Au-198(155, 156). Olivecrona treated two patients with Cushing's syndrome by electrocoagulation at craniotomy(144), while Jean Talairach and Pierre Tournoux of Paris described a stereotactic instrument for coagulation and for implanting gold (157). Nicholas Zervas of Boston improved on their method, and in 1979 reported good results in over 600 patients with general diseases (158). (p.6i) Ablation of the pituitary with ultrasound, applied at open operation by the transethmoidal route, was reported in 1965 by M. Arslan of Padua in five patients with cancer and one with Cushing's syndrome (159). (p.62) Pituitary Stalk Section Division of the stalk in animals reduces pituitary function and causes incomplete necrosis, but does not reduce the secretion of prolactin(160).

The Pituitary (P) • 109 Operations in man, in which the stalk had been divided at a high level during hypophysectomy for tumor, caused DI without interfering with anterior lobe function, while low section was almost equivalent to total hypophysectomy (161). Small series of operations for breast cancer were undertaken in the late 1950s by Valentine Logue in London (162) and le Beau in Paris(149). The results were poor, but the method was used again later, particularly for the treatment of diabetic retinopathy. (p.63) Pituitary Irradiation Attempts were made to ablate the normal pituitary by external irradiation with x-rays and y-rays(163, 164, 165), but this proved impossible without causing damage to other structures. However, in the mid-1950s at Berkeley, California, John Lawrence and Cornelius Tobias used proton therapy, whose properties seemed particularly suitable for external irradiation of the pituitary. Doses of 20,000 r or more were needed to destroy the pituitary, and these were effective in one-third of patients with breast cancer (166). A few developed DI or extraocular nerve palsies, but none suffered loss of vision or brain damage. Proton therapy was used for many years at Berkeley and later in Boston for destruction of the normal gland and for the treatment of tumors. (p.64) This form of therapy was not available elsewhere, and attention turned to the use of internal irradiation. Radon, a y-ray emitter with a short half-life (3.8 d), which could be inserted into the pituitary and left there, had been introduced transcranially(167, 168) and transethmoidally(169), with relief of pituitary disease, since 1934 (p. P.107). Radium was not used for destruction of the normal gland, but in 1955 Patrick Forrest of Glasgow, Scotland, inserted radon seeds transnasally under x-ray control in many patients with advanced breast cancer (124, 170). Gamma rays are highly penetrating, and it was difficult to place the seeds accurately. For these reasons, although many patients derived clinical benefit, several suffered severe DI and loss of vision, and pituitary tissue was not destroyed completely. Others reported similar results (171). Radioactive gold (Au-198; half-life 2.7 d), which emits less penetrating /3 particles (electrons) in addition to y-rays, was used at about the same time as radon by transsphenoidal needle implantation, but the clinical results and the extent of pituitary destruction were little better(124, 155, 157, 172). It was, however, used effectively later for pituitary tumors (p. P. 108). Others tried pure beta-ray emitters, hoping that they would destroy the gland without causing damage. Radioactive phosphorus (P-32; half-life 14 d) in liquid form(173) and yttrium (Y-90; half-life 64 h) in pellets(174, 175) were introduced transcranially, but did not live up to expectations(160,162, 176). At about the same time (1955), however, John Fergusson of London used yttrium rods transnasally for patients with prostatic and mammary cancer (177). Some patients had temporary rhinorrhea, but none developed meningitis. Visual disturbances were less common than

110 • History of Endocrine Surgery with the other isotopes. Clinical results were satisfactory, but the glands were not destroyed completely. In 1956 Forrest turned to transnasal yttrium(124) and, after much trial and error and many complications, devised and perfected a method of fixing two rods in the fossa with screws placed in its anterior bony wall. Finally he found a dose that regularly achieved uncomplicated destruction of the pituitary, comparable in extent to that following combined surgical and radiotherapeutic techniques, and with minimal complications (178). Many other workers employed yttrium transsphenoidally (160, 179), but only Russell Fraser and Graham Joplin at Hammersmith, London, achieved comparable results (180). Later they used similar methods for treating pituitary tumors very effectively (p. P. 108). Another isotope was employed later by Paul Harper in Chicago, who inserted needles containing strontium (Sr-90, a fi emitter; half-life twentyeight years), together with yttrium, for ninety minutes in each side(181), with similar results to those obtained by other methods. (p.65) Despite great inventiveness and devotion, no surgical or other method had been found that regularly caused complete destruction of the pituitary. Although the clinical results were often worthwhile, there was evidence that they depended partly on the degree of ablation (124,153) and that, in cancer at least, they were also related to the hormonal dependence of the disease (p. C.l).

(P.69)

Microsurgery of the Pituitary (1958-68) Microsurgery (Fig. P.3) was the next important development (181 A). The operating microscope had long been used in aural surgery, and ENT surgeons in Europe first employed it for pituitary operations. All used Chiari's transethmosphenoidal route, initially for removal of the normal gland, and only later for pituitary tumors. Lennart Gisselsson of Orebro, Sweden, started in 1957 or 1958 and performed about twenty operations before his early death (182, 183a). Niels Riskaer (Fig. P. 14) of Copenhagen, who saw him working, used the method in about fifty patients with breast cancer between June 1958 and December 1959(115). The microscope enabled him to see the whole gland and fossa clearly, and to confirm that no gross fragments of tissue remained. In May 1959 Riskaer demonstrated the procedure to visiting ENT surgeons from Britain and, using an image intensifier, displayed the operation on a television screen (183a). Among those present were Geoffrey Bateman of London and John Angell James (Fig. P. 15) of Bristol. Bateman adopted the method, with modifications, in July(122, 184). He viewed the operation transethmoidally, but removed the pituitary by the transseptal route. By November 1962 he had operated on seventy patients with normal glands and ten with pituitary disease. Next, in November 1959, Ronald MacBeth of Oxford used a supranasal approach for the microscope, and passed the instruments through the nose. By 1962 he had

The Pituitary (P) • 111 removed about forty pituitaries, including one containing a tumor(185). After careful preparations James then operated in March 1960(118, 186), employing the same two routes as Bateman and resecting the nasal septum when it hindered access. By 1968 he had treated nearly 400 patients (187). (P-70) The four published series of Riskaer, Bateman, MacBeth, and James included 560 patients. Over 80 percent had cancer, mostly of the breast, 8 percent diabetic retinopathy, and 4 percent pituitary disease. General anesthesia with intubation was used, sometimes supplemented with local anesthesia, and all surgeons employed the Zeiss free-standing operating microscope. They used a dental burr for penetrating the sphenoid and found it very effective in the conchal type (p. P. 10). Rhinorrhea, often accompanied by meningitis (despite prophylactic antibiotics), was a serious problem at first. James' solution was to close the track through the sella with a sandwich of fascia and muscle, which reduced the proportion of patients on whom he reoperated for CSF leakage from 17 to 1 percent. Steroid cover was provided for the operations, and thyroid hormone was usually given later. However, although the fossa generally appeared empty through the microscope, total removal of normal glands was unusual. In 1965 James described selective anterior hypophysectomy for diabetic retinopathy(118, 186). The operative mortality in the four series was 4 percent, while another 3 percent of patients succumbed to their diseases within a month. One percent died later from hypoadrenalism due to inadequate cortisone replacement. Direct comparison with the transcranial hypophysectomies, performed ten years earlier, is not possible, but the extracranial operations appear to have been rather safer for patients with advanced cancer. Ocular complications and anosmia were very rare, but DI was much the same as after craniotomy. (p 71) Microsurgical hypophysectomy was next undertaken independently in Montreal by Hardy (Fig. P. 16), a neurosurgeon, who employed the oronasal midline route (Fig. P. 17) together with the ancillary measures that he was using already (p. P.39)(121, 179, 188, 189). He operated first on a normal gland on October 13, 1965 (190a), and was soon able to perform extracapsular surgical ablation for breast cancer and selective anterior hypophysectomy for diabetic retinopathy. Some of the earlier patients suffered rhinorrhea, but none died or developed serious complications. He solved the problem of CSF leakage by wedging a cartilaginous graft from the excised nasal septum into the sella, to hold the muscle pack in place. In 1968(121) he reported his experience of 200 operations under televised fluoroscopy, 150 of them with the microscope. Most were undertaken for general disease, but some, as in the other series, were for pituitary tumors. (p.72) All these microsurgical operations were at least as effective in the treatment of general disease as other procedures used for ablation. (p.73)

112 • History of Endocrine Surgery SURGICAL TREATMENT OF PITUITARY TUMORS IN THE 1950s AND 1960s All the methods that were developed to ablate the normal pituitary after the advent of cortisone and antibiotics were soon used to treat pituitary tumors. As a result of their experience surgeons started to operate earlier than before, and their results improved. (p.74) Transcranial Hypophysectomy Bronson Ray's work in New York in the 1950s was outstanding (136,191). In the 1950s he ablated many normal glands (p. C.8) and concurrently operated on eighty pituitary tumors without mortality. Antibiotics and substitution therapy helped. In particular, penicillin allowed the frontal sinus to be breached without danger, and cortisone prevented the "slow recovery from operation, chronic invalidism and sometimes death," now seen to be due to hypoadrenalism, which some patients had suffered in the past. Tumors were removed as completely as possible and, except in patients with functioning lesions (about 20 percent), all recognizable normal tissue was preserved. Those tumors (about 10 percent) that extended well outside the fossa were dissected from the optic nerves and chiasm. About half the patients were irradiated afterwards. Only four (5 percent) died within three years of operation, none of them from pituitary disease, (p.75) The average operative mortality for transcranial hypophysectomy worldwide fell from 12 percent in the 1950s to 5 percent in the 1960s, most of the later deaths being associated with very large tumors (192). Not all surgeons treated tumors radically, and many continued to perform simple decompression. Eugene Stern of Los Angeles, however, found that the operative mortality and recurrence rates were lowest in patients whose tumors had been removed most radically, and recommended subtotal or total removal, as each case permitted(192). This policy was gradually adopted everywhere. In the early 1960s some neurosurgeons extended the use of microscopy to transcranial hypophysectomy and found that it facilitated the dissection of extrasellar tumors(193, 194, 195, 196, 197). (p.76) Transsphenoidal Microsurgery Transsphenoidal microsurgery was, however, advancing fast. The European series had included over twenty patients with pituitary disease, including acromegaly, Cushing's syndrome, and chromophobe tumors. In 1965 James found that tumors could be decompressed and partially removed, and reported selective removal of an anterior lobe adenoma with preservation of normal tissue(118, 186). Some patients obtained complete remission from these procedures. Hardy operated on tumors causing visual impairment and on those that extended into the sphenoid bone, but used

The Pituitary (P) • 113 radiotherapy initially for purely intrasellar lesions and often for those with uncomplicated suprasellar extensions. Pneumoencepholography and televised fluoroscopy provided excellent views of the tumors during their removal, and allowed many of those that extended upwards to be removed transsphenoidally. The suprasellar structures could be seen returning to their normal positions. Selective adenomectomy, with preservation of normal pituitary function, was often possible(121, 189). A false capsule of compressed normal tissue (p. P.96) could be seen with the operating microscope (but not with the naked eye) and did not need to be removed, provided it was free from tumor cells after curettage. Occasionally small intrasellar craniopharyngiomas and other rare nonpituitary tumors were removed by this route. Hardy made little use of radiotherapy after operation except to treat recurrent tumors. (p.77) Microadenomectomy The idea that very small pituitary tumors could cause major endocrine disease was not accepted readily. It started in 1927, when Cushing found a small adenoma at autopsy in an acromegalic patient whose fossa was of normal size (198). It was reinforced in 1932 by the fact that all but one of the eight adenomas in his patients with pituitary basophilism were less than 1 cm in diameter (85, 87). The door seemed to shut on the idea in 1936, when Russell Costello of the Mayo Clinic found, at autopsy, that nearly onequarter (22.5 percent) of people without clinical features of pituitary disease had small adenomas, including eosinophil and basophil lesions(199). (P.78) By 1969, however, Hardy found many small pituitary tumors at operation and used the term "microadenoma" to describe those of 1-8 mm in diameter (later defined as less than 10 mm in diameter) (200) within macroscopically normal pituitaries(121). Some of these were silent, but others caused syndromes associated with hypersecretion of hormones. (p.79) Cushing (in 1927) had the idea of "taking the next obvious step" of attacking the adenoma of acromegaly while the sella was still small, but he did not put it into practice (201). By 1968, however, Hardy had the confidence to do so and, on March 28, operated on an acromegalic patient whose fossa was normal on straight x-rays and standard tomograms. He found and removed a small adenoma, with marked clinical and biochemical improvement (190a), and soon reported similar results in eight other patients, one of them with Cushing's syndrome(121) (PSO) PARALLEL DEVELOPMENTS (1960-80) Normal Structure and Function Electronmicroscopy and immunofluorescence now revealed five distinct types of cell, each with a specific secretion(202, 203):

114 • History of Endocrine Surgery 1. somatotroph (ST): growth hormone (GH, somatotrophin); 2. lactotroph (LT): prolactin (PRL); 3. gonadotroph: follicle-stimulating hormone (FSH) and luteinizing hormone (LH) or (in the male) interstitial cell-stimulating hormone (ICSH); 4. thyrotroph (TT): thyroid-stimulating hormone (thyrotrophin) (TSH); and 5. corticotroph (CT): (adreno)corticotrophin (ACTH). (p.si) The hypothalamic control of the anterior pituitary by releasing (R) and inhibiting (I) hormones (H) or factors (F) had become clearer (203, 204). 1. GH is controlled by releasing and release-inhibiting factors. The latter (somatostatin) is a small peptide, found also in the gut and elsewhere, with other widespread inhibitory effects, and an analogue was soon used therapeutically in endocrine diseases. G H is a peptide, which was obtained from human cadavers and used for promoting growth in hypopituitarism. It is now prepared synthetically. 2. PRL release is controlled mainly by prolactin release-inhibiting hormone (PRIH)(205), later (in 1980) identified as dopamine. PRL, a peptide, was distinguished from G H in 1970. 3. FSH and LH (ICSH) are controlled by one or two releasing hormones, which are used for testing pituitary and gonadal function. They are both glycoproteins, and the former is used for inducing ovulation in hypopituitarism. 4. TSH is released by TRH, a tripeptide, which is used for testing pituitary and thyroid function. TSH is a glycoprotein. 5. ACTH is released by corticotrophin-releasing factor (CRF), whose identity proved elusive. The intermediate lobe and melanocyte-stimulating hormone (MSH) were no longer recognized in man, pigmentation being a function of ACTH (206). (p.82) There was still evidence that the pituitary secreted EPS and hemopoietin(207a). (p.83) Advances in Diagnosis Clinical manifestations of pituitary disease were assessed more critically (208), and laboratory tests became increasingly helpful(207b, 209,210, 211). RIAs for pituitary hormones were developed for clinical use. (p.84) New radiological techniques were introduced, but plain films, followed by coned lateral views, remained the standard procedures(212). Improved tomography sometimes revealed microadenomas only 4-5mm in diameter, which were confirmed at operation(213, 214). By 1978 abnormal fossae were seen radiologically in over 90 percent of patients with microadenomas (215), nearly all the normal ones being in patients with ACTHsecreting microadenomas(190b, 216). (p.85)

The Pituitary (P) • 115 P n e u m o e n c e p h a l o g r a p h y with tomography was the best procedure for demonstrating upward expansions of tumors and empty sellae (p. P. 102) (212, 217). Carotid angiography was used to define t h e limits of tumors not revealed otherwise, if an aneurysm was suspected, or if there was evidence of cavernous sinus involvement. Venography was sometimes helpful also. (p.86) Several classifications of sellae and tumors, based on radiological findings, were devised and proved useful for planning therapeutic policies and for comparing different series (213). H a r d y (200) recognized enclosed a d e n o m a s , which remained within t h e sellar sheath, and invasive tumors, which eroded the sellar floor and might also expand upwards. By "invasive" he did not imply histological penetration of normal tissues. (p.87) Computerized tomography (CT), a noninvasive procedure developed in Britain in 1972(218), was used first to demonstrate suprasellar tumors and extrasellar extensions of pituitary adenomas(212, 219). By 1980 it had greatly improved the definition of these lesions and also the detection of microadenomas (220). (p.88) Metrizamide cisternography, developed in Scandinavia, improved the evaluation of pituitary tumors and empty sellae (p. P. 102). At first it was used to complement CT scanning (221), but later the two procedures were combined(222). By 1980 they had replaced other methods in some centers, and angiography was needed only for aneurysms. (p.89) New Secretory Tumors Many tumors that had previously been regarded as nonfunctioning were found to secrete hormones. (p.90) Prolactinomas Amenorrhea and galactorrhea were known to be associated with various clinical syndromes and sometimes to be accompanied by pituitary tumors, which were described as chromophobe (207c). The symptoms had been attributed to overproduction of prolactin by the pituitary, whether tumorous or not (223, 224), and in 1966 and 1967 high levels of circulating prolactin were first reported in two such patients in France and Belgium, respectively(225, 226). Both had pituitary tumors, in one of which lactotrophs were found, and soon many more "prolactinomas" were recognized (227, 228). Surgical removal restored prolactin levels to normal and relieved symptoms (229). Hyperprolactinemia was also found in acromegalic patients with galactorrhea and in some patients with suprasellar tumors. Prolactinomas were presumed to secrete prolactin autonomously, and suprasellar lesions (including stalk section [p. P.63]) to block the hypophyseal portal system, releasing the prolactin brake. Soon workers in

116


Switzerland found that an ergot alkaloid, later named bromocriptine, suppressed lactation (230, 231), and others in London observed that it relieved symptoms in men and women with galactorrhea and hypogonadism associated with pituitary tumors and hyperprolactinemia(232, 233). Side effects were slight and prolactin levels fell to normal. It was concluded that prolactin inhibited the gonads and that hypogonadism, due to a chromophobe pituitary tumor, did not necessarily require a large lesion to impair pituitary function. Prolactinomas were then added to the list of functioning pituitary tumors(234, 235). It was postulated also that bromocriptine, a dopamine agonist, blocked the secretion of prolactin by enhancing the effect of dopamine. The implication, confirmed later, was that dopamine was PRIH(236). (P.9D Prolactinomas soon proved to be the commonest of all pituitary tumors, accounting for 70 to 80 percent in both sexes, hypogonadism being their main feature (237). In women galactorrhea was frequent, and microadenomas were found in more than half (238). In men secretion of milk was rare, but the tumors were often large and invasive(239). Prolactin levels correlated with the sizes of the sellae (234). Microadenomas usually ran a mild course, while those that were not recognized until they were large tended to be aggressive. (p.92) Thyrotrophinomas Enlargement of the pituitary in hypothyroidism, presumably due to thyrotroph hyperplasia, has been known for many years, and "secondary" pituitary tumors, aparently nonfunctioning, may develop also(240, 241). Recently the pituitary lesions have been confirmed as thyrotrophic(242, 243), and some have been treated effectively. (p.93) Much more rarely, since the 1930s, "primary" pituitary tumors have been reported in association with thyrotoxicosis (244,245,246), and in about 1970 a syndrome of pituitary tumor (often large), high serum TSH, goiter (generally small), and hyperthyroidism (usually mild) was recognized(243, 247, 248, 249). Treatment of the tumors usually relieved the thyrotoxicosis and cured the goiter. (p.94) Gonadotrophinomas It has long been known that pituitary tumors may develop in castrated boys (250), and more recently similar lesions have been found with other forms of hypogonadism. Men with long-standing gonadal failure and pituitary tumors that secrete gonadotrophins have been observed also, some suffering from hypopituitarism (241, 251, 252). Some gonadotrophinomas were apparently primary, developing in patients with normal gonads, but without specific endocrinological features(252). The tumors were large, but most were treated effectively. (p.95)

The Pituitary (P)

• 117

Pathology of Pituitary Tumors Microadenomas, which were endocrinologically active, were recognized generally within a few years. Hardy pointed out that larger pituitary tumors did not have true capsules(121). At first the neoplastic cells lay adjacent to those of the normal gland, but as the lesion enlarged it compressed them, reached the sellar sheath, and expanded it, forming the false capsule seen at operation. Philip Wrightson of Auckland, New Zealand, found that more than half the tumors excised at operation, including microadenomas, had invaded the dura mater histologically, sometimes extending into the bone and cavernous sinuses also (253). (p.96) Hardy recognized that each type of adenoma occupied a characteristic site in the pituitary(200). GH-secreting tumors were usually in the anterior, inferior part of the lateral wing, prolactinomas in a lateral wing also, but deeper or further back, and corticotrophinomas in the central core of the gland. With this knowledge the surgeon could find most tumors readily at operation. (p.97) Dott and Bailey's account of pituitary tumors, published in 1925(71), together with Cushing's description of basophilism(85, 86) and review of craniopharyngiomas(27b) in 1932, remained the standard works for many years. In the 1970s electronmicroscopy and immunocytochemistry increased knowledge of histopathology rapidly, as they had done for the normal pituitary. Many chromophobe adenomas were found to consist of secretory cells that were either in an inactive state, or secreting GH or ACTH so actively that they failed to retain granules (254). (p.98) The nomenclature of pituitary tumors was revised by Alex Landolt of Zurich in 1975(255) and by Kalman Kovacs and Eva Horvath in Toronto two years later. This pair proposed an important new classification of anterior lobe tumors based on 225 removed surgically(256, 257). They described eight types: 1. Growth hormone cell adenoma (21 percent) with acromegaly or gigantism; 2. Prolactin cell adenoma (32 percent) with galactorrhea, and hypogonadism; 3. Mixed growth hormone!prolactin cell adenoma (6 percent) with acromegaly and sometimes with amenorrhea and galactorrhea; 4. Acidophil stem cell adenoma (3.5 percent), apparently nonfunctioning clinically; 5. Corticotroph cell adenoma (13 percent) with Cushing's disease or Nelson's syn drome, or without obvious clinical features; 6. Thyrotroph cell adenoma (0.5 percent); 7. Gonadotroph cell adenoma (1 percent); and 8. Undifferentiated cell adenoma (23 percent) with hypopituitarism. One-third of this group were described as "oncocytomas," and two-thirds were later named "null cell adenomas" (258). (p.99)

118 • History of Endocrine Surgery A n o t h e r group of "unclassified" tumors (2 percent) produced two or more hormones, in all possible combinations, and endorphin. Pituitary carcinomas metastasized, but were not otherwise recognizable histologically(241). (p.ioo) Neurohypophyseal tumors. Two main types of the rare posterior lobe tumors were recognized: (1) infundibular or glial cell tumors (pituicytomas), which are highly malignant; and (2) granular cell myoblastomas (choristomas), which run a benign course and may cause hypopituitarism (259). (P.101) An "empty" sella, often enlarged, had been recognized at autopsy for many years (127), and x-rays sometimes drew attention to it in life from the late 1960s (217). It was either primary, due to a defect in the diaphragm, or secondary, resulting from pituitary damage or disease, and did not itself cause symptoms. (p.102) ALTERNATIVE TUMOR THERAPY Conventional Radiation Therapy By the early 1970s the effects of high energy radiotherapy on pituitary tumors were known(260, 261, 262), and many physicians, especially those without access to other facilities, used it initially for all their patients. T h e response was slow, but radiotherapists reported good and lasting results in over 80 percent of patients with acromegaly and with chromophobe tumors, and advised operation when radiotherapy failed. Few patients with Cushing's syndrome had been treated by radiotherapy, but some excellent results had been reported (p. A.59). Radiotherapists and most surgeons advised irradiation postoperatively in all patients with tumors treated surgically and, as in Cushing's large series (p. P.29), it reduced greatly the recurrence rate(65, 260). Some surgeons, however, only used radiotherapy for recurrent tumors (121, 263). (P.KB) Heavy Particle Irradiation After using proton therapy for destruction of the normal pituitary (p. P.64), Lawrence and Tobias changed to higher energy alpha particles in 1957 and soon began to treat pituitary tumors(210, 264, 265). In 1963 Raymond Kjellberg and Bernard Kliman also started to use proton therapy in Boston, treating tumors mainly(195, 263). In addition Kjellberg practiced transsphenoidal and transcranial microsurgical operations, when appropriate. (p.104) Experience in the two centers was similar. By 1973 over 500 tumors of all types had been irradiated, and by 1979, over 1,200. Patients with extrasellar spread, and those who had received radiotherapy previously, were

The Pituitary (P) • 119 especially liable to suffer damage to normal tissues and were therefore excluded. In Boston 86 percent of all patients received proton therapy, 11 percent underwent transsphenoidal hypophysectomy, and 2 percent had transfrontal operations. (p.ios) No patient died as a result of treatment. In Boston hypopituitarism was total in about 10 percent of patients, partial in 2 or 3 percent, and least common in those with microadenomas. DI was rare. The long-term results of heavy particle therapy were very satisfactory, and the beneficial effects were better and faster than those of conventional radiotherapy. Patients with microadenomas responded most rapidly. The outcome improved with advances in technique and with better selection of patients. By 1980 excellent results were seen in some 90 percent of all patients with secreting tumors, except for those with Nelson's syndrome (p. A.68)(265). The annual recurrence rate for adenomas of all types treated by protons was estimated to be 0.15 percent, which was better than that after any other form of treatment. Recurrences were treated surgically. In the 1980s the Berkeley program was discontinued because of the growing availability and success of pituitary microsurgery (142b), but the Boston work continued (266) (p.106) Internal Irradiation Radium applied locally for the treatment of pituitary tumors had been used effectively by Hirsch and by Dott (p. P.30, P.39), but had not found general favor. Radon had been introduced transethmoidally at open operation for the treatment of acromegaly in 1934 by William Lodge in Halifax, England, with general and visual improvement(169). Alfred Pattison in Newcastle-upon-Tyne treated two patients with pituitary basophilism by insertion of radon at craniotomy in 1934 and 1935, again with good results (167), and Hugh Cairns treated another patient in London in 1936(168). In the 1940s Douglas Northfield, also of London, used the same procedure in patients with Cushing's syndrome and acromegaly with some benefit.

(p.107)

Surgeons and physicians who were using gold and yttrium to ablate the normal pituitary (p. P.65) began to employ them for the treatment of pituitary tumors. Forrest in Glasgow and Cardiff, from 1956, and Fraser and Joplin in London, from 1959, used them singly or in combination in patients with acromegaly and Cushing's disease(267, 268, 269). They hoped to destroy the tumors without complications and to restore normal function. The Hammersmith group, who used the transethmoidal or transnasal route, published their results in several large series of patients with all types of adenoma. By 1979(270) they found that, although a few patients required second implants, the results were "competitive with most surgical series." Vision was improved in about 70 percent of the eyes with field defects, (P.IOS)

120 • History of Endocrine Surgery Between 1956 and 1972 Helmuth Penzholz in Heidelberg, following Bauer, treated tumors by the implantation of gold, but lost about 5 percent of his patients and changed to hypophysectomy (194). (p.109) Cryosurgery and Electrocoagulation Cryogenic destruction of the pituitary was reported in 1963 by Irving Cooper of New York, who passed a cannula containing liquid nitrogen through a frontal burr hole or via the nose(271). Robert Rand, a neurosurgeon in Los Angeles, who had found yttrium implantation too hazardous, soon became the chief exponent of cryosurgery and used the transsphenoidal route for ablation of normal glands and most pituitary tumors(272, 273). The operations were performed under local anesthesia, and the functions of the adjacent cranial nerves were monitored. Early intraoperative damage was seen in a few patients (10 percent), but when cooling was stopped all recovered. (p.no) The pituitary and its tumors are relatively resistant to cold, but a temperature of -170° to —190° C was found to destroy the normal gland almost completely, with clinical results similar to those of other methods. Seriously ill patients tolerated the procedure better than surgical hypophysectomy. (p.iii) All the common pituitary tumors were treated effectively, the greatest number being in acromegalic patients, many of whom had failed to benefit from radiotherapy previously. Tumors confined to the sella were ideal for treatment, but extensions up to 12 mm above the diaphragm were accepted. Larger ones were removed surgically, cold being used to destroy unresectable portions of growth in situ. The method was quickly adopted elsewhere (260, 274) and remained in use for some years (273, 275). Complications, including rhinorrhea and meningitis, seen in a few (10 percent) patients, mostly resolved with or without treatment(193). No operative deaths were reported. (p.112) Electrocoagulation was used by Zervas to treat acromegalic patients, in over 80 percent of whom the growth hormone levels returned to normal (158). All, however, developed panhypopituitarism. (p.m) TREATMENT OF PITUITARY TUMORS AFTER 1970 Pituitary tumors were seen in a new light. Whereas formerly only onethird had been known to secrete hormones, it was now realized that over three-quarters did so and that prolactinomas, previously described as chromophobe, were in fact the commonest tumors (241, 276, 277). Efforts were made to diagnose and treat functioning microadenomas at an early stage. Some of the methods of pituitary ablation that were being developed provided alternative forms of therapy, while others were seen to be comple-

The Pituitary (P) • 121 mentary rather than competitive (109, 278). Not all techniques were employed everywhere, and the choice often depended on the local facilities and skills. Conventional radiotherapy was generally available, and transcranial hypophysectomy was practiced by neurosurgeons in most major centers. Microsurgical transsphenoidal hypophysectomy came to be used more and more. The alternatives—internal and proton irradiation and other physical means of destruction—were used effectively in only a few places. The speed of response sometimes influenced the choice of method, surgical hypophysectomy being the fastest and external radiotherapy the slowest. (p.ii4) Transcranial operations were used infrequently, and mainly for adenomas with large intracranial extensions causing complications(196, 279). Improvements in neurosurgical techniques in general, including the use of the operating microscope, made operations on these large tumors much safer than formerly(65, 211). (p.115) The transethmosphenoidal route for hypophysectomy was still used by ENT surgeons, especially in Europe(278, 280). In 1969 and 1971 Hardy described his transsphenoidal technique in detail. He reported over 150 operations for pituitary adenomas in 1973, and over 500 in 1979(121, 189, 200, 276). The operative mortality was only 1.4 percent for secretory tumors. Other neurosurgeons followed Hardy's lead, soon reporting large series with similar results worldwide (275, 281, 282, 283). Charles Wilson in San Francisco did 250 operations with only one death (277). Surgeons who did fewer operations obtained poor results (284). Not many were yet ready to explore fossae that appeared normal (285), but within ten years Wilson(286) and some others(282, 287) were doing so. (p.ii6) The therapeutic objectives were to remove the tumor completely and to restore normal pituitary function, and Hardy used frozen sections of biopsies to define the tumor limits (200). It was not always possible to achieve both objectives at the same time, and sometimes neoplastic tissue was left behind deliberately (276). Methods used to destroy residual tumor were the same as those employed to eliminate remnants of the normal gland after total hypophysectomy (277,288). The frequency of histological invasiveness of tumors strengthened the case for routine postoperative radiotherapy (253, 277, 288), although many surgeons used it only when excision was patently incomplete. (p.in) The immediate results of treatment were usually assessed on clinical and (with secretory tumors) biochemical grounds as "cured," "improved," or "unchanged" (200). The earliest indication of remission was normalization of hormone levels, but all surgeons did not use the same criteria. Restoration of previously impaired pituitary function was assessed similarly. Indications for treatment, and its results, varied with the nature of the tumor and with the clinical syndrome. In general the outcome was best for microadenomas and worst for large invasive tumors (276). By 1980 the failure and

122 • History of Endocrine Surgery early recurrence rates after treatment for different tumors and syndromes were known(211). Subsequent measures included reoperation, sometimes with total hypophysectomy by either route ("sellar cleanout"), radiotherapy, and drugs in various combinations, but practices differed greatly. (p.ns) Prolactinomas The main indication for treating patients with microadenomas was sterility, if children were desired. There was little agreement about policy, and all methods were used. In 1974 Hardy reported microadenomaectomy in twenty young women. Prolactin levels fell to normal in all, symptoms were relieved in most, and pregnancies followed in four(214). Similar results in larger series followed soon, but the outcome in patients with larger tumors and higher prolactin levels (including most of the men) was poor (238, 277, 281, 289). In all, about two-thirds of patients in most series responded to transsphenoidal hypophysectomy, with or without radiotherapy (211). (p.119) Bromocriptine, alone or combined with radiotherapy, was sometimes employed, especially in Europe. It provided symptomatic and biochemical relief and also caused some tumors to shrink(290, 291). Experience with conventional radiotherapy alone was very variable (237). Internal irradiation with yttrium restored fertility in over two-thirds of women (270). Sometimes bromocriptine, hypophysectomy, and radiotherapy were used in varying combinations in different circumstances (281, 292). (p.120) Patients who became pregnant—a major objective of treatment— received special care, which varied from place to place, but most fared well and bore healthy children(234, 270, 293, 294). (p.121) Acromegaly and Gigantism Some relief of acromegalic features had often followed operations on the pituitary. In Cushing's series the main known cause of death was intracranial extension of the tumor (67), but in 1970 the mortality rate of untreated acromegalics over 45 was found to be nearly twice that of the general population, death being due mainly to vascular and respiratory diseases and diabetes mellitus(295). By this time GH could be measured, hypophysectomy was safe, and many patients came to be treated for endocrinological reasons. (p.122) "Cure" involved a fall of the serum GH level to normal (5 or 10 ng/ml), relief of headache and sweating, shrinkage of soft tissues, and improvement in diabetes and hypertension. The general appearance improved greatly, but skeletal changes were irreversible (296). Excessive growth in giants was arrested. (p.123) The methods of treatment were those which were used for pituitary tumors in general and were influenced by the fact that most of the tumors

The Pituitary (P) • 123 were large (215, 292). All methods gave good results in expert hands. Half the newly diagnosed acromegalics in the United States received proton therapy in the late 1970s(210, 263, 265). Transsphenoidal microsurgery, sometimes with radiotherapy, cured about three-quarters of the patients in most series(211, 292). Pituitary function in general was usually unchanged, but sometimes improved and occasionally deteriorated. A few patients (612 percent) (215, 292) required total replacement therapy. Bromocriptine was less effective than in the treatment of prolactinomas (211,290,291,292, 297,298). (p.m) Cushing's and Nelson's Syndromes Corticotrophinomas in Cushing's syndrome were usually small, and about 80 percent were cured by microadenomectomy (211,215). Those in Nelson's syndrome were often large, and far fewer responded (p. A.72). (p.125) Nonfunctioning Tumors Three-quarters of Cushing's patients had large chromophobe tumors(40), many of which must have been prolactinomas. True nonfunctioning tumors, which could not be diagnosed until the 1970s, rarely caused symptoms before they had enlarged beyond the confines of the sella (197). Microadenomas were often found at autopsy (260), but were rarely seen in life (215). Nearly all tumors that were diagnosed but not treated at once required treatment eventually, half of them causing permanent damage. Radiotherapy, with or without operation, controlled three-quarters of tumors for ten years, but operation alone was much less effective(260). Transsphenoidal hypophysectomy, whenever feasible, followed by radiotherapy, became the treatment of choice(109, 197). (p.126) Posterior Lobe Tumors Several of the rare posterior lobe tumors were removed surgically (259). Most patients with myoblastomas were cured by operation, while all those with glial cell tumors died within five years. (p.127) Craniopharyngiomas Craniopharyngiomas varied greatly in their behavior and rates of growth(299). Total removal was rarely possible, but, as with pituitary adenomas, the more radical the excision, the longer was the survival. On the other hand, some patients whose tumors had apparently been removed completely died from recurrence more than twenty years later. (p.128) Two advances in the 1960s greatly improved the outlook, but in different ways, and provided alternative methods of treatment. Cortisone rendered

124 • History of Endocrine Surgery radical removal of tumors relatively safe, while supervoltage radiotherapy proved very effective when combined with minimal surgical procedures. Other forms of irradiation had been disappointing (p. P.38). (p.129) Donald Matson of Boston, one of the first to follow Kahn as a proponent of radical surgery (p. P.35), found that every child treated before the introduction of cortisone had died within fifteen years (300, 301, 302). He gave cortisone cover and attempted total removal of the tumors, but did not use radiotherapy. By 1968 he had done primary operations on forty children without a death, but still lost 30 percent after operations for recurrence. Removal of the tumor was thought to have been complete in most patients, and these fared best. A few died later, but most of the survivors were attending school or working up to twelve years after operation. Nearly all required thyroid replacement therapy, and a few needed cortisone. Most grew normally, but all remained sexually infantile. Some surgeons employed transfrontal microsurgery to advantage(196). (PBO) The other approach, used by Simon Kramer and Wylie McKissock in London (303) and in Philadelphia (304), was to aspirate cysts through burr holes in children, or at craniotomy in adults, and then to irradiate the tumors. Patients of all ages were treated with results comparable with those of radical operations. The beneficial effects of irradiation led other surgeons to employ it postoperatively when radical removal was impossible (196, 305).

(P.131)

Stereotaxic intracavitary irradiation has also been used since the 1950s for craniopharyngiomas, especially in Stockholm(306) and more recently elsewhere (307). (p.132) Treatment of Hypogonadotrophinism It had long been possible to provide substitution therapy with thyroid and adrenocortical hormones and to induce and preserve secondary sexual characteristics with sex hormones, but restoration or preservation of pituitary function was still an important objective of treatment. Eventually, in the 1970s, human gonadotrophins became available to restore fertility when children were desired, so that total pituitary destruction no longer precluded parenthood (207d). (p 133) THE 1980s Until a century ago no operations had been performed on the pituitary. By the 1980s elegant microsurgical procedures to remove minute tumors were being undertaken routinely and safely in many centers with very good immediate and long-term results. Facilities for diagnosis were still improving, and the optimal combinations of surgery, radiotherapy, and drug therapy were being defined. New neuropharmacological therapeutic

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agents, related to bromocriptine and somatostatin, which influenced the hypothalamus and the pituitary, perhaps held the greatest promise of advance in the immediate future. (p.134) GENERAL SOURCES Cushing, 1912. See Ref. 18 Cope, 1916. See Ref. 34. Heuer, 1931. See Ref. 61. Jefferson, 1943. See Ref. 64. Johnson, 1951. See Ref. 4. Rosegay, 1981. See Ref. 66. Hardy, 1982. See Ref. 87. Welbourn, 1986. See Ref. 181A.

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65. MacCarty, C.S., Hanson, E.J., Randall, R.V., and Scanlon, P.W. Indications for and results of surgical treatment of pituitary tumors by the transfrontal approach. In: Kohler, P.O. and Ross, G.T., eds. Diagnosis and treatment of pituitary tumors. Amsterdam: Excerpta Medica, 1973: 139-45. 66. Rosegay, H. Cushing's legacy to transsphenoidal surgery. J. Neurosurg 1981;54:448-54. 67. German, W. J., and Flanigan, S. Pituitary adenomas: a follow-up study of the Cushing's series. Clin Neurosurg 1964; 10: 72-81. 68. Cushing, H. The meningiomas. Brain 1922; 45: 282-316. 69. Houssay, B.A., and Biasotti, A. Hypophysis, carbohydrate metabolism and diabetes. Endocrinology 1931; 15: 511-23. 70. Simmonds, M. Uber embolische Prozesse in der Hypophysis. Virchows Arch Pathol Anat Klin Med 1914; 217: 226-39. 71. Dott, N.M., Bailey, P., and Cushing, H. A consideration of the hypophysial adenomata. Br J Surg 1925; 13: 314-66. 72. Frazier, C H . A series of pituitary pictures. Arch Neurol Psychiat 1930; 23: 656-95. 73. Lindgren, E. A history of neuroradiology. In: Newton, T.H., and Potts, D.G., eds. Radiology of the skull and brain. St. Louis: C.V. Mosby, 1971; 1: 1-25. 74. Biggart, J.H., and Dott, N.M. Pituitary tumours: their classification and treatment. Br Med J 1936; 2: 1206-8. 75. Gramegna, A. Un cas d'acromegalie traite par la radiotherapie. Rev Neurol 1909; 17: 15-17. 76. Beclere, A. The radio-therapeutic treatment of tumors of the hypophysis, gigantism and agromegaly. Arch Roentg Ray 1909; 14: 142-50. 77. Beclere, A. Technique, resultats, indications et contra-indications de la Roentgenotherapic des Tumeurs Hypophysaires. Rev Neurol 1922; 38: 808-15. 78. Bailey, P. The results of roentgen therapy on brain tumors. Am J Roentgenol Radium Ther 1925; 13: 48-53. 79. Heinismann, J.I., and Czerny, C J . Die Rontgentherapie der Hypophysentumoren. Strahlentherapie 1926; 24: 331-35. 80. Towne, E.B. Roentgen-ray treatment of pituitary tumors. Arch Neurol Psychiat 1926; 15: 92-102. 81. Rand, C.W., and Taylor, R.G. Irradiation in the treatment of tumors of the pituitary gland. Arch Surg 1935; 30: 103-50. 82. Grant, F . C Pituitary tumors. Surg Gynecol Obstet 1950; 90: 629-31. 83. Towne, E.B. Treatment of pituitary tumors: the role of the Rontgen ray and of surgery. Ann Surg 1930; 91: 29-36. 84. Henry, A.K. Exposure of long bones and other surgical methods: Pituitary surgery by a new method. Bristol: John Wright, 1927: 69-80. 85. Cushing, H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932; 50: 137-95. 86. Cushing, H. Papers relating to the pituitary body, hypothalamus and parasympathetic nervous system. Springfield, IL: Charles C. Thomas, 1932: 161-74 Addendum: Pituitary basophilism. 87. Hardy, J. Cushing's disease: fifty years later. Can J Neurol Sci 1982; 9: 37580.

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134. Mahmoud, El. S.M. The sella in health and disease. Br J Radiol 1958; suppl 8. 135. Bateman, G.H. Destruction of the pituitary in cases of carcinomatosis secondary to mammary carcinomas. J Laryngol Otol 1959; 73: 631-53. 136. Ray, B.S., and Patterson, R.H. Surgical treatment of pituitary adenomas. J Neurosurg 1962; 19: 1-8. 137. Chabanier, H., Puech, P., Lobo-onell, C , and Lelu, E. Hypophyse et diabete. Presse Med 1936; 44: 986-89. 138. Elden, C.A. Pituitary-ovarian relationship in a human hypophysectomized female. Endocrinology 1936; 20: 679-80. 139. Stephens, D.J. Chloride excretion in hypopituitarism. Am J Med Sci 1940; 199: 67-75. 140. Elden, C. A., and Kummer, A.J. Clinical, laboratory and pathological study of partially hypophysectomized human female. J Clin Endocrinol Metab 1943; 3: 596-99. 141. Shimkin, M.B., Boldrey, E.B., Kelly, K.H., Bierman, H.R., Ortega, P., and Naffziger, H . C Effects of surgical hypophysectomy in a man with malignant melanoma. Ibid. 1952; 12: 439-53. 142. Stern, W.E. Personal communications: a 1988, b 1986. 143. Luft, R., Olivecrona, H., and Sjogren, B. Hypofysektomi pa manniska. Nord Med 1952; 47: 351-54. 144. Luft, R., and Olivecrona, H. Experiences with hypophysectomy in man. J Neurosurg 1953; 10: 301-16. 145. Fraser, T.R., and Joplin, G.F. Assessment of pituitary function after pituitary ablation. Proc R Soc Med 1960; 53: 81-84. 146. Forrest, A.P.M., Sim, A. W., and Stewart, H.J. Pituitary function tests after radioactive implantation of the pituitary. Ibid., 84-88. 147. Lipsett, M.B., and Pearson, O.H. Effects of hypophysectomy in man. Med Clin North Am. Philadelphia: W.B. Saunders, 1956; 40(3): 773. 148. Oppenheimer, D.R. Some pathological findings in cases with radioactive pituitary implants. J Laryngol Otol 1959; 73: 670-78. 149. Le Beau, J., and Foncin, J.F. Anatomical study of anterior pituitary remnants after (1) stalk section, (2) hypophysectomy. Acta Psychiatr Neurol 1960; 35: 13-26. 150. Gleadhill, C.A. The role of hypophysectomy in the treatment of advanced carcinoma. Neurochirurgia 1959; 2: 55-72. 151. Escher, F., Roth, F., and Cottier, H. Die paranasale trainsethmoidosphenoidale Hypophysektomie. Schweiz Med Wochenschr 1958; 88: 49-56. 152. Edelstyn, G.A., Gleadhill, C.A., Lyons, A.R., Rodgers, H.W., Taylor, A.R., and Welbourn, R.B. Hypophysectomy combined with intrasellar irradiation with yttrium-90. Lancet 1958; 1: 462-63. 153. Edelstyn, G.A., Gleadhill, C , and Lyons, A.R. A rational approach to hypophysectomy. Br J Surg 1965; 52: 953-57. 154. Freshwater, D.B., Crue, B.L., Shelden, C.H., and Pudenz, R.H. Further experience with a technique of total extracapsular hypophysectomy. Cancer 1957; 10: 105-10. 155. Bauer, K.H., and Schweitzer, L A . Radioactive gold implantation of the

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262. Gorden, P., and Roth, J. The treatment of acromegaly by conventional pituitary irradiation. Ibid., 230-33. 263. Kjellberg, R.N., andKliman, B. Lifetime effectiveness—a system of therapy for pituitary adenomas, emphasizing Bragg peak proton hypophysectomy. In: Linfoot, J.A., ed. Ref. 158: 269-88. 264. Lawrence, J.H., Tobias, C.A., Linfoot, J.A., et al. Treatment of pituitary tumors with heavy particles. In: Kohler, P.O., and Ross, G.T.,eds. Ref. 65: 253-61. 265. Linfoot, J.A. Alpha particle pituitary irradiation in the primary and postsurgical management of pituitary microadenomas. In: Faglia, G., Giovanelli, M.A., and MacLeod, R.M., eds. Pituitary microadenomas. London: Academic Press, 1980: 515-29. 266. Kjellberg, R.N. Personal communication, 1986. 267. Harrison, M.T., Joplin, G.F., Hartog, M., and Fraser, R. Acromegaly treated by needle-implantation of 198Au seeds in the pituitary gland. Proc R Soc Med 1960; 45: 53-57. 268. Joplin, G.F., Fraser, R., Steiner, R., Laws, J., and Jones, E. Partial pituitary ablation by needle implantation of gold-198 seeds for acromegaly and Cushing's disease. Lancet 1961; 2: 1277-81. 269. Forrest, A.P.M., Thomas, J.P., and Richards, S.H. Radioactive implants of the pituitary for endocrine disease. Proc R Soc Med 1970; 63: 616-18. 270. Joplin, G.F., Cassar, J., Doyle, F.G., Kelly, W.F., Mashiter, K., et al. Implantation of yttrium-90 or gold-198 seeds. In: Linfoot, J.A., ed. Ref. 158: 331-35. 271. Cooper, I.S. Cryogenic surgery. N Engl J Med 1963; 268: 743-49. 272. Rand, R.W., et al. Stereotactic cryohypophysectomy. JAMA 1964; 189: 255-59. 273. Rand, R.W. Neurosurgery. In: Ablin, R.J., ed. Handbook of cryosurgery. New York and Basle: Marcel Dekker, 1980: 153-93. 274. Cross, J.N., Glynne, A., Grossart, K.W.M., Jennett, W.B., et al. Treatment of acromegaly by cryosurgery. Lancet 1972; 1: 215-16. 275. Teasdale, G., Hay, I.D., et al. Cryosurgery or microsurgery for pituitary microadenomas? In: Faglia, G., et al., eds. Ref. 265: 503-6. 276. Hardy, J. Transsphenoidal microsurgical treatment of pituitary tumors. In: Linfoot, J.A., ed. Ref. 158: 375-88. 277. Wilson, C.B., and Dempsey, L . C Transsphenoidal microsurgical removal of 250 pituitary adenomas. J Neurosurg 1978; 48: 13-22. 278. Williams, R.A. Transsphenoidal hypophysectomy for acromegaly. Proc R Soc Med 1974; 67: 881-85. 279. Fager, C.A., Poppen, J.L., and Takaoka, Y. Indications for and results of surgical treatment of pituitary tumors by the intracranial approach. In: Kohler, P.O., and Ross, G.T., eds. Ref. 65: 146-551. 280. Richards, S.H., Thomas, J.P., and Kilby, D. Transethmoidal hypophysectomy for pituitary tumours. Proc R Soc Med 1974; 67: 889-92. 281. Werder, K.V., Fahlbusch, R., et al. Treatment of patients with prolactinomas. J Endocrinol Invest 1978; 1: 47-58. 282. Kuwayama, A., Kageyama, N., Nakane, T., et al. Treatment of Cushing's disease by transsphenoidal microsurgery. Neurol Med Chir (Tokyo) 1978; 18 pt II: 279-85. 283. Wajchenberg, B.L., Silveira, A.A., Goldman, J., et al. Evaluation of resec-

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tion of pituitary microadenoma for the treatment of Cushing's disease in patients with radiologically normal sella turcica. Clin Endocrinol (Oxf) 1979; 11: 323-31. 284. Burch, W. A survey of results with transsphenoidal surgery in Cushing's disease. N Engl J Med 1983; 308: 103-4. 285. Salassa, R.M., Laws, F.R., Carpenter, P . C , and Northcutt, R . C Transsphenoidal removal of pituitary microadenomas in Cushing's disease. Mayo Clin Proc 1978; 53: 24-28. 286. Tyrrell, J.B., Brooks, R.M., Forsham, P.H., Wilson, C.B., et al. Cushing's disease: selective trans-sphenoidal resection of pituitary microadenomas. N Engl J Med 1978; 298: 753-58. 287. Schnall, A.M., Kovacs, K., Brodkey, J.S., and Pearson, O.H. Pituitary Cushing's disease without adenoma. Acta Endocrinol (Copenh) 1980; 94: 297-303. 288. Wrightson, P. The limitations of surgical treatment of pituitary microadenomas. In: Faglia, M.A., et al., eds. Ref. 265: 465-72. 289. Fahlbusch, R., Faglia, G , Werder, K. von, et al. Differentiated therapy of microprolactinomas. Ibid., 443-46. 290. Wass, J. A.H., Thorner, M.O., Besser, G.M., et al. Reduction of pituitarytumour size . . . with bromocriptine. Lancet 1979; 2: 66-69. 291. McGregor, A.M., Scanlon, M.F., Hall, R., and Hall, K. Effects of bromocryptine on pituitary tumour size. Br Med J 1979; 2: 700-703. 292. Nabarro, J.D.N. Pituitary surgery for endocrine disorders. Clin Endocrinol (Oxf) 1980; 13: 285-98. 293. Magyar, D.M., and Marshall, J.R. Pituitary tumors and pregnancy. Am J Obstet Gynecol 1978; 132: 739-51. 294. Thorner, M.O., Edwards, C.R.W., Besser, G.M., et al. Pregnancy in patients presenting with hyperprolactinaemia. Br Med J 1979; 2: 771-74. 295. Wright, A.D., Hill, D.M., Lowy, C , and Fraser, T.R. Mortality in acromegaly. Q J Med 1970; 39: 1-16. 296. Williams, R.A., Oakley, N.W., Nabarro, J.D.N., et al. The treatment of acromegaly with special reference to trans-sphenoidal hypophysectomy. Q J Med 1975; 43: 79-98. 297. Wass, J.A.H., Rees, L.H., Besser, G.M., et al. Long-term treatment of acromegaly with bromocriptine. Br Med J 1977; 1: 875-78. 298. McGregor, A.M., and Ginsberg, J. Dilemmas in the management of functioning pituitary tumours. Br J Hosp Med 1981; April: 344-52. 299. Bartlett, J.R. Craniopharyngiomas—a summary of eighty-five cases. J Neurol Neurosurg Psychiatry 1971; 34: 37-41. 300. Matson, D.D., and Crigler, J.F. Radical treatment of craniopharyngioma. Ann Surg 1960; 152: 699-704. 301. Matson, D.D. Craniopharyngioma. Clin Neurosurg 1964; 10: 116-29. 302. Matson, D.D., and Crigler, J.F. Management of craniopharyngioma in childhood. J Neurosurg 1969; 30: 377-90. 303. Kramer, S., McKissock, W., and Concannon, J.P. Craniopharyngiomas. Treatment by combined surgery and radiation therapy. J Neurosurg 1961; 18: 217— 26. 304. Kramer, S., Southard, M., and Mansfield, C M . Radiotherapy in the management of craniopharyngiomas. Am J Roentgenol, Radium Ther 1968; 103: 44-52.

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305. Thomas, D.G.T. Brain tumors. In: Taylor, S., Chisholm, G.D., O'Higgins, N., and Shields, R., eds. Surgical management. London: Heinemann, 1984: 628-53. 306. Lindgren, E., and Westberg, G. Radioactive bismuth phosphate for the treatment of craniopharyngioma. Acta Radiol Ther Physics Biol 1964; 2: 113-20. 307. Pollack, I.F., Lunsford, L.D., Slamovits, T.L., et al. Stereotaxie intracavitary irradiation for cystic craniopharyngiomas. J Neurosurg 1988; 68: 227-33.

p.l.

P.l. Victor Horsley. Courtesy of Haymaker Collection, Neurology Archives, History & Special Collections Division, Louise M. Darling Biomedical Library, University of California, Los Angeles.

140

P.2.

P.3.

P.2. Incisions for transcranial hypophysectomy: (1) Horsley; (2) Krause; (3) Frazier (1st), Cushing; (4) Frazier (2nd), Naffziger, Anterior Trotter; (5) Frazier (3rd), Souttar; (6) Variant of 5. Courtesy of Doig Simmonds, Department of Medical Illustration, Royal Postgraduate Medical School. P.3. Incisions for transsphenoidal hypophysectomy: (1) Schloffer; (2) Kocher; (3, 4) von Eiselsberg; (5) Kanavel; (6) Halstead, Cushing, Dott, Guiot, Hardy; (7) Hirsch; (8) Chiari, Gisselsson, Riskaer; (9) Bateman, James; (10) Macbeth. From R. B. Welbourn, The evolution of transsphenoidal pituitary microsurgery. Surgery 1986; 100: 1185-90. 141

p.5.

PA.

P.6.

P.7.

P.4 Hermann Schloffer. Courtesy of I. Chirurgische Universitatsklinik, Innsbruck, Professor Dr. F. Gschnitzer. P.5. Schloffer's first operation. (Compare P.7 and P. 17.) Courtesy of N. Guleke and R. Zenker, eds., AUgemeine und spezielle Operationslehre: vol. 2, 2d ed. (Berlin/Heidelberg: Springer-Verlag, 1950), pp. 335-43. P.6. Anton v. Eiselsberg. Courtesy of Institut fur Geschichte d. Medizin der Universitat Wien. P.7. Cushing's transsphenoidal hypophysectomy. (Compare P.5. and P.17.) From JAMA 1914; 63: 1515-25. 142

P.8.

P.9.

P. 10.

P.ll.

P.8. Oscar Hirsch. Courtesy of Institut fiir Geschichte d. Medizin der Universitat Wien. P.9. Ottokar Chiari. Courtesy of Institut fur Geschichte d. Medizin der Universitat Wien. P.10. Fedor Krause. Courtesy of Freie Universitat, Berlin. P.ll. Charles H. Frazier. Courtesy of University of Pennsylvania. 143

P. 12.

P.13.

p.14.

P. 15.

P.12. Norman McO. Dott. Courtesy of Royal College of Surgeons of Edinburgh. P.13. Gerard Guiot. Coutesy of G. Guiot. P.14. Niels Riskaer. Courtesy of Mrs. E. Riskaer. P.15. John A. James. Courtesy of J. AngellJames.

144

P. 16. P. 17.

P. 16. Jules Hardy. Courtesy of J. Hardy, M.D. P.17. Hardy's transsphenoidal hypophysectomy. (Compare P.5 and P.7.) Courtesy of Clin Neurosurg 1969; 16: 185-217, and J. Hardy, M.D. 145


4 (A) The Adrenal Glands

Surgery of the adrenal glands emerged as part of abdominal surgery at the end of the nineteenth century, when abdominal masses were found at operation or autopsy to be adrenal in origin. Slowly, different adrenal syndromes and tumors were distinguished. The introduction of cortisone therapy in 1949 was a watershed in the development of surgery of the adrenal cortex. Previously adrenalectomy had been hazardous, and suddenly it was safe, except for operations on pheochromocytomas. These remained treacherous until the 1960s, when the effects of catecholamines on the circulation were understood and drugs were introduced to control them.

(A.i)

The adrenals were first described and illustrated on copper plates in 1552 by Bartholomaeus Eustachius, the Roman anatomist, who named them the "glandulae renibus incumbentes" ("glands lying on the kidneys") (1, 2, 3a). His work was printed in 1563 and again in 1714. Others described the glands also, noting cavities containing "black bile" within them and "ducts" leading to other structures. The glands received many other names. Thomas Wharton of London named them "glandulae renales" in 1656 (p. E.2), and Jean Riolan the younger, of Paris, in 1629 introduced the term "capsulae suprarenales," which persisted for many years. Baron Georges Cuvier, a Parisian naturalist, described differences between the cortex and the medulla in 1805, but these terms were first used by Emil Huschke of Jena, in 1845. (A.2) In the nineteenth century the cortex was found to be of mesodermal origin and to be invaded by sympathetic neural elements, which formed the

148


medulla and provided a rich nerve supply. It was regarded as a "bloodvascular gland," containing fat-like globules, and three zones were described: glomerulosa, fasciculata, and reticularis. The medulla resembled nerve ganglia and stained yellow or brown with potassium bichromate, for this reason being t e r m e d "chromaffin," "chromophil," and " p h e o c h r o m e . " Fragments of accessory or aberrant adrenal tissue, consisting of cortex and medulla, cortex alone (most commonly), or medulla only, were recognized in up to 90 percent of people. T h e last of these were called "paraganglia" and included the organs of Zuckerkandl. T h e r e was much speculation about the function of the adrenals(4), and George Gulliver, a L o n d o n surgeon, suggested in 1840 that they p o u r e d "a peculiar matter into the blood, which has doubtless a special u s e . " (A.3) Attention was focused abruptly on the functions of the adrenals by T h o m a s Addison of L o n d o n , who presented a paper in 1849 and published a monograph in 1855 entitled On the Constitutional and Local Effects o Disease of the Supra-renal Capsules (5). He described eleven patients with anemia, debility, feebleness of the heart, irritability of the stomach, and "a peculiar change of colour in the skin, occurring in connexion with a diseased condition of the suprarenal capsules." (Blood pressure was not mentioned because it was not measured clinically until the end of the century.) A t autopsy the adrenals showed gross disease, which was bilateral in eight cases and took the form of tuberculosis (scrofula), metastatic carcinoma, or, in one case, atrophy. Addison felt that this association of clinical and pathological features must throw light on the function of the glands. His work attracted much attention, especially in France, where A r m a n d Trousseau of Paris saw a similar patient with tuberculous adrenals, confirmed microscopically, and proposed the n a m e "Addison's disease" for the syndrome. However, there was much controversy, and some people attributed the clinical features to tuberculosis in general or to involvement of the sympathetic ganglia, rather than to adrenal destruction. Even twenty years later, when over 300 cases had been recorded, the disease was not generally accepted or understood. (A.4) Immediately after Addison's report the Parisian physiologist Charles E d o u a r d Brown-Sequard e m b a r k e d on animal experiments to determine whether the adrenals were essential to life (6). Bilateral adrenalectomy in many animals always resulted in death within a few hours, but, surprisingly, removal of one adrenal was often fatal t o o , although the animals lived longer. George Harley of L o n d o n obtained the same results, but found that most animals developed peritonitis (these were pre-Listerian times), which may have been the cause of death. However, one dog survived unilateral adrenalectomy, and two rats remained well after removal of both glands. These results and others were confusing, but Brown-Sequard likened his animals' symptoms to those of patients dying from Addison's disease and concluded that the adrenals were indeed essential to life. (A.5)

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• 149

In the 1880s and 1890s adrenal atrophy, uncomplicated by tuberculosis, was recognized in many patients. Walter H a d d e n of London thought that the histology of this lesion resembled that of the thyroid in myxedema, and suggested that Addison's disease might similarly result from deficiency of an internal secretion. Surgical adrenalectomies, now with antiseptic technique, showed clearly that the adrenals were vital organs. D e a t h after their removal was generally attributed to the accumulation of toxic products, which they were thought to remove from the blood, or from nervous shock. However, the idea of an essential internal secretion received support in 1891 from George Murray's effective use of thyroid extract in myxedema (p. T.43). William Osier of Baltimore prepared a similar extract of pigs' adrenals in 1896, and gave it by m o u t h for the treatment of Addison's disease, with success in one case (7). H e attributed both diseases to the loss of internal secretions. (A.6) In 1893 George Oliver of H a r r o g a t e , England, in searching for a means of treating the disease, had prepared an extract of the suprarenals that caused constriction of the arteries. Together with E d w a r d Schafer of London he found that, when injected intravenously into dogs, it caused a dramatic rise in blood pressure, constriction of the arterioles, and rapid forcible beating of the heart. They thought that absence of this extract, which was derived from the adrenal medulla only, was responsible for the great weakness that followed adrenalectomy and that characterized Addison's disease. This discovery attracted great interest, and an active constituent of the medulla, "epinephrine," was isolated in 1897. The closely related true product, "adrenalin," was purified in 1901, found to be a catecholamine, and synthesized in 1904. T h e n a m e " e p i n e p h r i n e " persisted in America and "adrenaline" in Britain. It was the first h o r m o n e to be discovered, although this term was not coined until 1905 (p. E . 5 ) . Because of its vasoconstrictive effect, adrenaline found an immediate use in the control of h e m o r r h a g e , when administered locally, especially in surgical operations. (A.7) H o p e s that epinephrine was the adrenal secretion, whose absence caused the clinical features of Addison's disease, were dashed by the fact that it failed to benefit patients or to sustain animals after adrenalectomy. Its deficiency might account for the low blood pressure (which was now recognized) and muscular weakness in Addisonian patients, but not the other features. It soon became clear that the adrenal atrophy associated with Addison's disease affected the cortex only and that the medulla remained intact. T h e search for cortical extracts was resumed by several workers in the United States; from 1926 onwards, preparations that prolonged the lives of adrenalectomized animals were reported and, in 1927, named "cortin." In 1929 they were used successfully for treating Addison's disease, and soon found a place in the management of patients undergoing surgical excision of adrenal tumors. T h e next twenty-five years saw intense activity in the search for the active principle of the adrenal cortex. (A.8)

150 • History of Endocrine Surgery SUPRARENAL TUMORS Adrenal tumors and "hypertrophy" have been recognized for many years, but their nature was uncertain and their nomenclature confused until well into the present century (8). Cortical and medullary lesions were not clearly distinguished. Around the turn of the century, however, several varieties of tumors, some of them with distinct syndromes, were described in the following order: 1. 2. 3. 4. 5. 6.

1870 (Loretz): Ganglioneuroma (p. A.136). 1892 (Birch-Hirschfeld): Hypernephroma (p. A.18). 1896 (Manasse): Medullary adenoma with chromaffin reaction (p. A. 110). 1899 (Ramsay): Carcinoma and sarcoma (p. A. 10). 1901 (Pepper): Congenital sarcoma of liver and suprarenal (p. A. 137). 1905 (Bulloch & Sequeira): (a) Carcinoma or hypertrophy of adrenal cortex with hirsutism and sexual precocity (p. A. 19-21); (b) lympho-sarcoma without these features (p. A. 19). 7. 1907 (Hutchison): Suprarenal sarcoma in children with metastases in the skull (p. A.137). 8. 1908 (Alezais & Peyron): Paraganglioma (p. A.110). 9. 1910 (Wright): Neurocytoma or neuroblastoma (p. A.137). 10. 1912 (Pick): Pheochromocytoma (p. A. 110). The significance and relationships of all these are discussed later. (A.9) In 1899 Otto Ramsay, a gynecologist in Baltimore, reported three patients with large, palpable malignant tumors, all of whom had undergone operation, and reviewed sixty-four other published reports (9). He described thirty-seven of the tumors as carcinomas and thirty as sarcomas, the latter being relatively commoner in the first decade of life. Pigmentation and circulatory disturbances were absent, but some features—weakness, gastrointestinal symptoms, and anemia—resembled those of Addison's disease, the only clinical manifestation of adrenal pathology that was then recognized. Two children and an adult had profuse growth of hair. Diagnosis was difficult in all patients and impossible in many. The tumors spread rapidly and the prognosis was bad. Surgery gave the only hope of relief, but only five operations had been reported (including Ramsay's three), and only two had been successful. The first of these patients, both of whose swellings had been regarded as renal or splenic in nature, was operated on by Knowsley Thornton (Fig. A.l) in London in 1889(10, 11, 12). The second (described in the paper) was well two years after Howard Kelly in Baltimore had removed a "fibro-myxosarcoma." This paper was soon followed by others reporting adrenal operations(13,14). Mayo Robson of Leeds, England, added three, two of which were in adults, who survived the removal of

The Adrenal Glands (A) • 151 large tumors. One (in 1891) had a sarcoma and died a month later, while the other (in 1897), with a "struma lipomatosa suprarenalis" (adenoma), remained well for two years. An infant with an inoperable "round-celled sarcoma" died from an attempt to remove it (in 1899). In 1905 it was still stated that no adrenal tumor had been diagnosed before operation (15). (A.IO) ADRENALECTOMY The first operations on the adrenals (Fig. A.2) were to remove large abdominal swellings, and Thornton reported the first known case in 1889. He was well prepared for this, having been house surgeon to Joseph Lister, from whom he learned antiseptic technique, and assistant to Spencer Wells, a pioneer of abdominal surgery and hemostasis. He employed an incision that Carl von Langenbuch of Berlin had used seven years earlier for cholecystectomy(10,16). This was T-shaped, the horizontal (or diagonal) limb running along the edge of the liver and the vertical one down the lateral border of the rectus abdominis. The incisions in the Baltimore cases were horizontal and directly over the tumors in two and in the midline of the abdomen in the third (9). Robson recommended an incision through the linea semilunaris and urged wide exploration to assess the operability of a tumor before embarking on its removal (13). These pioneers met problems and complications with which others later became familiar. Thornton's tumor weighed at least 20 pounds (9 kg) ("The lodging house people [where the operation was performed] had no proper weights for so large a mass, but . . . this one weighed fully 20 lbs"). He found it necessary to remove the kidney also, because its very large blood vessels supplied the growth. The main difficulties in the other cases were hemorrhage, rupture of the tumors, and adhesions. Thornton's patient developed an abscess, which nearly proved fatal until, three months after the operation, it burst into a bronchus, discharging quantities of pus, after which the patient slowly recovered. Hemorrhage from the vena cava, which lies close to the right adrenal, and wound infection, especially in Cushing's syndrome, long proved major problems. (A.H) For many years surgeons approached large adrenal tumors in the same way as those in the kidneys. The incisions were as already described, either anterior and vertical through the peritoneal cavity, or lateral, horizontal, and retroperitoneal. Later, oblique posterior lumbar incisions came to be used also (17). The adrenals lie above the kidneys, and these incisions often failed to provide adequate access. For this reason surgeons moved headward, resecting the twelfth or eleventh ribs, as they did for growths in the upper pole of the kidney(18,19). Lennox Broster of London, a pioneer adrenal surgeon, removed adrenal masses through a long, oblique, intercostal incision immediately over the gland (presumably below the ninth or tenth rib), going across the pleural cavity, through the diaphragm posteriorly, and

152 • History of Endocrine Surgery into the retroperitoneal space (20). Positive pressure anesthesia was not then in use (in the 1920s), but the temporary pneumothorax caused few problems. Broster also devised special forceps for gripping the gland (21). (A.i2) In 1909 George Crile of Cleveland, O h i o , was removing normal glands by the lumbar route for general (nonadrenal) diseases (p. H.2)(22). By 1912 surgeons were considering diagnostic exploration of the adrenals to find tumors that were suspected clinically, but not felt (p. A.25), and by the 1920s they undertook this occasionally. By then they also explored the adrenals in patients with virilism with the object of excising hyperplastic glands. These operations were difficult because, while it was desirable to inspect both glands before removing o n e , no incision regularly gave adequate access to both of them at the same time. Broster explored the a b d o m e n to inspect the adrenals and any extraadrenal swellings, and to determine the patient's sex, and two or three weeks later he removed the larger (hyperplastic) gland at thoracotomy(20). H u g h Young (Fig. A.3) of Baltimore, a pioneer urologist, found himself unable to assess the adrenals adequately at laparotomy and explored them by the lumbar route instead, turning the patient during the operation(23a). This awkward procedure led him, in 1936, to devise a simultaneous bilateral posterior approach, which allowed both glands to be inspected thoroughly before either was removed and which provided a very smooth postoperative course (Fig. A.4) (24). H e did not resect a rib, but others later found it simpler to extend the incision upwards and to remove the twelfth or the eleventh extrapleurally. A n o t h e r incision, which allowed inspection of both adrenals and the whole a b d o m e n , was an upper abdominal "roof-top" or "bilateral Kocher" incision, which was used extensively from the 1940s. The route to the right adrenal was straightforward and above the d u o d e n u m . The left could be reached in three ways: (1) through the lesser o m e n t u m , above the stomach, (2) through the gastrocolic ligament, below the stomach, and (3) laterally, after mobilization of the spleen. T h e last provided the best access, but carried the small risk of rupture of the splenic capsule. (A.i3) Preoperative diagnosis and localization of adrenal tumors improved steadily from about 1930, when pyelography was introduced, until the late 1970s, when they were virtually perfected (p. A.76-80). During all this time, however, surgical exploration played an important role. Adrenal surgery received a great impetus in the 1950s when adrenalectomy came to be used commonly for the treatment of advanced cancer of the breast and prostate (p. C.6). This experience m a d e surgeons more ready and able to operate skillfully for adrenal disease than previously. Pituitary surgery benefitted in the same way (p. P.52, P.74). (A.i4) Three main approaches to the adrenals emerged, and eventually most experienced adrenal surgeons used them all, according to the circumstances (25). Each had its own advantages and drawbacks. (A.15)


• 153

1. The anterior roof-top incision was suitable when the subcostal angle was wide, but a midline approach, sometimes extended by a lateral incision at right angles, was better when the angle was acute. The whole abdomen could be explored, and hyperplastic adrenals or small adrenal tumors, as in Conn's syndrome, could nearly always be excised from either gland. Extraadrenal tumors, especially pheochromocytomas, could also be removed, sometimes with additional incisions. Major disadvantages were that large tumors (more than about 5 cm in diameter) could not be removed and that wound infection, which was common in patients with Cushing's syndrome, often resulted in a subphrenic abscess. (A.isa) 2. A lateral retroperitoneal incision, through the bed of the eleventh or twelfth rib, allowed one adrenal to be examined thoroughly and normal or tumorous glands to be excised. The peritoneum could be opened and the other adrenal and the whole abdominal cavity explored, although not so readily as from the front, but intraperitoneal lesions or those in the other adrenal could not be removed. In patients with Cushing's syndrome the Mayo surgeons, who had the greatest experience, explored both glands at first by this route before removing either, but later learned to recognize an atrophic gland so that they could sew up, confident of finding an adenoma on the other side (26). Many patients could stand being turned from one side to the other during the operation, but others, particularly adults with Cushing's syndrome, required two operations. Pneumothorax was no longer troublesome, because positive pressure anesthesia was commonplace in the late 1940s, when those operations were first undertaken. Large tumors were best approached laterally, and a higher incision through the bed of the tenth rib, especially on the right, across the pleural cavity, and extended well up and down, gave excellent access. (A.i6) 3. Young's posterior approach, extended upwards if necessary, allowed both adrenals to be examined thoroughly and removed. Small tumors were also accessible, but large ones could not be excised, and the abdominal contents were out of reach. Some surgeons had used this approach very early in Cushing's syndrome (27), and by about 1980 most found it the best for hyperplastic glands and small tumors, a few even using it for pheochromocytomas. By this time adrenalectomy in experienced hands had become a straightforward procedure with few special problems, but it still caused serious hazards for the novice (28). (A.n)

THE ADRENAL CORTEX The first adrenal tumor to which hormonal disturbance was attributed was the hypernephroma. This name was given to benign and malignant growths of the suprarenals and the kidneys by Felix Birch-Hirschfeld of Germany in 1892(1). The term implied that renal tumors arose in adrenal rests, a

154 • History of Endocrine Surgery mistaken view that h a d been proposed by Paul Grawitz of Greiswald in 1883(29). (A.is) Adrenogenital Syndrome (1905-29) Anomalies of sexual development have been found in animals and man from very early times, but were long shrouded in ignorance and superstition (30). However, virilism in girls was known to accompany malignant adrenal tumors in the eighteenth century and to be associated with bilateral hypertrophy early in the nineteenth (1). This phenomenon was highlighted in a paper titled "On the relation of the suprarenal capsules to the sexual organs," published by William Bulloch and James Sequeira of London in 1905(31). They described one child and reviewed eleven others, reported since 1756, in whom adrenocortical tumors had been found. Ten girls and two boys, aged from 1 to 14 years, suffered from precocious growth of sexual hair. Most also had premature development of the genital organs, some (including their own patient) were obese, and one had overgrowth of the whole body. Another patient, a woman of 32, had hirsutism, amenorrhea, and a similar adrenal tumor. All thirteen patients died within two years from malignant adrenal growths, many of them with metastases. The tumors were described by several names, including hypernephroma and sarcoma, and several were clearly of adrenocortical origin. Three of these patients underwent unsuccessful operations. (A.19) T h r e e children with similar clinical features h a d been born with ambiguous external genitalia, which caused confusion during life. T w o of these were certainly female and, unlike t h e other patients, lived to the ages of 40 and 50, respectively, o n e dying from what may have been an adrenal crisis(32). H y p e r t r o p h y of the adrenals was found at autopsy. Four further adult patients with hypoplastic or atrophic adrenals and retarded development of sexual characters were described as suffering from " t h e opposite condition," and a causal relationship between the two p h e n o m e n a was implied. T h e state of the pituitaries was not mentioned, and it seems m o r e likely that hypopituitarism was responsible for both the adrenal and the sexual features. Finally, thirteen young children without signs of p r e m a t u r e development were reported. All h a d adrenal tumors, twelve of t h e m malignant, most of which were described as sarcomas. Many of these were probably medullary tumors. (A.i9a) O t h e r similarly masculinized patients were soon reported, especially in France (33). T h e condition was n a m e d "adrenal virilism" or " t h e adrenogenital s y n d r o m e , " a n d several varieties, distinguished by t h e age of onset, were described. Later t h e terms "macrogenitosomia praecox" and "infant Hercules" were used to describe the syndrome in boys. (A.20) Ernest Glynn of Liverpool, who had examined many of these tumors, concluded (in 1912) that the adrenal cortex was concerned with growth and sexual characters, and the medulla with blood pressure(34). Most adren-

The Adrenal Glands (A) • 155 ocortical tumors were malignant hypernephromas, which were often associated with sexual abnormalities. The latter were almost invariable in children, usual in young women, and apparently absent in older women and in men. The sexual changes took the form of an increase in maleness and a decrease in femininity. The bilateral congenital adrenal lesion, causing pseudohermaphroditism in girls or, less commonly, precocious pseudopuberty in boys, which had previously been described as "hypertrophy" or "tumor," was in fact "hyperplasia." Tumors and hyperplasia causing these sexual abnormalities sometimes developed in ectopic cortical tissue, but not in the kidneys. (A.21) Most patients with adrenal tumors and virilism died from malignancy (12, 31, 34), but some were treated effectively. Thornton's patient was a very hirsute woman of 36, who was much improved by removal of a large tumor in 1889. However, the lesion recurred after two years, when she died(10,ll). The original tumor was preserved in the Royal College of Surgeons in London and was probably destroyed in an air raid in 1941 (35). In 1909 Emil Bovin of Stockholm (36) removed a paraovarian adrenal rest tumor from a similar patient aged 28. Menstruation returned, but her beard persisted. In 1912 Gordon Holmes of London saw a woman of 24 who for eight years had suffered amenorrhea, progressive virilism, and loss of libido, and who had developed a preference for the society of women (12). He prescribed thyroid, pituitary, and ovarian extracts, but without effect. Two years later a mass was felt, displacing the kidney downwards, and Percy Sargent removed a large benign adrenocortical tumor. The patient recovered rapidly and was well nine years later. In Norway, in 1921, Arthur Collett of Christiania (now Oslo) described a girl, aged 2, who had become progressively virilized for eighteen months and who had a palpable tumor in the left adrenal(37). After six months' treatment with thymus tablets, Alexander Brekke removed a hypernephroma weighing 10 g. Her hair and musculature regressed, but her voice remained deep and her clitoris large two years later. This was probably the first successful adrenal operation in a child. In 1926 Graham Simpson of Sheffield(38) removed two large adjacent hypernephromas from a woman of 36 with virilism of recent onset. The patient improved, but died with recurrence two years later. In 1928 Kenneth Trubshaw of Chester reported the remarkable case of an inoperable hypernephroma in a virilized girl of 15, which apparently regressed after biopsy and local infection(39). She had been described as "a living skeleton, covered with an abundant growth of hair," and had seemed to be near death. However, three years later she was "immensely improved." Then, in 1929, William Thompson of Liverpool removed a large adrenocortical tumor from a 2-year-old girl with virilism. She recovered rapidly and was well one year later (40). (A.22) The effects of these tumors and of their surgical removal seemed to confirm that they caused virilism, perhaps by producing internal secretions (12). (A.23)

156 • History of Endocrine Surgery Polyglandular Syndrome Soon after the recognition of adrenal virilism in 1905, reports of patients with related, but rather different, features appeared, most of whom also had adrenocortical tumors or hyperplasia. The most striking additional sign (as in Bulloch and Sequeira's own patient) was obesity (41). Leonard Guthrie and Walter d'Este Emery of London reported ten children whom they described as "precociously obese," a term that they ascribed to Parkes Weber, also of London (42). Autopsies were performed on nine, and hypernephromas were found in eight. A boy aged 4, whom they likened to "a burly brewer's drayman," died from tuberculosis and at autopsy had a hypernephroma but no recognizable adrenal tissue on the other side, (A.24) In 1912 Harvey Cushing described the "polyglandular syndrome," whose features included facial and truncal obesity, hirsutism, and amenorrhea (p. P.31) (Fig. A.5). He considered exploring the adrenals, but did not do so. In 1921 Charles Achard and Joseph Thiers of Paris reported a similar condition, which they named "diabetes of bearded women," in a patient of their own and in six others (43). One of these patients had already been described by the same name (43A). The main features were hirsutism, obesity, glycosuria, decreased carbohydrate tolerance, hypertension, and menstrual disorder. All had adrenocortical hyperplasia or tumors, and in their patient (with adrenal hyperplasia) the pituitary appeared superficially normal at autopsy. In 1924 N.M. Itsenko of Rostov on Don, USSR, described a woman with a pituitary tumor, bitemporal hemianopia, painful adiposity, hirsutism, cutaneous hemorrhages, excitability, and myxedema(44). He suggested secondary hypothalamic and hypophyseal hypofunction and adrenocortical hypertrophy to account for the clinical features. In 1926 Parkes Weber of London described a woman of 28, similar to the patients reported by Achard and Thiers. Large adrenals and a tiny pituitary basophil adenoma ( 4 . 5 x 3 mm) were found at autopsy, but Weber felt that this small tumor could not account for the disease (45). However, in 1932 Cushing described sixteen patients with the polyglandular syndrome (including Weber's), which he attributed to pituitary basophilism, with possible secondary hyperplasia of the adrenal cortex (p. P.32). The clinical features, in addition to obesity, hirsutism, and amenorrhea, included a round, dusky, cyanosed face, wasted limbs, subcutaneous ecchymoses, arterial hypertension, polycythemia, skeletal decalcification, kyphosis, possible renal stones, and pigmentation. Cushing did not refer to Achard and Thiers' syndrome, although later it came to be regarded by many as synonymous with pituitary basophilism (46, 47). Cushing's papers attracted great attention and provoked controversy, but the condition soon came to be known as "Cushing's disease." The similarity of the clinical and laboratory features and of the published photographs of patients with and without adrenal tumors left little doubt that they were closely related(48,49), and the term "Cushing's

The Adrenal Glands (A) • 157 basophil pituitary syndrome" was even used to describe the clinical features of some patients with adrenal tumors (50). Before long the name "Cushing's syndrome" was applied to both groups of patients and to some with the same features from other causes. In Eastern Europe the pituitary form of the disease is linked with Itsenko's name to stress the view (not expressed in his paper of 1924) that the primary disturbance is hypothalamic(51). (A.25) In 1899 Ramsay (9) had questioned the wisdom of removing one adrenal when the other was abnormal, and in 1906 Guthrie and Emery(42) had found no normal adrenal tissue in a child with "precocious obesity" who died with a unilateral hypernephroma. Although patients with pure adrenal virilism had had tumors removed successfully, several with Cushing's or closely related syndromes had died in "shock" several hours after straightforward operations. At autopsy their remaining adrenals were found to be atrophic(17, 40, 52). The significance of this finding became apparent later (p. A.47).

(A.26)

Treatment of Virilizing Adrenal Hyperplasia (1926-52) The benefits of removing tumors from patients with adrenal virilism led Broster (Fig. A.6) to suggest that partial excision of hyperplastic glands might be equally effective. He recognized three varieties of virilizing hyperplasia in women: (1) congenital pseudohermaphroditism, (2) postpuberal virilism, and (3) the Achard-Thiers syndrome, which he later regarded as synonymous with Cushing's syndrome. He undertook preliminary laporatomy to assess the adrenals and then removed the larger gland completely at thoracotomy. He performed this operation first in 1926, and in 1932 reported the results in three typical patients, one from each group(20). The woman with postpuberal virilism lost her excess hair within three months, and her menses returned. The pseudohermaphrodite, who was treated after puberty, improved slightly, while the patient with the Achard-Thiers syndrome was unaffected. Later Broster recognized a fourth group of women with postmenopausal virilism (53). He published his results regularly and by 1939 had operated on fifty patients, with one operative death, probably due to adrenal insufficiency (21, 46, 54). The largest number had postpubertal virilism, and all derived benefit, which he described as "good" in about 70 percent. The other groups of patients did not do so well. Broster's practice then evolved in two main ways(55). First, he found that congenital pseudohermaphroditism was best treated before puberty, when "clinical improvement of an entirely different order was achieved." The patients developed secondary sexual characters, lost their hirsutism, and grew luxuriant hair on their scalps. He reared the children as girls and performed clitoridectomy. Second, considering that more extensive adrenal resection might provide better results, he removed progressively more tissue, ending up with "subtotal adrenalectomy." Although six of thirty-seven patients (16

158 • History of Endocrine Surgery percent) died after this procedure, the survivors fared much better than those who had had one gland removed. (A.27) Hugh Young was the other main advocate of adrenalectomy for virilizing hyperplasia (23b, 24). From 1933 onwards he removed a third or more of each gland at one operation, employing (from 1936) his posterior approach (p. A. 13). The results were similar to those of Broster, especially in female pseudohermaphrodites. Young found, by endoscopy and contrast radiography, that the urethra and vagina in these patients opened into a persisting urogenital sinus, and employed plastic operations to provide separate openings for them in the perineum. He shortened the clitoris instead of amputating it. (A.28) Most clinicians did not share Broster's and Young's enthusiasm and were unimpressed by the results of adrenalectomy. However, no other effective measures were available, and the treatment of virilizing hyperplasia remained unsatisfactory until 1950(56). (A.29) Cushing's Syndrome Before the Advent of Cortisone (1932-49) After 1932 many patients with pituitary basophilism and related conditions were reported(54, 57, 58, 59). Cushing's syndrome and adrenal virilism were not always clearly distinguished (60), and the term "suprarenal cortical syndrome" was sometimes used to describe both. Edwin Kepler at the Mayo Clinic(61) stressed the frequency of intermediate forms, especially with adrenal carcinomas, but Fuller Albright of Boston, a pioneer of metabolic balance studies, was convinced that they were "entirely different and fundamentally opposite conditions" (62). Cushing's syndrome was characterized by atrophy of tissues and, in childhood, lack of growth, all attributable to a hypothetical "sugar hormone." Virilism was associated with hypertrophy of tissues and very rapid growth, perhaps caused by a "nitrogen hormone." Diagnosis was made mainly on clinical grounds, without specific laboratory aids, and all the syndromes were probably diagnosed too often (58, 63). The essential lesion in Cushing's syndrome was obscure(64), some maintaining that a basophil adenoma, when present, stimulated oversecretion, hyperplasia, or even neoplasia of the adrenal cortex, while others regarded the adrenals as the source of the disease. Some patients with apparently healthy endocrine glands had tumors in other organs, particularly the thymus, pancreas, or bronchus. In 1935 Arthur Crooke of London observed that the cytoplasm of the basophil cells in the pituitaries of twelve patients with unequivocal Cushing's syndrome showed hyaline changes, whatever the underlying lesion(65). The cells of basophil adenomas, however, were not affected. This was the only constant change in the endocrine glands, and Crooke regarded it as the primary lesion, while others considered it to be secondary. (A.30)

The Adrenal Glands (A) • 159 Early attempts at rational treatment were directed at the pituitary by Cushing himself, owing to his "growing conviction" that basophilism was the root of the disease (p. A.25). His first patient underwent subtemporal decompression, and two others received x-ray treatment, all with great improvement. By 1933 there was clear evidence that the pituitary secreted an adrenocorticotrophic factor (66), which was later recognized as a hormone and named (adreno)corticotrophin (ACTH), and this reinforced Cushing's concept. In 1933 or 1934 Howard Naffziger, a neurosurgeon in San Francisco and a pupil of Cushing, undertook partial hypophysectomy in a patient with florid Cushing's syndrome whose fossa was "ballooned," but who had no neighborhood symptoms (67). He partially removed an "adenoma" whose cells were not basophilic and whose nature remained obscure. However, a "spectacular transformation" followed for about a year, after which some features of the disease returned. Pituitary irradiation was given without benefit, but eighteen months later an adrenal tumor was suspected. Surgical exploration revealed normal glands, which were subsequently irradiated (1,200 r), again without improvement. Finally, about six years after the hypophysectomy (April 1940), subtotal adrenalectomy was proposed, but declined, and the patient died. Another of Cushing's pupils, Alfred Pattison of Newcastle-upon-Tyne, treated two patients with Cushing's syndrome by insertion of radon into the pituitary at craniotomy in 1934 and 1935, and other patients were treated similarly at about the same time, all with some improvement (p. P. 107). (AJI) In the 1940s Albright attempted to suppress corticotrophic activity with testosterone, but without benefit, except for temporary promotion of protein anabolism(68). Other hormones and weight reduction were also ineffective. Pituitary irradiation was the best method of treatment at this time, nearly half the patients showing improvement, sometimes for long periods(69, 70). The dosage, however, was less than 3,000 r in nearly all, whereas the optimal dose appeared to be about 4,500 r in four weeks(71). Some radiotherapists gave higher doses still, claiming recovery in half the patients (72). (A.32) Kepler maintained that, whatever the underlying cause, the development of Cushing's syndrome required the presence of the adrenal cortex (64). He and his colleagues at the Mayo Clinic had not obtained good results from pituitary irradiation and therefore concentrated on adrenalectomy. The principal surgeons were Waltman Walters (Fig. A.7) and James Priestley (Fig. A.8), and the other internists were Russell Wilder, Randall Sprague, and Robert Salassa. There were three main problems: (1) to determine the nature of the adrenal lesion, (2) to relieve the syndrome in patients without adrenal tumors, and (3) to prevent operative deaths from adrenal insufficiency. In ten female patients whom they reported in 1934(57), the adrenals were tumorous in five (four carcinomas and one adenoma), hyperplastic in three, and apparently normal in two. One tumor was palpable, one was seen

160


on x-ray (p. E.52-53), three were found at operation, and all five were removed. Three of these patients developed acute adrenocortical failure, and one of them died. She had been treated (in 1923) with blood transfusion and adrenaline before specific measures were available (17). The other two received cortical extracts and recovered. Three of the five patients with tumors underwent remission. (A.33) F o u r of t h e five patients with n o n t u m o r o u s adrenals h a d half of each gland r e m o v e d . T h e y were n o t given cortical extract a n d did n o t develop insufficiency, b u t o n e died from infection. N o n e derived benefit. T h e last patient was t o o ill for operation a n d was found at autopsy t o have a thymic tumor with very large adrenals. Some other surgeons treated patients with nontumorous glands in the same way and claimed better results, but partial adrenalectomy was not adopted generally, any more than it was for virilizing hyperplasia(27, 58, 68, 73). By 1938 the Mayo group had removed tumors successfully from sixteen consecutive patients, most of whom had Cushing's syndrome (74), and ten years later their results were even more impressive (75). Elsewhere, however, adrenal crises were all too frequent after removal of these tumors (76), and by 1943 more than 80 percent of such patients were reported to have died. On the other hand, removal of tumors for virilism was usually uncomplicated (47). The success with tumors causing Cushing's syndrome at the Mayo Clinic was apparently due largely to the potent preparation of cortin that was made there (p. A.41). (A.33a) Because of this M a y o experience, Kepler proposed in 1942 that they should use total adrenalectomy for patients with Cushing's syndrome without adrenal tumors (77). This procedure was even more hazardous in man than in animals. Charles Huggins of Chicago used it soon after to treat four patients with prostatic cancer, but only one survived for three months (p. C.6). The Mayo group therefore began in August 1945 to employ subtotal adrenalectomy, removing all of one gland and about 80 percent of the other (26). Despite intensive care and large doses of cortin, the postoperative course was often stormy, and six of twenty patients died. (A.34) The bleak prospects for most patients with Cushing's syndrome up to this time were described by Charles Plotz and colleagues from New York in an important and much quoted paper, "The natural history of Cushing's synd r o m e " (70). Analysis of 222 patients (including 33 of their own) showed a high incidence of arteriosclerosis, psychosis, and osteoporosis. Therapy had been effective in only five (15 percent) of their patients—irradiation of the pituitary in three and excision of adrenal adenomas in two. Half of all the patients had died within five years of the onset of the disease, the duration of survival ranging from one to twenty years. The commonest causes of death in the whole series were bacterial infection, cardiovascular disease, surgical operations (20 p e r c e n t ) , and carcinoma of the adrenal glands, thymus, and pancreas. Antibiotics had not influenced the infections, and the operations had been complicated by adrenal insufficiency, infections, and poor wound healing. T h e outlook was indeed depressing. (A.35)


• 161

Adrenocortical Tumors (1930-50)

Although adrenocortical tumors were rare, details of nearly 300 patients were published between 1930 and 1949(76,78). Pathologically, most were recognized as carcinomas, and metastases were often seen initially or soon after operation. Adenomas were usually small and were diagnosed less frequently. The term "hypernephroma" was no longer used, except to describe renal carcinomas(79). The clinical features were, in order of frequency, virilism, Cushing's syndrome, and mixed Cushing's syndrome and virilism, which together accounted for three-quarters of the patients. The remainder had the newly described syndromes of virilism in boys, feminization in men, or other rarities, while some tumors apparently did not secrete hormones and a few defied classification. Three-quarters of the patients underwent operation, and one-third died postoperatively. The mortality was greatest in patients with Cushing's syndrome, many of whom had atrophy of the nontumorous adrenal, and least in those with nonsecreting tumors, in whom atrophy was not seen. Some of the results were surprisingly good in those who survived operation. (A.36) Virilism, which was well known in women and girls, was also recognized in boys, in whom it caused precocious isosexual pseudopuberty. This had been reported about twenty times by 1940, and six patients had undergone operation, three of them successfully (59, 80, 81). (A.37) "Feminization" in men, attributed to estrogen excess, was observed in 1918, but only about twelve patients were reported in the next thirty years(45, 82, 83, 84). Most patients were aged between 25 and 45, but one was a boy of 15. All suffered mammary enlargement, testicular atrophy, and loss of libido, and all had malignant tumors. An excess of estrogens was found in the urine of some patients. Gundaker Holl of Graz, Austria, removed a tumor from one man in 1929, with restoration of male sexuality within six months, and others later reported operations with good early (A.38) results (85). Some tumors causing Cushing's syndrome had been found in ectopic adrenal tissue, and in 1944 the Mayo group collected fourteen patients with such lesions, including Bovin's (p. A . 2 2 ) , who probably had simple virilism(86). All the others, however, had a mixed Cushing's and virilizing syndrome. T h e tumors were in the ovary, or close to it, but the histological features suggested an adrenal, rather than an ovarian, origin. All were removed surgically, with, surprisingly, only one operative death, and all but one of the survivors were apparently cured. (A.39) In 1930 H o r a c e A n d e r s o n of Johnstown, Pennsylvania, described an adrenocortical carcinoma with fatal hypoglycemia, but no other metabolic disturbance(86A). A b o u t ten similar patients with " A n d e r s o n ' s syndrome" were reported in the next thirty years (87). The hypoglycemia seemed to be caused by the t u m o r s , because in some cases it was corrected by their removal. O t h e r rare syndromes included diabetes mellitus in a patient with

162


no other signs of adrenal disease, who was cured by removal of a large tumor (88). Very rare benign adrenal tumors, containing hematopoietic and adipose tissue, were first described in 1905 and named myelolipomas in 1929(89). Most were symptomless and were discovered incidentally at autopsy.

(A.40)

Parallel Developments The Search for Cortical Hormones The search for cortical hormones was pursued intensively in the 1930s. The efficacy of cortical extracts (cortin) was tested by their capacity to sustain animals after adrenalectomy and to restore the health of patients with Addison's disease (90). Until about 1940 it was assumed that cortin was a single substance and that its essential role was the regulation of mineral metabolism. After all, patients with Addison's disease were found to be deficient in sodium and chloride, but retained potassium; sodium chloride was beneficial therapeutically; and excessive consumption of potassium was harmful. T h e search was led by two chemists, Edward Kendall (Fig. A.9) (who had earlier isolated thyroxine [p. T.51]) at the Mayo Clinic and Tadeus Reichstein in Zurich and Basle. In 1937 deoxycorticosterone ( D O C ) , the first product of the adrenal cortex to be synthesized, was found to be a steroid, and the next year it was used to correct the mineral abnormalities of Addison's disease. Soon it was employed with cortin and saline to support patients after the removal of adrenal tumors. However, in excessive dosage it either caused hypertension and e d e m a , which could be prevented by reduced sodium intake, or resulted in prostration and paralysis, which could be counteracted by potassium. Whole adrenal extract, on the other hand, could be given in unlimited dosage, at least for a short time. F u r t h e r m o r e , unlike the extract, D O C did not produce a sense of well-being in patients with hypoadrenalism. D O C was clearly not cortin. By this time, however, other adrenal steroids had been found, notably two similar c o m p o u n d s , later n a m e d cortisone and cortisol, with identical functions. A t first they were thought to be unimportant because they had little effect on mineral metabolism. In the late 1930s, however, cortin was found to be active also in carbohydrate and protein metabolism, facilitating gluconeogenesis (62). In 1940 it was realized that the adrenal cortex produced several steroids, two types of which, acting together, were essential to life. O n e was cortisone/ cortisol, which came to be known as the glucocorticoid or "sugar h o r m o n e . " The other was an unidentified mineralocorticoid, thirty times m o r e potent than D O C , which remained in an " a m o r p h o u s fraction" after all the known steroids had been removed from Kendall's cortical extract. (A.4i) Until then crude adrenal extracts and D O C had been prepared commercially, but the pure glucocorticoids were very scarce. By 1948, however, a


• 163

few grams of cortisone were available for clinical investigation, and Addison's disease was chosen for study. But Philip Hench, a rheumatologist at the Mayo Clinic, persuaded Kendall to provide enough to treat patients with rheumatoid arthritis. The effects were spectacular, and in 1950 Kendall, Hench, and Reichstein were awarded a Nobel Prize. There was an immediate clamor for cortisone, and soon a simpler method of preparation was found. The effects on adrenal and pituitary surgery, and on medicine and surgery as a whole, were immense. (A.42) The potent mineralocorticoid in Kendall's amorphous fraction was isolated, analyzed, and synthesized between 1952 and 1955 by James Tait and Sylvia Simpson in London, Reichstein and workers at CIBA Laboratories in Basle, and their colleagues(91). It was named electrocortin at first and aldosterone later. (A.43) Soon after t h e discovery of c o r t i s o n e , active synthetic a n a l o g u e s , notably prednisone, prednisolone, and dexamethasone, were introduced and proved useful therapeutically and in the investigation of adrenal disease. Similarly, fludrocortisone, a potent synthetic analogue of aldosterone, introduced in 1956, rapidly replaced D O C for replacement therapy, (A.44) Related work resulted in the discovery of other steroids, including androgens, estrogens, and progestogens from the adrenals and from the gonads. T h e physiological roles of these other adrenal steroids were not known, but they appeared to be important pathologically. (A.45) Physiology Vigorous research into the physiology and pathology of the adrenal cortex accompanied the discovery of the cortical hormones. T h e two inner zones (fasciculata and reticularis) were found to synthesize and secrete cortisol and sex hormones under the influence of corticotrophin ( A C T H ) , whose secretion was itself regulated by the hypothalamus and by cortisol (p. P.46). The zona glomerulosa secreted aldosterone, mainly in response to the electrolytic and fluid status of the body, mediated via renin from the kidneys and angiotensin in the blood. Cortisol and cortisone were in chemical equilibrium and had the same actions. They were secreted in a circadian rhythm, their blood levels being highest in the morning and lowest around midnight. T h e glucocorticoids catabolize protein, encourage gluconeogenesis, influence the distribution of fat, play a minor role in electrolyte metabolism, help to maintain the blood pressure, and play a vital role in the response of the body to stress. W h e n glucocorticoids are secreted or administered in excess, these effects are exaggerated, blood pressure is raised, inflammatory reactions are inhibited (hence their action in rheumatoid arthritis), and wound healing is disturbed. After some time all the features of Cushing's syndrome develop (92). Unless stimulated by corticotrophin of pituitary origin, excess of cortisol inhibits A C T H secretion, and the adrenal cortex atrophies. T h e adrenal androgens are virilizing and

164 • History of Endocrine Surgery anabolic, while estrogens are feminizing, but both are unimportant physiologically. Aldosterone controls electrolyte changes in the distal renal tubules, intestines, and sweat glands, promoting the retention of sodium and chloride and the excretion of potassium. (A.46) Pathology Lesions of the adrenal cortex, associated with hypersecretion of hormones, had long been recognized as bilateral hyperplasia (diffuse or nodular) and unilateral tumors (adenomas and carcinomas) (93). Excess of cortisol, androgens, estrogens, and aldosterone caused Cushing's syndrome, virilism, feminization, and Conn's syndrome (aldosteronism, described in 1955 [p. A.81]), respectively. In Cushing's syndrome due to hyperplasia the adrenals secreted cortisol at a constant rate, and the blood level remained at its normal morning peak most of the time. Excess of ACTH caused adrenocortical hyperplasia and, in time, Cushing's syndrome, while hypopituitarism resulted in atrophy (p A.26). Adrenal tumors, on the other hand, were largely autonomous, and those that secreted cortisol inhibited the secretion of ACTH and caused the nontumorous gland to atrophy. For this reason death from adrenal failure often followed surgical removal of tumors that secreted cortisol. Cortisol excess from any source also caused Crooke's hyaline changes in the pituitary basophils. Tumors of other organs, associated with Cushing's syndrome, included bronchial oat cell carcinoma and carcinoids, thymomas, and islet cell tumors of the pancreas. Later (in 1961 and 1962), when ACTH could be measured, they were found to secrete it and to cause the ectopic ACTH syndrome (p. M.21). Hyperplastic and tumorous adrenals, causing virilism, were found by Howard Vines, a pathologist and colleague of Broster, to turn red with the Ponceau-Fuchsin stain (46). This reaction was associated with androgen excess. (A.47) Investigation of Adrenocortical Disease (1930-50) Measurements of androgens and estrogens in the urine by bioassay and by chemical methods were used to investigate adrenocortical syndromes in the 1930s, but unfortunately they were not helpful in patients with early disease, when they were needed most(46, 6 1 , 8 1 , 82, 94). (A.48) Measurement of urinary 17-ketosteroids (later known in Britain as 17-oxosteroids), developed in the 1930s, became in the next decade the first general test of adrenocortical function (75). These steroids are mainly metabolites of androgens, derived principally from the adrenals in both sexes and from the testes also in men. Their excretion was increased in patients with adrenal virilism and reduced in those with Addison's disease. They were of less help in the diagnosis of Cushing's syndrome (68, 70). Very high levels were usual with adrenal carcinomas of all types. Several methods for measurement of "corticosteroids" (glucocorticoids and their metabolites) in the urine came into use in the late 1940s. Although relatively nonspecific, they


• 165

were more helpful than the 17-ketosteroids in the diagnosis of Cushing's syndrome (69). The excretion of both these groups of steroids fell immediately after the removal of adrenal tumors (75) or total adrenalectomy. (A.49) Other nonspecific laboratory findings, which sometimes assisted the diagnosis of Cushing' syndrome, included hyperglycemia and hypokalemia(61, 69, 70). Cushing's syndrome and Addison's disease had opposite effects on the electrolytes.

(A.SO)

R a d i o g r a p h y b e c a m e a n essential part of t h e investigation of Cushing's syndrome. Most patients had osteoporosis, often with spontaneous fractures and kyphosis, and some had small renal calculi. Despite the frequency of pituitary tumors, only two patients with abnormal fossae had been reported by 1949 (69). (A.SD In the 1930s x-rays were used regularly to locate hyperfunctioning lesions that were suspected clinically. Plain films and pyelograms, used widely at this time, sometimes suggested the presence of tumors(20, 59, 66, 80), and later tomography improved the diagnostic accuracy (95). (A.52) The first method used to demonstrate the adrenals themselves was retroperitoneal insufflation of gas by the lumbar route. This was introduced in Europe in the 1920s, but complications, including mediastinal emphysema and air embolism, occasionally fatal, had been reported(94), and the method was not used widely until George Cahill of New York described it again in 1935(96). Oliver Cope and Richard Shatzki in Boston found that it was safe and useful for visualization and exclusion of small tumors, but that hyperplastic glands could not be seen(94). The Mayo group, who did not find insufflation helpful(26,61), and Broster and Young, neither of whom used it, preferred pyelograms, followed by surgical exploration of the glands and immediate treatment of any lesions that they found. In general, tumors were confirmed in only one-third of patients in whom they had been suspected radiologically(70). Insufflation was improved in various ways, including simultaneous pyelography and tomography, presacral (instead of lumbar) injection, and the use of different gases, particularly carbon dioxide, which reduced the risks. Although leaving much to be desired, this remained the best available procedure for the next few years (97). (A.53) Cushing's and Adrenogenital Syndromes after Cortisone As soon as the surgeons at the Mayo Clinic obtained cortisone, they used it for subtotal adrenalectomy in the treatment of Cushing's syndrome. The first patient received it preoperatively on December 3, 1949(98), and in little over a year eighteen patients had been treated and all had survived operation (26). Three injections of 200 mg were usually given intramuscularly before operation, and the dosage was tapered off afterwards. One adrenal crisis was treated with adrenocortical extract. A delayed reaction was often seen ten to twenty days after the second operation. This was characterized by anorexia, vomiting, weakness, fever, tachycardia, and

166


pains in the muscles and joints, but no fall in blood pressure. It sometimes persisted for four to six weeks and responded promptly to cortisone. All but one of the first twenty patients who survived subtotal adrenalectomy (both before and after the introduction of cortisone), and who lived long enough to be assessed, underwent remission. Two of these, however, required further removal of adrenal tissue, and three patients suffered recurrence within three years owing to regeneration of adrenal remnants. Chronic adrenal insufficiency with Addisonian pigmentation was a problem in some, but the patients were well maintained with cortisone. (A.54)

Other surgeons in the United States and Europe soon reported similar results(27, 99, 100, 101, 102). Norepinephrine infusions were found to provide effective treatment of postoperative adrenal crises until 1957, when intravenous preparations of cortisol (hydrocortisone) were introduced and proved more effective (103). Attempts were made to avoid problems arising from the unpredictable behavior of the small adrenal remnant. Hartwell Harrison of Boston employed total adrenalectomy, with permanent replacement therapy (99). Fritz Linder of Berlin transplanted some resected adrenal tissue into a superficial muscle so that it could be readily removed if the syndrome persisted or recurred(104). Cope, of Boston, whose work with Albright, from the 1930s, paralleled that of the Mayo group, had lost only one of eighteen patients since employing cortisone. He maintained that Cushing's syndrome was primarily an adrenal disorder, and preserved 5 to 10 percent of each gland in the hope of restoring normal function. His results, however, were similar to Priestley's. Some irradiated the pituitary after operation to discourage adrenal enlargement (101). (A.55) In general, normal adrenal function was restored in less than 10 percent of patients by subtotal adrenalectomy. The management of Addison's disease and total adrenalectomy with cortisone, salt, and DOC was proving relatively simple and, for these reasons, many surgeons regarded total adrenalectomy as the treatment of choice. By 1961 the Mayo group felt that it was "well justified in many cases" (105), especially in those with large pituitary tumors (106). By this time also oral fludrocortisone was available as a simple substitute for aldosterone. (A.56) Cortisone also provided effective cover for the removal of adrenal t u m o r s causing Cushing's s y n d r o m e , a n d in 1955 C o p e reported excision of eleven a d e n o m a s with o n e operative death (68). All such patients u n d e r w e n t remission, and adrenal function was restored eventually in nearly all. Patients with adrenal carcinoma, most of w h o m n o w survived operation also (107), usually h a d rapid remissions a n d regained adequate adrenal function, (A.57) T h e results of adrenalectomy in many series of patients in the succeeding years were consistently g o o d ( 1 0 8 , 109, 110, 111, 112). W o u n d infection however, was c o m m o n , a n d t h e mortality was 2 to 5 percent, p u l m o n a r y embolism being a c o m m o n cause of death. Remission followed rapidly in

The Adrenal Glands (A) • 167 nearly all the survivors and was usually complete in one year. Patients who suffered recurrence after subtotal adrenalectomy were treated effectively by removal of the adrenal remnants, which was comparatively simple when one gland had been removed completely (113). Later iodocholesterol scanning (p. A.78) aided localization when the site of the remnant was unknown. A few patients were weaned off therapy after total adrenalectomy, and a very few suffered recurrence, probably as a result of hyperplasia of ectopic adrenal tissue or of incomplete operations (114). More than half the patients who received autografts after total adrenalectomy regained normal adrenal function(115), but the procedure was used very little. After bilateral adrenalectomy two-thirds of the patients survived from five to fifteen years and one-half for twenty years (116). After removal of benign adenomas nearly all patients lived in good health for many years(116, 117). Those with carcinomas fared badly, and very few lived longer than five years (116). (A.58) Alternative or additional methods of treatment were often used. External irradiation of the pituitary with 4,500 to 5,000 rad in one month was employed in many centers, often as the primary method of treatment. At Nashville, Tennessee, 20 percent of adult patients were cured and another 25 percent considerably improved (117), while 80 percent of children were cured (118), but the responses were much slower than those following adrenalectomy. Intensive irradiation of a small area of the pituitary, reported from Copenhagen in 1980, gave excellent early results(119). Proton irradiation of the pituitary cured two-thirds of patients in the early years (from 1957) and almost 90 percent later (p. P. 106). Partial pituitary ablation by interstitial irradiation of the pituitary with seeds of Au-198 was described in six patients with Cushing's syndrome by Russell Fraser and Graham Joplin from London in 1961 (p. P. 108). By 1973 fifty-seven patients had been treated with Au-198, Y-90, or both(120). Full remission followed in two-thirds when the fossa was normal, but in only one-fifth when there was an obvious tumor, and half the patients required replacement therapy. Patients who failed to respond or who relapsed were reimplanted or treated by other means. Overall survival was similar to that following adrenalectomy. By 1979 the results were as good as those following surgical operations. As with external irradiation, children responded particularly well (121). Patients with recurrence after total adrenalectomy also obtained remissions (122). (A.59) Treatment of Cushing's syndrome with drugs that inhibit the secretion of cortisol was introduced in the later 1950s(123, 124). They were employed initially as alternatives to pituitary irradiation or surgical operations, and for symptomatic relief of patients with incurable tumors. The first drug was amphenone, which was soon superseded by metyrapone (first known as SU 4885). Drugs that inhibit the secretion of all adrenal steroids followed, aminoglutethimide in the mid-1960s and tilostane a decade later. The use of metyrapone and aminoglutethimide, either alone or in combination, per-

168 • History of Endocrine Surgery sisted into the 1980s. Mitotane (first known as o,p' DDD), which causes necrosis of normal, hyperplastic, and neoplastic adrenocortical tissue, came into use in the late 1950s and has also survived. All proved effective to varying degrees, but required close supervision and were liable to complications. They found their main roles as adjuncts to more definitive forms of therapy, such as pituitary irradiation(125), and in the preparation of patients for adrenalectomy or hypophysectomy (126). Mitotane alone is potentially curative, but is also very toxic, and proved most valuable in the treatment of adrenal carcinoma (p. A.96). (A.60) While these alternative measures were evolving, adrenalectomy underwent refinements and operative morbidity was reduced. Four factors were probably responsible: (1) preoperative use of drugs, especially metyrapone (126); (2) measures to prevent deep venous thrombosis (108); (3) the use of prophylactic antibiotics and of vitamin A (127) to prevent wound infection and dehiscence, respectively; and (4) widespread employment of Young's posterior approach for removal of benign lesions (25,128). Adrenalectomy continued to have a valuable place in the treatment of Cushing's syndrome in selected patients (124) (A.6i) Adrenogenital Syndrome Adrenocortical extract and D O C failed to save the lives of patients who died after extensive adrenalectomy for virilism. Cortisone, however, revolutionized the situation, rendering subtotal adrenalectomy safe(55). It also had another more important effect, for Lawson Wilkins of Baltimore, a pioneer of pediatric endocrinology, found in 1950 that the administration of cortisone alone suppressed the abnormal secretion of androgens in congenital virilizing hyperplasia and provided an effective form of treatment (129). From then on adrenalectomy was rapidly superseded for this condition and for the adult variety (97, 130). Operations were still required to remove adrenal tumors, to determine the sex of patients in whom it was ambiguous, and to correct external genital defects. (A 62) Surgery in Adrenal Insufficiency

In 1897 August Jonas of Omaha, Nebraska, removed a large abdominal mass from a patient with features suggestive of Addison's disease (131). The lesion was tuberculous and in the adrenal. The other gland was probably unaffected, because the patient was cured, and Jonas remarked that "when both adrenals are involved, the most enterprising surgeon would scarcely have the hardihood to remove both glands." At least three other operations for unilateral removal of caseous adrenals were described at about the same time (132), and an operative route for "excision of the suprarenal glands in cases of Addison's disease" was described in 1906(133). Nevertheless, the condition acquired a sinister reputation among surgeons. Tuberculous

The Adrenal Glands (A) • 169 lesions requiring operation often developed elsewhere, and even minor procedures sometimes precipitated acute crises (1). In 1933 Waltman Walters reported fifteen operations on Addisonian patients (132). Eleven had died after major procedures, but three had survived minor ones. Cortical extract had been used successfully in one patient to cover orchiectomy for tuberculous epididymitis. No report of a successful major operation in an Addisonian patient was found. (A.63) Several attempts to relieve Addison's disease by transplantation of t h e adrenals from animals and m a n were m a d e from 1897 onwards, but mostly without success (1). Probably t h e best result was obtained in 1916 by Frederick Pybus of Newcastle-upon-Tyne, w h o inserted subcutaneously the freshly bisected glands of an adult accident victim (134). T h e patient recovered, lost his pigmentation, and returned to full work as a miner. Symptoms r e t u r n e d after two years, a n d a second transplant (of only half a gland) o n e year later, although not so effective as t h e first, allowed him to u n d e r t a k e light work for at least five years. Some other good short-term results were r e p o r t e d ( 1 3 5 ) . O n e patient, w h o received a graft from a n e o n a t e , was in excellent health four m o n t h s later (136), and two w h o h a d fresh grafts of hyperplastic glands from patients with adrenal virilism were well a year later(137, 138). (A.M) By t h e early 1950s t h e role of t h e adrenal cortex in t h e response of t h e body to surgical stress was recognized, and cortisone h a d transformed t h e lives of patients with A d d i s o n ' s disease. They could b e operated on safely, and adrenal grafts were no longer needed(139,140). At the same time other causes of adrenal failure, which might complicate operations other than adrenalectomy and hypophysectomy, were being recognized frequently and treated effectively (141). These included acute hemorrhage and exhaustion of the adrenals, the dysfunction of virilizing hyperplasia, in which cortisol secretion is deficient, and hypophyseal failure(139). (A.65) T h e benefits of cortisone h a d hardly b e e n discovered when adverse effects became apparent (92). Cortisone therapy unfortunately caused adrenal atrophy, and impairment of adrenal function often outlasted treatment for a long time. The stress of a surgical operation could then prove fatal, as reported in one patient in Tucson, Arizona, in 1952(142) and in two at the Mayo Clinic the next year (143). It was suggested that ACTH would have the same effect. Many similar observations were soon made(144), and it became routine practice to warn patients of the dangers, to inquire about steroid therapy before all surgical operations, and to give additional steroids prophylactically and therapeutically when appropriate (145, 146). Some surgeons also measured adrenal function to assess the need for therapy(147), while others either prescribed it routinely(144, 145, 146) to patients who had had steroids or ACTH in the past, or gave it intravenously in emergency (146). With experience and education the problem practically vanished.

(A.66)

170 • History of Endocrine Surgery Pituitary Tumors in Cushing's Syndrome In the first twenty years after Cushing's description of pituitary basophilism in 1932 (p. P.32), pituitary adenomas were found at autopsy in many patients with this disease(70,148), but very few were recognized in life(69, 80, 149). Many more were found in life later on, but their significance remained obscure for years. (A.67) Pigmentation, which was t o prove very important, was present in four of Cushing's original patients, including the first, and was regarded as a "hypophyseal manifestation." It often appeared temporarily in the scars after adrenalectomy (103) and sometimes persisted in a more generalized form, as in several of Priestley's(26) and Cope's(68) patients. In 1955 Rudolf Siebenmann of Zurich described a woman with Cushing's syndrome who had signs of a pituitary tumor but a normal fossa on x-ray (150). The syndrome remitted after subtotal adrenalectomy, but recurred a year later, together with pigmentation. She died after removal of the adrenal remnant, and a large pituitary adenoma was found at autopsy. In 1958 Don Nelson and colleagues in Boston reported a patient who was in remission three years after total adrenalectomy and who developed pigmentation, chiasmal compression, a large sella, and very high levels of ACTH in the blood and of MSH in the urine (151). She responded well to treatment of a pituitary adenoma. The combination of pigmentation, a large sella, and high plasma ACTH in patients in remission after removal of hyperplastic glands came to be known as "Nelson's syndrome" and was observed independently by several others at about the same time(106, 152, 153). (A.68) Very soon, however (1959), Robert Salassa and Collin MacCarty at the Mayo Clinic reported that 10 percent of their patients had sellar enlargement and 7 percent had pigmentation also after operation (106). Most of these already had large sellae before operation, and half of them had clinical signs of pituitary tumor. Two patients (2 percent) had recurrence of Cushing's syndrome also, as in Siebenmann's case(154). Over half the tumors were confirmed histologically. Pituitary adenomas were not seen in thirtyfour patients with Cushing's syndrome due to adrenocortical tumors nor in those who had undergone adrenalectomy for other diseases. The next year (1960) Nelson's group reported nine further cases after adrenalectomy and described their syndrome fully (155). Pigmentation had developed in all ten patients one to eight years after operation, and all had high blood ACTH levels. Seven pituitary fossae had been x-rayed before operation and were normal, but eight of the ten were enlarged afterwards. Some of the patients then had ocular signs. (A.69) Soon over forty patients with Cushing's syndrome and histologically verified pituitary tumors (and many others with suspected tumors) had been reported worldwide (156). In most the tumors had been found when the syndrome was diagnosed, but in a few it antedated the syndrome, and in

The Adrenal Glands (A) • 171 one-fifth it did not reveal itself until after adrenalectomy. One-third were basophil and two-thirds chromophobe. One-quarter were malignant, and nearly half of these had metastasized outside the skull. Clearly, large pituitary tumors associated with Cushing's syndrome were very aggressive. Chromophobe tumors were the most sinister, and only about one-quarter of those treated were cured (157). Treatment of these patients depended on the circumstances (158). At the Mayo Clinic, when the tumor and the syndrome were clinically mild, the pituitary was irradiated initially. If the syndrome was severe or failed to respond, total adrenalectomy was employed, and craniotomy was undertaken for serious local complications. Results were best when the tumors appeared after adrenalectomy, intermediate when they accompanied Cushing's syndrome, and worst when they preceded it. (AJO) While all these tumors were being recognized in life, ideas about their significance were evolving. Severe pigmentation was rare in untreated Cushing's syndrome(159, 160), but increasingly common after adrenalectomy. Its cause was not known, but, like that in Addison's disease, it was attributed variously to ACTH, MSH, or both(158). Assays for these hormones, which were closely related, were biological and insensitive. The assay for ACTH used by Nelson (161) did not detect it in normal subjects or even in those with untreated Cushing's syndrome, but a more sensitive assay later showed that patients with Cushing's syndrome, including the ectopic ACTH type, and Addison's disease had elevated levels, and that those with Nelson's syndrome had the highest of all(155, 162). In 1958, when he reported his first patient, Nelson proposed that adrenalectomy might have stimulated the secretion of ACTH and the growth of pituitary tumor (151), and in 1959 Salassa suggested that adrenalectomy might enhance the growth of pituitary tumors already present (106). The fact that the most active pituitary tumors in Cushing's syndrome were chromophobe made it difficult to accept the concept of pituitaty basophilism (155), but evidence was accumulating that the chromophobe cells in these tumors, far from being inert, were secreting ACTH so actively that they did not store it in granules (156, 157, 158). At the same time the idea was gaining ground that the basic disorder in Cushing's syndrome lay in the hypothalamus or in the pituitary, with or without tumor formation, rather than in the adrenals, (AJI) Nelson's syndrome was recognized widely in the 1960s and 1970s, and diagnosed earlier than before, but it was soon realized that the features of pigmentation, sellar enlargement, and elevated ACTH did not always coincide. In adults pigmentation and large sellae were each reported in up to one-third of patients after adrenalectomy (not always together), and the proportions increased with the passage of time (163). Two-thirds of children had one or both of these characteristics, while only one-third were normal (164). The pigmentation was found to be caused by ACTH itself, rather

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than M S H (which does not occur in man [p. P.82]), and studies of A C T H by radioimmunoassay revealed very high levels in about 5 percent of patients before operation and in about one-third after (165). Some 85 percent of these were pigmented. Pigmentation was more frequent and A C T H levels were higher after total adrenalectomy than after subtotal. O n e report suggested that Nelson's syndrome could be prevented by irradiation of t h e pituitary at the time of adrenalectomy (117), but it was not generally confirmed (166). Many of these tumors were treated, and in the 1970s surgeons began to undertake transsphenoidal microsurgical operations. Patients with benign lesions, which were diagnosed early, usually fared well, but results were still worse than those for other types of tumor (p. P. 125). Those with histologically invasive tumors, perhaps 10 percent of the whole, died soon, whatever form of treatment was used (120, 121, 165, 166). (A 7 T h e syndromes described by Siebenmann and Nelson focused attention on pituitary tumors in Cushing's syndrome, but were seen to represent only certain aspects of the total spectrum of the disease. Interest in these tumors and the rapid development of pituitary microsurgery in the 1970s directed attention to adenomectomy as the first line of treatment in Cushing's syndrome. (A.73) Investigation of Adrenocortical Disease (1950-80) Measurements of adrenal steroids in the blood and urine improved greatly and became available generally (97, 167). Methods for glucocorticoids, including urinary free cortisol, made it possible to diagnose Cushing's syndrome confidently, and other individual steroids were of help in special circumstances. Measurement of aldosterone, renin, and angiotensin for the diagnosis of aldosteronism (p. A.81) were available in some centers.

(A.74)

It b e c a m e easier t o distinguish b e t w e e n adrenal tumors and hyperplasia in patients with Cushing's s y n d r o m e . A d r e n a l carcinomas usually secreted very large quantities of steroids, a n d all tumors secreted autonomously, while hyperplastic glands r e m a i n e d A C T H - d e p e n d e n t . This observation formed t h e basis of the d e x a m e t h a s o n e suppression and m e t y r a p o n e stimulation tests, a n d in t h e early 1960s these helped to differentiate b e t w e e n t h e lesions (105). A reliable radioimmunoassay ( R I A ) for A C T H , introduced in the mid-1960s, also assisted greatly in t h e diagnosis of Cushing's synd r o m e (168). Most patients with pituitary-dependent disease had high blood levels and n o circadian r h y t h m . Levels were usually higher still in the ectopic A C T H s y n d r o m e and highest after adrenalectomy. Conversely, A C T H was undetectable in patients with adrenal tumors. (A.75) Radiology of the adrenals left m u c h to b e desired at this time, and by 1955 C o p e regarded plain films, after good p r e p a r a t i o n , as just as informative as insufflation(68). Nevertheless, t h e latter was often used u p to t h e mid-


• 173

1970s(167). New procedures, however, were introduced for cortical and medullary tumors. Selective sampling of caval blood was used first in 1955 for the measurement of catecholamines and only later for steroids (169). Sampling from the adrenal veins followed and, when successful, improved localization (170, 171). Venous sampling led to phlebography, which sometimes revealed tumors (aldosteronomas) less than 1 cm in diameter(170, 172). Phlebography, however, gained a bad reputation among surgeons because it sometimes infarcted or ruptured the adrenals, making subsequent operations difficult (173). Infarction of the whole glands or of adrenal tumors by retrograde injection of sclerosing fluids was also used therapeutically, sometimes with success (28). thera A o r t o g r a p h y by the lumbar r o u t e , first used in t h e 1930s, sometimes outlined vascular adrenal tumors(174). Selective angiography was used commonly in t h e 1960s for t u m o r s a n d hyperplasia and was refined later by film subtraction (175). All these m e t h o d s required experience and skill, a n d were invasive. They were liable to cause bleeding, to d a m a g e t h e adrenals, and, in patients with p h e o c h r o m o c y t o m a s , to precipitate hypertensive crises, which were sometimes fatal(170, 176). (A.77) Noninvasive imaging was introduced in t h e 1970s. Scintigraphy of t h e adrenal cortex, developed by William Beierwaltes in A n n A r b o r , Michigan, was first used in m a n in 1970(177). Analogues of cholesterol, labelled with 1-131, were concentrated by normal a n d hyperplastic cortical tissue a n d by functioning a d e n o m a s , causing Cushing's and C o n n ' s syndromes and adrenal virilism. They were not taken u p by malignant or nonfunctioning t u m o r s . Medullary t u m o r s were suspected when cortical tissue was displaced, distorted, or destroyed. (A.78) Ultrasonography was applied to adrenal lesions in 1973 (178). Although it required experience a n d skill, it did n o t involve ionizing radiation a n d was adopted widely (179). C o m p u t e d axial t o m o g r a p h y ( C A T or C T scanning) of the body was introduced in 1975 a n d was also used whenever t h e expensive apparatus b e c a m e available (180). Ultrasound a n d C T scanning were both valuable for localizing lesions in the adrenals and elsewhere a n d , as m e t h o d s improved, C T scanning e m e r g e d as t h e best of t h e imaging techniques (179, 181, 182). C T scanning a n d ultrasonography of t h e a b d o m e n were so valuable a n d so readily available that they were often employed as early investigations in patients in w h o m any abdominal tumors were suspected. O n e result was that adrenal masses were seen unexpectedly, and many of these "incidentalomas," as they were called, were investigated in other ways a n d r e m o v e d surgically w h e n appropriate (182, 183). (A.79) U p to t h e mid-1960s small adrenal tumors were often difficult to find. By 1981 radiologists were almost embarrassed by t h e n u m b e r of effective tools from which to choose. In each center t h e choice d e p e n d e d on what was available a n d o n t h e expertise of t h e o p e r a t o r s , and surgeons very rarely found themselves operating in t h e wrong place (128). (A.SO)

174 • History of Endocrine Surgery Primary Aldosteronism—Conn's Syndrome In 1954, two years after the discovery of aldosterone, Jerome Conn (Fig. A. 10) of Ann Arbor, Michigan, who had long been interested in adrenal mineralocorticoids, described the syndrome of primary aldosteronism (184, 185). The first patient was a woman of 34 who had intermittent tetany, paresthesiae, periodic muscular weakness and paralysis, polyuria, polydipsia, and mild hypertension (BP 170/110 mmHg), but no edema. Laboratory tests showed severe hypokalemic alkalosis, hypernatremia, impaired renal tubular reabsorption of water, and an excess of aldosterone in the urine. Conn considered that total adrenalectomy, followed by substitution therapy, should abolish the metabolic abnormality, and William Baum (Fig. A. 11) operated on December 14, 1954. He found a cortical adenoma in the right adrenal and removed the whole gland, taking a biopsy from the left. The tumor was round, 4 cm in diameter, 14.8 g in weight(186), and deep yellow on its cut surface. Microscopy showed an encapsulated cortical adenoma and atrophy of the zona glomerulosa in the other gland. The tumor contained much aldosterone. All the symptoms were relieved, the metabolic abnormalities were corrected in ten days, the blood pressure fell to normal in eighteen days, and the patient remained well for at least five years (186). (A.SI) Within six weeks of the first report four other patients with primary aldosteronism were found elsewhere, and three were cured by removal of adenomas. This led Conn to advise that the electrolytes should be measured in hypertensive patients and that, if hypokalemic alkalosis was found and could not be readily explained, the adrenals should be explored surgically. More patients with primary aldosteronism were soon discovered in many countries, and thirty-one of them were reviewed in 1959(187). Single small (1-4 cm) adrenal adenomas, brilliant yellow on section, were the commonest lesions, and the patients were cured when they were removed. Histologically, these adenomas were indistinguishable from those causing other syndromes. However, a few patients with the same clinical and metabolic features had hyperplastic, carcinomatous, or apparently normal adrenal glands. The first with hyperplasia, affecting the two outer zones, was reported from Groningen, Holland(188), in 1956. A boy of 17 with malignant hypertension had had polydipsia since the age of 2 and was cured by removal of the whole of one gland and nine-tenths of the other by Leendert Eerland. He was maintained on cortisone. (A.82) By 1961 Conn had details of 108 patients with cortical adenomas, nine of them in his own care, nine from the Mayo Clinic, and smaller numbers from elsewhere(186). Their ages ranged from 15 to 70 years, and 70 percent of them were between 30 and 50. Nearly three-quarters were female. The adenomas were single in 90 percent, multiple on one side in a few, and bilateral in two. Some patients had hypertension only, others had periodic


• 175

muscular weakness, nocturnal polyuria, and headache also, while a few had the additional symptoms of paresthesiae and tetany. Investigations now also revealed mild proteinuria, neutral or alkaline urine of low specific gravity, increased urinary free aldosterone with normal excretion of glucocorticoids and androgens, hypokalemic ECG changes, and little sodium in the sweat. Adenomas were removed surgically from seventy-nine patients, with relief of symptoms and rapid reversal of the metabolic changes in three-quarters. The blood pressure fell to normal in two-thirds and was lowered in another 20 percent, but remained high in some (14 percent). Primary aldosteronism was clearly a curable form of hypertension that could be recognized in some symptomless hypertensive subjects by examination of their electrolytes and ECGS.

(A.83)

Nine other patients (including the Dutch boy) had hyperplastic or normal glands and differed from those with adenomas in several ways. They were all young (9 to 23 years), seven had had symptoms nearly all their lives, six of them were males, and five had malignant hypertension. T h e absence of tumors was discovered at operation, and all but one were cured or improved by total or subtotal adrenalectomy. Conn suggested that these patients had "congenital aldosteronism." N o n t u m o r o u s glands were found in nine additional patients who, like those with adenomas, were older than the previous group and mostly female. Removal of the hyperplastic glands corrected the electrolyte metabolism in all, but failed to lower the blood pressure in seven. Conn suggested that either primary steroid-induced hypertension had become irreversible or that the aldosteronism was secondary to a renal lesion.

(A.84)

Within a few years this secondary form of aldosteronism, caused by activation of the renin-angiotensin mechanism, was found to develop in two sets of circumstances. In o n e , the plasma volume was reduced by excessive use of diuretics, in certain renal diseases, after continued vomiting or diarrhea, and in conditions that caused edema (which is not present in primary aldosteronism). In the other, renin production was increased by renal lesions, including ischemia, tumors, and hyperplasia of the juxtaglomerular apparatus. Adrenalectomy was of no help in secondary aldosteronism, but surgical correction of unilateral renal lesions or nephrectomy was sometimes effective (p. H . 8 ) . Further refinements in diagnosis were clearly needed so that unavailing operations could be avoided. (A.85> Many of Conn's tumors had been sought by x-ray, but only a few of the larger ones had been seen, and most were discovered at operation(189, 190). It was some years before any surgeon treated many patients with aldosteronism, so that no consistent policy for dealing with the various lesions was developed at first. Single adenomas were subjected to unilateral adrenalectomy or adenomectomy, hyperplastic or normal-looking glands were removed totally, subtotally or unilaterally, and carcinomas were excised as widely as possible (190). Most patients received potassium sup-

176 • History of Endocrine Surgery plements, cortisone, and/or ACTH over the period of operation, and no operative deaths were reported at this time (187), although many patients died without operation (191). However, in the 1960s several surgeons reported series of their own. Reginald Smithwick(192) and Hartwell Harrison(193) from Boston, Reed Nesbit from Ann Arbor(191, 194), William Silen from San Francisco (195), and James Priestley from the Mayo Clinic(196) published their experience of 139 patients, 50 of them from Rochester. Smithwick, who always explored the adrenals while undertaking sympathectomy for hypertension, had found at least ten adenomas and three pairs of hyperplastic glands, causing aldosteronism, in 2,825 patients, and had removed many of the tumors. This incidence of 0.5 percent in patients undergoing operations for hypertension was the same as he had found earlier for pheochromocytoma (p. A. 117). One of Smithwick's patients was well fifteen years later. Some patients had been prepared for operation with the aldosterone antagonist, spironolactone, first used in 1962 by JackMobley and colleagues at Marrilton, Arkansas(195,196,197). Since bilateral total adrenalectomy might be needed in any patient, some surgeons gave cortisone before operation (196), while others simply administered hydrocortisone intravenously when required. Diuretic and antihypertensive drugs were withheld for a month before operation. Two operative deaths (1.4 percent) due to bleeding were reported, one from the site of a renal biopsy (195), the other from the adrenal bed (196), but there were few other serious complications.

(A.86)

One-third of t h e a d e n o m a s were small, soft, multiple, or bilateral, a n d often very difficult t o find. W h e n n o t u m o r was apparent a n d t h e diagnosis seemed certain, Priestley r e m o v e d t h e whole of one gland a n d half or all of the other, and in o n e case found a small a d e n o m a in the remaining portion of gland at a second operation. T h e results of operation were excellent w h e n tumors were r e m o v e d . Smithwick a n d Harrison, unlike C o n n , also found that five adults without t u m o r s benefitted from adrenalectomy. (A.87) Ten years after he first decribed t h e syndrome Conn postulated that changes in the serum electrolytes were late manifestations and that the other features alone provided adequate grounds for diagnosis and justified early operation(198, 199, 200). Four of eighteen unselected patients with normokalemic hypertension met these new criteria. Small tumors were found and removed, and all t h e patients were cured. This led Conn to assert that 20 percent of the hypertensive population probably suffered from normokalemic aldosteronism, but later he reduced this estimate to 10 percent (185). Nesbit found that these tumors were exeptionally difficult to identify. Sometimes he removed and sliced successive halves of each gland, starting on the left, where tumors were most common, and in two patients he found tiny a d e n o m a s in t h e final segments (200). Other workers failed to find normokalemic aldosteronism often and concluded that it was "a rare variant of a rare disease"(195, 2 0 1 , 202). (A.SS)

The Adrenal Glands (A) • 177 The distinction between primary and secondary aldosteronism was simplified when assays for renin and angiotensin were developed in the 1960s(194, 201, 203, 204, 205). The blood levels were very low in primary aldosteronism, as a result of sodium retention and hypervolemia, and high in the secondary disease(206, 207). In the 1970s attention turned to distinguishing between tumors and nontumorous glands, to investigating nonsurgical methods of treatment, and to locating tumors before operation. The biochemical abnormalities tended to be greater in patients with adenomas than in those without. In particular, the blood levels of aldosterone, sodium, and carbon dioxide were higher and those of renin and potassium were lower. The differences, however, were small and the two groups could only be separated confidently by computer-aided analysis, a method developed and used effectively in Glasgow (208). Another difference between the groups was that the plasma aldosterone levels rose in normal subjects and in those with hyperplasia when they were upright and active, while those in most patients with adenomas fell under the same conditions (209, 210). This formed the basis of a test that was used widely (173, 211). Spironolactone therapy lowered the blood pressure significantly in patients with adenomas, but had little effect in those with hyperplasia (211). (A.89) R e p o r t s of m o r e operations confirmed that surgical removal of single a d e n o m a s was usually beneficial, even w h e n t h e hypertension was severe (212), a n d that adrenalectomy for n o n t u m o r o u s lesions was less effective(202). C o n n ' s congenital aldosteronism was n o longer mentioned. Analysis of fifty patients o p e r a t e d on by A n d r e w Kay in Glasgow a n d K e n n e t h O w e n in L o n d o n was particularly informative (213, 214). Unilateral adrenalectomy for a d e n o m a s always reduced the blood pressure and often restored it t o n o r m a l for some years. Of ten patients with hyperplasia, two died after o p e r a t i o n , and the blood pressure fell to normal in only two of the remainder. N o precise diagnosis was reached in t w o other patients. Spironolactone, with or without potassium supplements, was generally given for at least four weeks to p r e p a r e patients for operation (167, 207). This corrected t h e metabolic disorders, including the low plasma renin, reduced the blood pressure to about the same level as the subsequent adrenalectomy, and could be continued for years if operation was not undertaken. Side effects were u n c o m m o n , but a very few patients (3 percent) could not tolerate the drug(207). A potassium-retaining diuretic, amiloride, was less effective but was useful in these circumstances (203). W h e n a tumor could be excluded confidently, spironolactone combined with hypotensive drugs became the preferred treatment. The risk of overlooking a malignant tumor was very slight(195, 203). (A.90) All methods of adrenal imaging and venous sampling were used in turn to identify tumorous and hyperplastic glands (p. A.76), but the small size of many aldosteronomas m a d e them difficult to demonstrate. By 1980 the most accurate methods proved to be selective venous sampling, which revealed

178


adenomas successfully in over 90 percent of patients and hyperplasia in three-quarters (173), and scintigraphy, which demonstrated adenomas correctly in nearly 80 percent of cases. By this time two or more methods were usually used for every patient, venous sampling and scintigraphy probably being the most popular, and the great majority of unilateral adenomas were displayed confidently before operation. For this reason it was usual to explore one side only, and the posterior route was becoming the most popular(116, 128, 211, 212). (A.9i) By 1980 less than 1 percent of the hypertensive population were considered to have primary aldosteronism (215), although estimates as high as 2 percent, and even higher in Black Americans, were sometimes made(216). W h e n aldosteronism was diagnosed, it was relatively easy, in centers adequately equipped, to distinguish between the primary and secondary diseases and, in the former, between patients with tumor and those with hyperplasia. A p p r o p r i a t e and effective treatment could be provided for nearly all. (A 92) Adrenocortical Tumors (1950-80) The pattern of presentation of adrenal tumors changed during the 1950s, 1960s, and 1970s as a result of the discovery of aldosteronomas in 1955 and the recognition of incidentalomas in the late 1970s. By this time, at the Mayo Clinic, the commonest type of cortical tumor to be removed was a nonfunctioning adenoma (31 percent) (128). Benign aldosteronomas were second (26 percent), adrenocortical carcinomas third (23 percent), and cortisolsecreting adenomas fourth (16 percent). Myelolipomas (3 percent) and virilizing adenomas (0.7 percent) accounted for the remainder. (A.93) The diagnosis of cortical adenomas improved steadily during the three decades, and localization procedures were refined. Virilism in adult women is not u n c o m m o n , and in the late 1970s scintigraphy was revealing some curable adrenal a d e n o m a s , not previously suspected(217). With cortisone replacement, when appropriate, operative mortality was almost nil and most patients were cured. A few, however, whose lesions had been regarded as benign, unexpectedly developed metastases later. (A.94) Many more carcinomas were reported, still presenting unsolved problems (107, 218). T h e tumors developed at all ages and most commonly in males, although m o r e were diagnosed in life in females. They affected both sides equally. T h e r e was a median lag of eight months between the onset of symptoms and diagnosis, by which time a mass was often felt and local invasion and distant metastases were commonly found. T h e principal endocrine features, present in over 90 percent, were (in order of frequency) Cushing's syndrome, virilization, a mixed hormonal syndrome, feminization, and aldosteronism. Rarely, carcinomas secreted corticosterone or deoxycorticosterone (DOC)(219, 220), either alone or with other steroids,

The Adrenal Glands (A) • 179 with effects similar to those of aldosterone, but with edema. Anderson's hypoglycemic syndrome was also reported rarely (221). The principal nonspecific features were pain and an abdominal mass. Urinary steroid excretion was raised, often greatly, in 80 percent of patients, including many of those without endocrine syndromes (222). Most patients in whom the diagnosis was made were treated by surgical excision of the primary lesion, when possible, often with temporary subjective and objective remission. Local recurrences were sometimes excised, and radiotherapy was used for inoperable tumors, but without benefit. The outlook was still bad, being worse for men and for patients with syndromes of steroid excess than for women and those with nonfunctioning tumors. However, no good statistics on survival were obtained before the introduction of chemotherapy. (A.95) In 1948 the insecticide DDD was found to cause atrophy of the adrenal cortex in dogs. The related o,p' DDD (later known as mitotane) was more potent and less toxic (223). In 1959 Delbert Bergenstal and associates at Bethesda, Maryland, found that it decreased steroid excretion and caused regression of metastases in many patients with adrenocortical carcinomas (223, 224). Unfortunately, all suffered anorexia and nausea, and some developed other reversible toxic reactions. The American National Cancer Institute sponsored a worldwide trial in 186 such patients, which was reported by Adolph Hutter and Donald Kayhoe of Bethesda (218). The drug was given orally, and the dose was increased to 8 or 10 g daily if it was tolerated, but toxic effects were common. Urinary steroids fell by more than 50 percent in two-thirds of patients, and measurable lesions shrank in onethird. Endocrine symptoms, when present, were often relieved. The median survival from onset was about four years and was rather longer in females than in males. Patients whose tumors responded lived longer than those who obtained no relief, and in females 90 percent of responders were alive three years after diagnosis, compared with 55 percent of nonresponders. Mitotane then came into general use for advanced adrenal carcinoma, but acquired a bad reputation because of its toxicity, which was related to dosage, and few patients survived more than five years (116). Adrenal blocking agents were often used for symptomatic relief, particularly in patients with Cushing's syndrome, when chemotherapy was ineffective or was not tolerated, (A.96) Attempts were made to diagnose and treat the lesions sooner by earlier exploration of tumors, including incidentalomas, without time-consuming preliminary investigations (225), and by such measures as brush biopsy of intravenous thrombi (226). Efforts to treat them more effectively included radical operations with thoraco-abdominal incisions, extrafascial dissection, splenectomy, partial pancreatectomy(227), and resection of intravenous extensions of tumors (228). Mitotane was sometimes administered in very large doses before recurrent lesions or metastases were apparent. Some surgeons gave large doses to all patients for a short time immediately after operation, and then smaller ones (1-2 g/day), which were tolerated better,

180


indefinitely. This policy appeared to increase the mean survival after operation to almost four years in one series(229). The Mayo experience, however, was more representative, only one-third of patients surviving two years after operations in the 1970s (128). Clearly, more effective measures were still needed. (A.97)

Pituitary Microsurgery for Uncomplicated Cushing's Syndrome With the success of adrenalectomy for the treatment of Cushing's syndrome, very few pituitary operations were performed as the primary form of treatment in the 1950s (230,231). In the early 1960s, however, when interest in the surgery of pituitary tumors was revived (p. P.74), surgeons increasingly employed hypophysectomy by all routes for this disease, (A 98) Discrimination between pituitary, adrenal, and ectopic lesions in Cushing's syndrome was unreliable at this time, and even in the mid-1970s errors were not uncommon (124). This was unimportant when adrenalectomy was used initially, because it controlled the syndrome at once and other tumors could be treated when they came to light. It was vital, however, when hypophysectomy was undertaken, and several patients who failed to respond to this operation were later found to have other lesions (p. M.24)(232, 233). The introduction of RIA for ACTH in the mid-1960s helped greatly (168), and each advance in radiology increased the proportion of microadenomas that could be detected (p. P.85). Those in Cushing's syndrome, being the smallest, were the most difficult to find, but by the early 1980s some lesions as small as 2 mm could be seen (234). (A.99) Most surgeons at first required t h e sella to be enlarged before operating, but G e o r g e D a l t o n , an E N T surgeon in Birmingham, England (a pupil of Angell James), used the transethmosphenoidal route for radical hypophysectomy in thirteen patients with radiologically normal fossae between 1963 and 1974(233, 235). Single adenomas were found in seven patients, basophil hyperplasia was described in three, Crooke's changes only were seen in two, and no abnormality was recognized in one. All had remissions, which were complete and lasting in twelve. Most patients required replacement therapy and, surprisingly, three women became pregnant. Jules Hardy, a neurosurgeon in Montreal, preferred microadenomectomy, sparing the normal tissue, in the hope of restoring normal pituitary function (p. P.80) (236, 237). He first undertook this procedure in 1963 in patients with abnormal fossae, but five years later (1968) he had the confidence to proceed without x-ray signs of a tumor (238, 239). By 1980 Hardy had operated on twenty-four patients and by 1982 on seventy-five, two-thirds of whom had normal fossae (234). Some neurosurgeons, including Charles Wilson in San Francisco and Rudolf Fahlbusch in Munich, followed this


• 181

practice, b u t others remained m o r e cautious(240, 241). T h e Mayo group, for instance, studied t h e pituitary fossae intensively and found radiological evidence of tumors in 80 percent of patients, w h o m they operated on (242). T h e others received radiotherapy or underwent adrenalectomy. (A.IOO) Pituitary microsurgery was difficult and required special expertise (237, 240). Some operations h a d to b e a b a n d o n e d owing to technical difficulties, and inexperienced surgeons obtained poor results(243, 244, 245). T h e outcome was much better, however, in expert hands. Small enclosed tumors, which were seen on x-rays (in about 30 percent of patients in Hardy's series), were found and excised selectively without complications. A d e n o m a s were seen at operation in 70 percent of patients with normal fossae, often by m e a n s of exploratory incisions into the gland. If n o t u m o r was found (about 20 percent of cases) total hypophysectomy ("sellar cleanout") was u n d e r t a k e n by prior agreement, or the central, mucoid part of the gland, which contains most of t h e basophil cells, was removed selectively. Minute basophil a d e n o m a s were sometimes found histologically in t h e excised tissue, occasionally in t h e posterior lobe. N o n t u m o r o u s glands (about 15 percent) showed C r o o k e ' s changes only. Remission followed in over 80 percent of all these patients. A few tumors (5 percent of Hardy's) were radiologically invasive, and total hypophysectomy was attempted, but only a quarter of these patients were cured. T h e operative mortality was 2 to 3 percent, mostly following difficult operations on invasive tumors. Patients who underwent remission were d e p e n d e n t on cortisone replacement for three to twelve m o n t h s and occasionally for longer. Many remained well for five years or m o r e , and H a r d y had one in remission for seventeen years. T h e syndrome recurred rarely ( 2 - 3 percent). In most, however, normal pituitary-adrenal function was restored, a n d in some a circadian rhythm was reestablished. O t h e r disorders of pituitary function were often corrected, and some w o m e n b e c a m e pregnant. All w h o underwent total hypophysectomy and many w h o h a d selective partial resection required hormonal replacement. Those w h o were not cured by operation or w h o suffered recurrence were treated, usually effectively, by radiotherapy, total hypophysectomy, or adrenalectomy. (A.ioi) Cure of the syndrome by selective a d e n o m e c t o m y and consequent return of normal function supports Cushing's hypothesis that a basophil pituitary t u m o r is t h e primary lesion in these patients. T h e minute size of some a d e n o m a s indicates h o w actively they secrete A C T H . In other patients without a d e n o m a s , relief of t h e syndrome by hypophysectomy suggests primary dysfunction at a higher level. (A.102) Throughout the 1980s attention was still focused on pituitary microsurgery for the treatment of Cushing's syndrome, and increasing numbers of surgeons developed the requisite skills. At the same time the results of operations and the relative roles of these and other forms of therapy were being assessed. (A.103)

182 • History of Endocrine Surgery THE ADRENAL MEDULLA The hormones of the adrenal cortex were found only after their presence had been suspected on account of the clinical features of adrenal disease. O n the other hand, the medullary h o r m o n e , adrenaline, was discovered and studied in detail long before a pathological role was found for it. Unlike the cortex, the medulla was not essential to life, and replacement of its secretion was not needed after adrenalectomy. Walter Cannon's theory that adrenaline was secreted in emergency, in response to emotion, was widely accepted. Adrenaline caused tachycardia, increased the metabolic rate, accelerated glycogenolysis, dilated the pupils, and caused mental excitement and anxiety, all of which prepared the body for fight or flight(97). Another view, that the constant secretion of small amounts of epinephrine maintained the normal blood pressure and that steady hypersecretion caused essential hypertension, did not receive strong support (1,246). Eventually a pathological function was found for adrenaline, when it was realized that its injection reproduced many of the clinical features of pheochromocytomas and that these tumors synthesized and secreted it in large quantities. (A.KM) In 1946 norepinephrine (noradrenaline), another catecholamine, was identified by Ule von Euler of Stockholm as the adrenergic neurotransmitter and was found to be secreted, together with adrenaline, by the adrenal medulla (3b). It caused peripheral vasoconstriction and was concerned mainly with the regulation of blood pressure. Unlike adrenaline, it slowed the heart and had few metabolic and central nervous effects. In 1949 noradrenaline was also found in pheochromocytomas. In the 1950s the synthetic pathway for the catecholamines was found to pass from tyrosine through D O P A , dopamine and noradrenaline, to adrenaline(97). Measurement of catecholamines and their metabolites, particularly metanephrines (metaadrenalines) and vanillyl mandelic acid ( V M A ) , in the body fluids proved of great value in the diagnosis of pheochromocytomas. Similarly, assays of dopamine and its final product, homovanillic acid ( H V A ) , aided the recognition of other medullary tumors. (A.IOS) Two types of receptors, a and /}, which mediated the effects of the catecholamines, were identified on physiological and pharmacological grounds in the late 1940s (167). Norepinephrine was found to stimulate the a receptors primarily, while adrenaline affected both types equally. T h e receptors mediated {inter alia) constriction of arterioles and veins, and therefore controlled blood pressure and blood volume, while the j3 receptors regulated the heart rate and the excitability of the myocardium. Drugs that blocked each type of receptor specifically were developed, and in the 1960s their use rendered operations for pheochromocytomas safe. (A.106) Norepinephrine therapy, by intravenous infusion, proved valuable for maintaining the blood pressure after removal of pheochromocytomas and


• 183

for treating adrenal crises after operations for Cushing's syndrome. For some years in the 1950s and 1960s many other patients dying in hypotension were treated with norepinephrine, but lives were rarely saved(97). (A.107) Although the biochemical diagnosis of medullary tumors was quite different from that of cortical lesions, their radiological investigation was very similar.

(A.IOS)

Pheochromocytoma

Pheochromocytomas were among the first adrenal tumors to be recognized, but they were not understood or treated safely for many years (p. A.9)(247, 248). An account of Minna Roll, aged 18, whose lesions were probably of this type, was published in 1886 by Felix Frankel of Freiburg im Breisgau(249). For a year she had suffered intermittent attacks of palpitations, anxiety, vertigo, headache, vomiting, and constipation. Her pulse was rapid and strong, and the artery was tense, but the blood pressure was not recorded. (Sphygmomanometers came into use about ten years later.) She was pale, had a goiter, and later developed retinopathy. Fever, dyspnea, chest pain, and cold sweats followed, and after nine days in hospital she died, apparently from circulatory failure. Autopsy revealed bilateral adrenal tumors, one the size of a fist, the other smaller. They were chromaffin positive, very vascular, consisted largely of spindle cells, and were regarded as medullary angiosarcomas. The kidneys showed parenchymatous inflammation, all the arteries were thickened, and the heart was hypertrophied. The goiter was not described. Frankel attributed the clinical features mainly to nephritis and regarded the adrenal tumors as symptomless ("latent") because there were no signs of Addison's disease. (A.109) Similar tumors, regarded as medullary in origin, but given various names, were described by pathologists within the next few years(250, 251), and in 1896 Paul Manasse of Strasbourg described the chromaffin reaction in several of them (252). Identical tumors were soon found in extraadrenal chromaffin tissue, and in 1908 Henri Alezais and Felix Peyron in Marseilles named these paragangliomas(253). In 1912 Ludwig Pick of Berlin proposed the n a m e pheochromocytoma for all these tumors in the adrenal and elsewhere (254). However, the names were used interchangeably for many years until all eventually came to be called pheochromocytomas (97). T h e syndrome of paroxysmal hypertension in life, associated with pheochromocytomas found at autopsy, had been observed at least twice since Frankel's report (254A), but little attention was paid to it until Marcel Labbe and his colleagues reported a case in Paris in 1922(255). (A.IIO) The first few pheochromocytomas to be operated on were not diagnosed beforehand. In 1923 E u g e n e Villard of Lyon removed a "malignant suprarenal paraganglioma" from a patient who died in shock that was disproportionate to the severity of the operation (256). Three years later two

184 • History of Endocrine Surgery pheochromocytomas were removed successfully, the first by Cesar Roux (Fig. A. 12) of Lausanne, Switzerland, a pupil of Kocher, whose patient was described in an MD thesis on suprarenal paragangliomas(257). Madam S., aged 33, had suffered attacks of vertigo and nausea for two years. These may have been hypertensive crises, but there is no reference to blood pressure in the whole thesis. A mass the size of an orange was felt under the right costal margin, and x-rays suggested a primary hepatic tumor. Laparotomy on February 25, 1926, revealed a mass attached to the adrenal, which Roux removed uneventfully. The patient recovered and was well eighteen months later. The tumor was a typical benign pheochromocytoma 13 cm in diameter. This report was not generally known for many years (258). The second patient, reported in 1927, was investigated and treated at the Mayo Clinic(259, 260). Mother Joachim, a nun from Ontario, had suffered paroxysms of hypertension with associated symptoms for eighteen months, and the referring physician wrote, "I feel much as Festus felt in sending Paul to Rome, not having any definite accusation against him." The systolic pressure rose to 320 mmHg, but there were no abnormal signs between the attacks. Perhaps because of Crile's work (p. H.2)(22), the symptoms were thought to be mediated through the sympathetic nerves, and cervical sympathectomy by Alfred Adson was considered. Charles Mayo suggested that "toxins were intermittently discharged" and, since lumbar pain was a feature of the attacks, considered that an approach through the splanchnic nerves might be more beneficial. Fortunately, he undertook a laparotomy on October 9,1926, and found a tumor the size of a lemon behind the tail of the pancreas. It was apparently separate from the adrenal, was removed uneventfully, measured 6 x 4 cm, and was thought to be malignant. It was given various names (259, 260), but recent examination shows it to be a typical benign pheochromocytoma with cortical tissue at the edge (261). Recovery was rapid, all the symptoms ceased, the blood pressure remained normal, and the patient was well for eighteen years, eventually dying from coronary thrombosis. (A.HI) This same year (1926) Louis Vaquez and Edouard Donzelot of Paris diagnosed a pheochromocytoma in life, but could not locate it (262). Charles Laubry treated the adrenal areas with x-rays with apparent benefit for six months, after which symptoms recurred (263). Operation was urged, but the patient died before it could be performed, and the presence of a tumor was confirmed at autopsy(264). Next, in 1928, Maurice Pincoffs of Baltimore also diagnosed but failed to locate a pheochromocytoma in life (265). Arthur Shipley explored the left side and, feeling a tumor on the right, removed it successfully two weeks later. The patient suffered severe shock, but recovered (266). A year later Miles Porter and his son from Fort Wayne, Indiana, reported a similar case(267). (A.112) By 1934 some sixty patients with supposed pheochromocytomas had been reported, most of them at autopsy, but less than half were regarded as definite(1). They were equally common in the two sexes, and some were

The Adrenal Glands (A) • 185 found in children. Over 80 percent of the patients had hypertension, which was not always paroxysmal, but pressure on a palpable tumor sometimes precipitated an attack. Pheochromocytomas had been found at autopsy in two patients who had died in labor (268, 269). Tumors varied in weight from a few grams to 1 kg. Few pathologists had much experience of them, and they were often diagnosed incorrectly (267). Apparent malignant changes were often observed histologically, but metastases had been reported in only two patients. The tumors were sometimes associated with neurofibromatosis (von Recklinghausen's disease). (AID) Pheochromocytomas were thought to secrete a pressor substance, perhaps epinephrine, which was responsible for the clinical features, and this was found in several tumor extracts from 1911 onwards (1, 270). In 1929, 60 mg of adrenaline were extracted from one tumor, and in 1935 Edward Kendall obtained 120 mg in crystalline form from another(254A, 270). In the same year adrenaline was found in the blood of a patient during a hypertensive crisis, but not after removal of a tumor, when the crises had stopped (271). Sudden death in patients with pheochromocytomas was attributed to adrenaline excess (272) and postoperative shock after their removal to adrenal insufficiency(273). (AIM) Diagnosis of pheochromocytomas was difficult, even in patients with paroxysmal hypertension, and the symptoms were often attributed to Graves' disease (270). The only diagnostic aids were x-rays of the adrenals, and plain films and pyelograms were sometimes helpful (271). However, by 1940 about twenty successful operations had been performed (271, 274), including three at the Mayo Clinic (254A) and two in Chicago by Alexander Brunschwig(275, 276). Some patients developed severe hypertension while the tumor was being handled (276) in addition to profound hypotension afterwards. (A.IIS) During the next ten years (the 1940s) several diagnostic tests were proposed (277). These included provocation of a paroxysm by massage of the tumor, bending or stooping, the application of cold (the cold pressor test), and the injection of mecholyl, adrenaline, or tetra-ethyl-ammonium chloride (or bromide). The histamine test, introduced by Grace Roth and Walter Kvale at the Mayo Clinic, was the most reliable (278). While investigating the possible role of histamine as a hypotensiwe agent to prevent the hypertensive storms during operations on pheochromocytomas, they found that it raised the blood pressure in these patients, while failing to do so in others. Apparently it released catecholamines from the tumor. In patients with sustained hypertension the blood pressure was lowered by the adrenolytic agents benzodioxane (279) and phentolamine (280, 281). (A.116) Norepinephrine was first identified in pheochromocytomas in 1949 and, like epinephrine, was found to be responsible for some of the clinical features(282, 283). Catecholamines were present in large amounts in the blood and in the urine, but it was some time before suitable assays were generally available for diagnostic purposes(277, 284). X-rays, which now

186


included pneumography, were often used for localization and were positive in over half the patients (277). With increasing awareness of pheochromocytomas and the new diagnostic aids, many more cases were recognized. In 1951 John Graham of Boston analyzed 207 reports of hypertensive patients with definite tumors, but excluded 32 with normal blood pressure (277). His analysis provided a definitive account of the major features of pheochromocytomas. Smithwick, Graham's senior colleague, had found eight tumors incidentally in 1,700 patients undergoing sympathectomy for hypertension (0.5 percent), and estimated that in the United States some 800 people died annually from these potentially curable lesions. One-third of the patients had died without operation, usually as a result of cardiovascular disease and sometimes after trauma, including that of unrelated surgical operations or childbirth. All but two of the tumors were in the abdomen, 90 percent of them in the adrenals, with a slight preponderance on the right side. The others were in the paravertebral spaces, in front of the great vessels, in the organ of Zuckerkandl, or in the celiac ganglion. Adrenal tumors were bilateral in 10 percent, and a very few other patients had two tumors, either outside the adrenals or one in the gland and one elsewhere. The two extraabdominal pheochromocytomas were in the left thoracic paravertebral space. Malignancy had been diagnosed in 11 percent. The hypertension was paroxysmal or sustained, or of both types. There were many symptoms, headache, palpitation, vomiting, and sweating being the commonest, and their duration and frequency were very variable. Tumors were palpable in 13 percent of cases. Drug therapy had been used without benefit, and five patients had been treated by irradiation of the adrenals, with temporary relief in two. (A.in) Attempts at surgical removal had now been made in 125 patients, 33 (26 percent) of whom had died. The incisions had been lumbar in nearly twothirds, abdominal in one-third, and combined or thoracic in a few. Smithwick and Graham had nine patients, all of whom had survived—the largest personal series at that time. (Two more patients, one of whom died without operation, are mentioned elsewhere[285].) They employed intratracheal gas-oxygen-ether anesthesia and made a point of occluding the venous return of a tumor as soon as possible. For hypertension during operation they crushed the splanchnic nerve and injected amyl nitrite or, latterly, a new adrenergic blocker. For hypotension they infused blood and epi nephrine, but had not had the opportunity to use norepinephrine. They favored total removal of a tumorous gland, even if some cortical tissue could be saved, because of the risk of malignancy. After operation adrenocortical extract was injected if much cortex had been removed, and after forty-eight hours of intensive care the patients were usually stable. Of the ninety-two who had survived operation most were cured, but four suffered recurrence. Tumors developed in the other adrenal in two, and metastases appeared in one.

(A.I

The Adrenal Glands (A) • 187 Other characteristics of pheochromocytomas were soon reported (286, 287). The basal metabolic rate was sometimes raised, and 10 percent of patients had diabetes, which was usually relieved by removal of the tumor. Other associated conditions included von Hippel's and Lindau's diseases. Tumors were sometimes familial and were then often bilateral or multiple. Lesions had been found very rarely in the neck and in the brain. Occasionally pheochromocytomas caused the ectopic ACTH syndrome (p. M.25). (A.ii9) Two estimates of the incidence of pheochromocytoma were made at the Mayo Clinic. First, fifteen tumors were found in 15,984 consecutive autopsies (0.1 percent) (287A). Twelve of the patients had been hypertensive, and pheochromocytomas had been suspected in three. Second, 7,993 hypertensive patients were screened, and tumors were found in 51 (0.64 percent) (286). This figure was very close to that (0.5 percent) found by Graham and Smithwick at sympathectomy in hypertensive patients (277). (A.120) Five years after Graham's analysis Priestley and his colleagues reported a remarkable series of fifty-one patients (286). All had been diagnosed in life, mostly with the help of the histamine and phentolamine tests and measurement of catecholamines in the blood. They used plain x-rays and intravenous urograms only to locate the tumors and, if their sites were not known before operation, relied on a transverse epigastric incision. Fortunately most patients were thin, and Priestley removed sixty-one tumors from these fifty-one patients without an operative death. These superb results were the outcome of excellent gentle operative technique and close cooperation with internists, anesthesiologists, pharmacologists, and nurses, and the use of two specific therapeutic agents, namely, phentolamine for hypertension and norepinephrine for hypotension. By 1960 the series included sixty-nine patients, one of whom had died without the tumor being found(288). Sufficient cortical tissue could usually be preserved to retain function when tumors were bilateral, but hydrocortisone was required sometimes. When the blood pressure did not fall after removal of a tumor, another lesion was suspected and sought. Malignant tumors were found in 14 percent of the patients, most of whom developed metastases and died within a year. Blood pressure returned to normal in three-quarters of those with sustained hypertension, and all paroxysms ceased. (A.121) Pheochromocytomas were now coming to light all over the world, and by 1957 over 600 had been reported (289). Many were treated surgically, with good results in some small series (287, 290, 291). Other surgeons, however, were not able to match Priestley's achievements for another ten years, when the effects of catecholamines on the heart and circulation were appreciated and drugs were developed to control them. Until then operations remained hazardous (290, 292). Norepinephrine was secreted by nearly all tumors, epinephrine by some, especially those in or near the adrenals(169), and dopamine by a few, particularly by malignant tumors(248, 287). It was

188 • History of Endocrine Surgery suggested in 1960 by Shannon Brunjes and his colleagues in Los Angeles that vasoconstriction, due to the action of catecholamines on a receptors, caused hypovolemia and that removal of the tumor allowed the vascular bed to expand suddenly, with consequent hypotension and postoperative shock(293). This hypovolemic hypothesis was supported by Brunjes' own observations, negated by others(292, 294), and finally, after ten years, confirmed and accepted(295). In the meantime a-blocking drugs, given preoperatively either to expand the blood volume or to lower the blood pressure, greatly reduced hypertensive paroxysms and postoperative shock (296). Ample blood transfusion perioperatively also reduced hypotension and made the use of norepinephrine unnecesssary(292, 294). In a series at the Cleveland Clinic in Ohio forty-six patients underwent successful operations with the help of preoperative blood transfusion only (297). The first a blocker to be used was phentolamine, which acts for a short time and had to be given by frequent intravenous injections (296). The long-acting phenoxybenzamine, administered by mouth, was used by Alastair Robertson of London in 1962, and by many others soon afterwards, and proved more effective (292, 294, 298). It was employed also for the long-term management of patients who were unfit for operation. A drug that inhibits catecholamine synthesis (a-methylparatyrosine) was introduced at about the same time for both preoperative and long-term therapy (292) and came to be used mainly for patients with incurable malignant tumors. (A.122) The optimal dosage of phenoxybenzamine was not agreed on for some time. A team in London, led by Max Rosenheim and including Robertson, Eric Ross, and Bernard Harries, first attempted complete blockade. This rendered the patient normotensive and abolished the hypertensive and hypotensive crises of operation (299, 230). Later they preferred partial a blockade, which enabled complete removal of a tumor to be confirmed at operation by a fall in blood pressure and made it possible for a residual tumor to be recognized by a rise in pressure when it was squeezed. Excessive rises were easily controlled by phentolamine, and falls by blood transfusion. These procedures were adopted generally. (A.123) Control of tachycardia and cardiac arrhythmias, caused by over-stimulation of /? receptors, was achieved first with the local anesthetic lidocaine (lignocaine) (292) and later with /3 blockers, especially propranolol, which came into use soon after phenoxybenzamine and proved very effective (292, 299, 300). The value of these drugs and of blood transfusion was immediately apparent, and all now appreciated that operations on pheochromocytomas need not be dangerous (292). Even the Mayo group, who had used phenoxybenzamine and propranolol since 1965 and 1969, respectively, and whose results had been so good before, confirmed that they decreased the "frightening and nightmarish hazards of surgical procedures" (301). Opinions differed about whether one or both blockers should be used in all patients or only for specific indications. Most used

The Adrenal Glands (A) • 189 partial a blockade routinely and reserved /? blockers for patients with cardiac problems(302, 303, 304, 305). The matter was complicated by the introduction of labetalol, a combined a and /? blocker, which was used by some, but did not provide adequate control(306). Many stressed the need for a blockade before invasive localization procedures to prevent dangerous hypertensive crises (304, 307). During operation intravenous phentolamine, phenoxybenzamine, or sodium nitroprusside was given to control excessive rise of blood pressure, and propranolol was used for acute cardiac problems. Hypertensive crises were liable to follow {3 blockade alone, and a blockers were always given first (300, 302). (A.124) It was observed that "successful surgery for pheochromocytoma depends more on the activities cephalad to the anesthetist's drapes than to those in the immediate operative field" (308). Gas, oxygen, and ether had been safe and effective in the past, and cyclopropane had been avoided because it caused arrhythmias. In the 1960s and 1970s halothane and related anesthetics proved better, especially after the advent of (3 blockers. At the same time monitoring procedures during and after operation had advanced greatly, and the ECG and arterial and venous pressures were displayed and recorded electronically. (A.125) By 1970 operations for removal of pheochromocytomas had become safe, but up to one-third of tumors remained unrecognized, and many patients still died, sometimes after minor surgical operations (305, 309, 310). For this reason much attention was paid to diagnosis of the syndrome and the localization of suspected lesions. Patients who required screening included those with hypertension who failed to respond to therapy, all suffering paroxysms, those with medullary carcinoma of the thyroid (MEA II [p. M.6]) or neurofibromatosis, and pregnancy or diabetes associated with hypertension (305). The histamine and phentolamine tests had been superseded because of complications and misleading results, and alternatives, including stimulation with tyramine or glucagon, had failed for the same reasons (308). Refinements in the measurement of catecholamines and their metabolites had greatly improved the accuracy of diagnosis (171, 308). There was, however, a "cryptic hard core" of patients whose tumors were silent and who presented an unsolved problem. Many of these were extraadrenal, large, and malignant (310). Measurement of catecholamines by selective venous sampling, introduced by von Euler in 1953, was the first such method to be used for adrenal tumors and was very informative (283). (A.126) Radionuclide scanning of pheochromocytomas had been attempted for years, but proved very elusive, although it was achieved with technetium in the 1970s(311). However, by 1980 Beierwaltes' team had found an adrenergic neuron blocking agent, I-131-raeta-iodobenzylguanidine (MIBG), which was concentrated specifically by these tumors, whether benign or malignant, primary or metastatic, in adrenal or extraadrenal sites(312).

190 • History of Endocrine Surgery Within a short time MIBG was in use elsewhere and enabled lesions to be detected with facility at sites, such as the mediastinum, that had proved inaccessible before (309). It was hoped that a scheme of investigation based on venous sampling and MIBG scanning, together with CT and angiography, would bring more tumors to light (113). (A.127) The long-term results of operations for pheochromocytomas in large series of patients were reported in the 1970s and proved very satisfactory. In the Mayo series, 93 percent with benign tumors and 43 percent with malignant lesions lived five years. The former proportion is similar to that for the general population (301). In a British series from three centers two-thirds survived in good health for ten years (benign and malignant lesions combined) (305). (A.128) Special Varieties of

Pheochromocytomas

Malignancy was reported in several of the early tumors (249, 256), and by 1936, six or seven malignant cases had been traced (1). Later the proportions varied from 3 (287) to 14 percent in large series (286), although some special centers had many more (226). Eventually it was realized that benign tumors often appeared malignant histologically and that some apparent metastases were multiple primary tumors. The only reliable criterion was the presence of tumor in tissues that did not normally contain chromaffin cells. By this standard about 10 percent, as reported by Graham and by Priestley, seemed to be the true figure (113, 305). Results of treatment were relatively poor, but two surgeons, Hartwell Harrison from Boston(313) and William Scott from Nashville, Tennessee (303), reported good results for many years after aggressive, radical surgical removal of primary, secondary, and recurrent lesions. Radiotherapy and drug treatment provided palliation. MIBG, which was so successful for imaging, was introduced for therapy of malignant lesions in 1983, with some initial promise(314). (A.129) Bladder tumors. A pheochromocytoma was first reported in the bladder in 1953 (315), and accounts of over 100 such tumors were published in the next thirty years(316). (A.130) Pheochromocytomas in pregnancy. Between 1909 and 1955 about twenty cases of pheochromocytoma had been reported complicating pregnancy, with maternal and fetal mortalities of 50 and 42 percent, respectively(268, 269, 316). By 1971, however, many tumors had been recognized during pregnancy, and the benefits of early diagnosis were appreciated (317). In such cases over 80 percent of the mothers and two-thirds of the fetuses survived. Joseph Schenker and Israel Chowers of Jerusalem recommended that the tumors should be removed as soon as they were diagnosed and that the pregnancy should be allowed to continue, if possible, until the fetus was judged viable. Cesarean section should then be performed(317). In 1977 David Leak and colleagues from Hamilton, Ontario, advised control of the

The Adrenal Glands (A) • 191 tumor with blocking agents until term and then cesarean section and removal of the tumor before the onset of labor (318). The relative merits of these different therapeutic policies had not been established by 1980, and the fetal mortality remained very high. (A.OI) Pheochromocytomas in children, first reported in 1904, presented serious problems, which were studied by Harris Shumacker of Indianapolis in 1956(319) and David Hume of Richmond, Virginia, in 1960(287). The hypertension tended to be very severe, the tumors were often multiple, bilateral, and ectopic, and the operative mortality was high. Death frequently resulted from failure to recognize a second tumor at operation (320). When these lessons had been learned and modern methods were applied to management, the results improved. In 1974 Eric Fonkalsrud from Los Angeles reported seven personal cases without an operative death(321), and by 1980, when two other series were reported without mortality (322, 323), the special dangers attending operations for pheochromocytomas in children had apparently been overcome. (A.m) Renal artery stenosis associated with pheochromocytoma was first reported in 1958 by Harrison and colleagues in Boston (324). Accounts of about forty patients with both these lesions were published in the next twenty-five years (305, 310, 325). Removal of the tumor alone relieved the hypertension in nearly half the patients, but correction of the stenosis or nephrectomy was needed in the remainder. (A.133) Bilateral tumors. After Frankel's first report of tumors in both adrenals in 1886, it became clear that pheochromocytomas were bilateral in about 10 percent of sporadic cases, 20 percent of children (320), 50 percent of patients in susceptible families, and 70 percent of those with ME A I I (p. M.6). They developed simultaneously or consecutively, were sometimes in multiple ectopic sites (320), and, in ME A II, were often preceded by medullary hyperplasia(326) (p. M.10). The first successful diagnosis and surgical removal of tumors from both adrenal glands in two members of one family were reported from Baltimore in 1947 and 1948(327, 328). In 1953 bilateral tumors were removed successfully from three members of the same family by Priestley, and these three patients subsequently developed medullary thyroid carcinomas (p. M.6). At one time, when tumors were found bilaterally, uninvolved cortical tissue was preserved if possible (288). Later some advocated total removal of affected adrenals with biopsy of apparently normal glands(321); some (in MEA II) removed obvious tumors only, but followed their patients carefully (328A); while others practiced total bilateral adrenalectomy routinely in patients with MEA IIA (329). The best course of action is still undecided. (A.134) In the 1980s the main problem still was that many pheochromocytomas were not suspected in life. Once they had been, diagnosis, localization, and treatment were usually straightforward. Malignant lesions were difficult to

192 • History of Endocrine Surgery manage, but aggressive surgery and possibly irradiation with MIBG held promise. The best ways of managing tumors in patients with MEA II were still undecided, but did not cause serious problems. (A.135)

Ganglioneuroma and Neuroblastoma Ganglioneuromas and neuroblastomas had been known for many years before their pathological endocrine functions were recognized. The former were named in 1870 by Wilhelm Loretz of Frankfurt-am-Main because of the well-formed ganglionic nerve cells of which they were composed (330), and they have kept their original name. These benign growths arose from the adrenal medulla and from sympathetic ganglia, and were commonest in adults. They ran a slow course and were rarely recognized in life. Reports of 51 had been collected by 1915, and 143 by 1935, about 90 percent of them in extraadrenal sites (331, 332, 333, 334). Less than 10 percent had been explored surgically, and two-thirds of these had been removed. In children one-third of a large series had had effective operations (335). (A.136) Neuroblastomas were quite different. At first they were often confused with other malignant tumors, especially sarcomas. For instance, in 1901 William Pepper of Philadelphia described six children suffering from "congenital sarcoma of the liver and suprarenal" (336), and in 1907 Robert Hutchison of London reported ten children with "suprarenal sarcoma" and metastases in the skull (337). These syndromes came to be known as "Pepper's" and "Hutchison's," respectively. In 1910 Homer Wright of Boston described both these tumors as neurocytomas or neuroblastomas, derived from primitive sympathetic ganglia (338). Many other tumors were reported, usually in infants, some of them at birth, occasionally in older children, and rarely in adults. They were highly malignant, were nearly always recognized by the presence of large primary tumors or secondary deposits, and ran a rapidly fatal course. Surgical operations usually revealed inoperable growths (333). However, the tumors were found to be radiosensitive, and by 1951 twenty-five patients were known to have survived two years or more after operation and/or radiotherapy(338A). (A.137) Lesions with features of both types of tumor were also described and named ganglioneuroblastomas. Sometimes one variety changed into another, and occasionally malignant tumors underwent spontaneous regression (339). Cushing reported the remarkable case of a child, aged 2, who had a thoracic and intraspinal neuroblastoma, causing paraplegia, with intracranial metastases (340). The primary was biopsied, and the child received Coley's toxin. The signs of intracranial tumor disappeared, and ten years later the persisting spinal lesion was removed and then found to be a ganglioneuroma. (A.138)

The Adrenal Glands (A) • 193 Neuroblastomas were treated vigorously, and two series, each of over 100 patients, were reported in the 1930s. Symptoms were usually nonspecific, and most tumors were found accidentally as swellings. The commonest site was the adrenal, and many were visible radiologically. In the early 1950s the outcome of treatment in over 600 patients from nine centers was described(339). Combinations of surgical excision, which was rarely complete, radiotherapy, and chemotherapy resulted in nearly one-quarter surviving three years. (A. 139) Twenty years later one-third of children survived two years (341). The proportion increased to over 80 percent for tumors confined to their sites of origin, but decreased to 5 percent for those that had metastasized to the skeleton and some other sites. A group of patients with remote disease confined to liver, spleen, or bone marrow fared as well as those with localized disease. Therapeutic trials were undertaken in the 1970s, but no great improvement in results was achieved until it was possible to diagnose tumors earlier. (A.HO) It was not until 1932 that any of these lesions was recognized as an endocrine tumor. That year, however, Evelyn Rogers of New York reported paroxysmal hypertension in an Italian furrier aged 46(342). He was thought to have a pheochromocytoma, and x-rays showed a mass in the left abdomen. Operation was considered too hazardous, and both adrenal regions were treated with x-rays, with "slight improvement." However, the patient died, and a ganglioneuroma the size of a large grapefruit was found near the left adrenal. After nearly twenty years two similar patients were described. Evan Calkins and colleagues from Baltimore studied a hypertensive girl aged 7 with paroxysmal sweating and tachycardia and an abdominal mass(343). A neuroblastoma, containing epinephrine-like substances, was removed by Mark Ravitch, and the tumor bed was irradiated. Symptoms were relieved, but in six months they recurred, and the child died from a stroke and widespread metastases. Then George Mason, a thoracic surgeon in Newcastle-upon-Tyne, reported an infant suffering from hypertensive crises, which were controlled by phentolamine (344). The urine contained pressor amines,and x-rays showed a mediastinal tumor that was removed and found to be a neuroblastoma, containing both epinephrine and norepinephrine. Symptoms were relieved and the baby remained well for at least one year. (A.141) Another clinical syndrome was reported in 1952 by Harold Hawfield and Gordon Daisley from Washington, D.C.(345). A female infant aged 10 months developed severe diarrhea and steatorrhea, and three months later she was emaciated, dehydrated, and had facial flushing. X-rays showed calcification in the right adrenal region, and laparotomy revealed a benign ganglioneuroma, 4 cm in diameter, which was removed easily. In three days the stools were normal and remained so, and the child was rapidly cured,

194


although no active substance could be extracted from the tumor. Five years later (1957) three young children with ganglioneuromas and one with a ganglioneuroblastoma were reported. All had chronic diarrhea, and two of them also suffered hypertension and sweating (346). They were cured by surgical excision of the tumors, followed in one case by radiotherapy. It was suggested that the tumors secreted a neurohumoral substance that affected the motility of the gut. The catecholamines were not measured in these children, but before long excessive excretion was found in similar patients (347, 348). Treatment, when effective, relieved the symptoms and reduced catecholamine excretion to normal. (A.142) It was soon discovered that nearly all neuroblastomas secreted large quantities of DOPA, dopamine, and norepinephrine (but not epinephrine), and that these and their metabolites were excreted in the urine (349, 350). Hypertension and other clinical effects of catecholamines were rare, perhaps because DOPA antagonizes norepinephrine, although the blood pressure sometimes rose excessively during operation (349, 351, 352). Some pregnant women, however, whose fetuses had neuroblastomas, had clinical features of catecholamine excess, which cleared after delivery (353). Measurement of VMA became very useful for diagnosis of neuroblastomas and for monitoring the effects of treatment, and by 1970 it was possible to recognize half the tumors before they were palpable (350). (A 143) Some ganglioneuromas and very few neuroblastomas caused diarrhea, and those that did so nearly always secreted catecholamines. The origin of the diarrhea remained obscure. Catecholamines themselves could hardly be reponsible, since pheochromocytomas and most neuroblastomas, which nearly always secreted them, did not cause it. In 1973, however, high blood levels of a new compound, vasoactive intestinal peptide (VIP), were found in six patients suffering from the syndrome of watery diarrhea and hypokalemia, five of whom had pancreatic islet cell tumors and one a "ganglioneuroblastoma" (p. G.43). It seemed that VIP might be the missing neurohumoral agent, since its pharmacological effects were consistent with the syndrome. Before long seven such patients were cured by surgical excision of their tumors(354). Blood VIP levels, which were high initially, were restored to normal, and large quantities of peptide were extracted from the lesions. These neural vipomas were recognized as paraendocrine apudomas, like those of the pancreatic islets. (A.m) By the 1980s surgery of the adrenal glands was almost confined to primary adrenal diseases, although adrenalectomy was occasionally undertaken for the relief of Cushing's syndrome due to corticotrophinomas in the pituitary or elsewhere. Precise biochemical and anatomical diagnoses enabled surgeons to plan effective operations, and ancillary measures rendered them very safe. Invasive radiological methods were being used increasingly for


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adrenal ablation. Patients with malignant adrenal tumors still fared badly, but the outlook for those with neuroblastomas was improving as a result of early biochemical diagnosis. (A.HS) GENERAL SOURCES Young, 1937. See Ref. 23. Broster, Vines et al., 1938. See Ref. 46. Kendall, 1971. See Ref. 90. Manger & Gifford, 1977. See Ref. 248. Hardy, 1982. See Ref. 234. Wilson, 1984. See Ref. 2. Welbourn, 1987. See Ref. 247. REFERENCES 1. Rolleston, H.D. The endocrine organs in health and disease. Oxford: Oxford University Press; London: Humphrey Milford, 1936: 301-84. 2. Wilson, L.G. Internal secretions in disease. J Hist Med Allied Sci 1984; 39: 263-302. 3. Medvei, V.C. A history of endocrinology. Lancaster, England: MTP Press, 1982: a 107-9, b 557-58. 4. Shumacker, H.B. The early history of the adrenal glands. Bull Hist Med 1936; 4: 39-56. 5. Addison, T. On the constitutional and local effects of disease of the suprarenal capsules. London: Samuel Highley, 1855. 6. Brown-Sequard, E. Recherches experimentales sur la physiologie et la pathologie des capsules surrenales. Arch Gen Med (Paris) 1856; 8: 385-401, 572-98. 7. Osier, W. Six cases of Addison's disease. Int Med Magazine 1896; 5: 3-11. 8. Willis, R.A. Pathology of tumours. London: Butterworth, 1948. 9. Ramsay, O. Malignant tumors of the suprarenal gland. Johns Hopkins Hosp Bull 1899; nos. 94-95-96: 20-29. 10. Thornton, J.K. Abdominal nephrectomy for large sarcoma of the left suprarenal capsule: recovery. Trans Clin Soc London 1890; 23: 150-53. 11. Myrtle, A.S. Abscess subsequent to removal of left kidney. Ibid., 154-57. 12. Holmes, G. Virilism associated with a suprarenal tumour. Q J Med 1925; 18: 143-52. 13. Robson, A.W.M. Removal of the suprarenal capsule. Br Med J 1899; 2: 1100-101. 14. Curtis, B.F. Nephrectomy for suprarenal tumor. Ann Surg 1900; 31: 759-60. 15. Richards, O. Growths of the kidney and adrenals. Guy's Hosp Rep 1905; 59: 217-332. 16. Langenbuch, C von. Ein Fall von Exstirpation der Gallenblase. Bed klin Wochenschr 1882; 19(48): 725-27. 17. Keyser, L.D., and Walters, W. Carcinoma of the suprarenal. JAMA 1924; 82: 87-88.

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A.l.

A.l. J. Knowsley Thornton. Courtesy of F. E. Keane, Album of the fellows of the American Gynecological Society, 1876-1930 (Philadelphia: 1930).

A.2.

A.2. Incisions for adrenalectomy: (1) L. Thornton(Y), R. Robson()); (2 and 3) Ramsay; (4 and 5) Renal; (6) Young: L. Original, R. Later; (7) Roof-top; (8) Thoraco-lumbar. Courtesy of Doig Simmonds, Department of Medical Illustration, Royal Postgraduate Medical School. 212

A3.

A.5.

AA. A.6.

A.3. Hugh H. Young. Courtesy of the Alan Mason Chesney Medical Archives of The Johns Hopkins Medical Institutions. A.4. Young's Operation. From H. H. Young, Hermaphroditism & Related Adrenal Diseases (London: Baillier Tindall & Cox, 1937), Figure 161. A.5. Cushing's first patient (1912). From The Pituitary Body & Its Disorders (Philadelphia: Lippincott, 1912), Figure 283 A.6. Lennox R. Broster. Courtesy of Charing Cross & Westminster Medical School. 213

A.7.

A.8.

A.9.

A. 10.

A.l. Waltman Walters. Courtesy of Mayo Foundation. A.8. James T. Priestley. Courtesy of Mayo Clinic. A.9. Edward C. Kendall. Courtesy of Mayo Clinic. A.10. Jerome W. Conn. Courtesy of J. W. Conn, M.D.

214

•

A.ll. A.12.

A.ll. William C. Baum. Courtesy of William C. Baum, M.D., M.S., F.A.C.S. A.12. Cesar Roux. Courtesy of Professor F. Saegesser. 215


5 (PT) The Parathyroid Glands

Parathyroid surgery started quite suddenly in Vienna in 1925, when Felix Mandl (Fig. PT.l) had the courage to break new ground by seeking a parathyroid tumor and removing it from the neck of a patient with von Recklinghausen's disease, with remarkable benefit (1, 2). The next year in Boston Joseph Aub and Walter Bauer independently diagnosed overproduction of parathyroid hormone in a similar patient and recommended an operation (3). These bold steps brought together several apparently unrelated observations and investigations made in the previous two centuries, and especially in the last fifty years. (PT.I) Osteitis fibrosa cystica was described, though not so named, in France and England in the eighteenth century and has recently been recognized in ancient skeletons in Egypt (4) and North America. Tetany was observed after thyroidectomy in dogs in 1836 and in man in 1879 (p. T.45). A parathyroid gland was seen at autopsy in an Indian rhinoceros from the London Zoo by Richard Owen in 1850, but his observation, published in 1862, passed unnoticed until 1905. Two pathologists—Rudolf Virchow and Robert Remak of Berlin—may have noticed the parathyroid glands in man in Owen's time. However, credit for their recognition and fully illustrated anatomical and histological description in several animals and in man belongs to Ivar Sandstrom (Fig. PT.2), a medical student in Uppsala, Sweden(5, 6, 7). His work was undertaken between 1877 and 1880 and included dissection of fifty human bodies. He named the new structures "glandulae parathyroideae"; he did not guess what their normal role might be, but suggested that they might give rise to important tumors. Sandstrom's paper was rejected by German editors, but was published in Swedish in

218 • History of Endocrine Surgery Uppsala in 1880 and was barely noticed elsewhere. The parathyroids were observed independently by Cresswell Baber in England in 1881, but were not recognized generally until Eugene Gley in Paris and others began to study their functions in the 1890s. As more patients with M E N 2 were recognized, Glen Sizemore, G u a n Chong, and colleagues at the Mayo Clinic proposed in 1975 that the syndrome should be subdivided into two groups, A and B , based on the phenotype(26). Both h a d M C T and pheochromocytomas. Those in 2A had a normal bodily configuration and usually parathyroid disease. Patients in 2B often had a marfanoid habit, neuromas of the tongue and lips, and prominent corneal nerves, but their parathyroids were normal. Half their own patients were classed in each group, and the majority of both had positive family histories. Those without affected relatives were assumed to have undergone spontaneous mutations. O n e patient had C cell hyperplasia(27, 28), but not M C T , and another had adrenal medullary hyperplasia(29) without pheochromocytoma. They considered both these lesions to be the precursors of tumors. (M.IO) The same year (1975) Rashid Khairi and colleagues from Indianapolis independently described four people, three of them related, with the M E N 2B syndrome of mucosal n e u r o m a , bumpy lips, marfanoid habitus, M C T , and pheochromocytoma, and referred to it as " M E N 3 " (30). In reviewing over fifty reported cases (but not the Mayo patients), they noted that many had hypertrophied corneal nerves, skeletal defects, and alimentary abnormalities, including diffuse ganglioneuromatosis. This last was also noted by Aidan Carney and colleagues at the Mayo Clinic as a major component of M E N 2B (31). O n e of these patients had been included by Hayles in his 1960 p a p e r ( 1 3 , 14a).

(M.II)

M E A — L a t e r Developments Descriptions of these syndromes were modified in various ways as experience increased. T h e nomenclature varied greatly. " M E , " used originally for "multiple endocrine," has persisted. Both "polyglandular" and "pluriglandular" have been used by some (7), but are liable to be confused with Cushing's polyglandular syndrome. " A " stood for " a d e n o m a s " or "adenomatosis" at first, often being replaced by " N " for "neoplasia." These are all unsatisfactory, because the glands are often hyperplastic or car-

274


cinomatous. For this reason some have preferred "A," implying "adenopathy" or "adenosis" (meaning "disease of glands"), both of which include the full range of lesions (32, 33). MEA I (or 1) and ME A I I (or 2) are sometimes called "Wermer's syndrome" and "Sipple's syndrome," respectively. MEA IIA (or a) is sometimes referred to simply as MEA II, and MEA IIB (or b) as MEA III (or 3). The qualifications "inherited," "familial," and "peptic ulcer" have been generally dropped. (M.12) The extent of the lesions in the MEA I syndrome was found to be greater than originally thought, and the parathyroids, pancreas, and pituitary were seen to be involved in all patients, if examined pathologically(34). The spectrum of lesions was found to be greater also. In the pituitary, somatotrophinomas and prolactinomas were recognized relatively often(35, 36) and corticotrophinomas very rarely. In the pancreas insulinomas and gastrinomas were relatively common, while glucagonomas(37) and vipomas(38) were sometimes encountered also. Islet cell lesions were often multiple and took the form of adenomatous hyperplasia. (M.D) By 1977 (two years after its subdivision into two groups) MEA I I A and B had become more clearly distinguished (39). Thyroid and adrenal lesions were present in both, but MCT generally progressed more rapidly in B. Parathyroid hyperplasia was usual in A, but rare in B. A was familial without special facial and bodily features, while B was usually sporadic with a characteristic phenotype. (M.H) For some years patients have been described who exhibited some features of more than one MEA syndrome. Pheochromocytoma is the commonest lesion and was found in one of Cushing's acromegalic patients in 1964(40) and in one of Steiner's patients with Cushing's disease in 1968(23). More recently there have been several other similar cases (41) and many different combinations of lesions (42, 43, 44, 45). Familial cases of pheochromcytoma and islet cell tumor (s) have been described from three different ethnic backgrounds(46). The list continues to grow. (M.i5) In the 1960s the lesions in MEA II had been attributed to a neural crest defect, and later many of those in all the syndromes were recognized as apudomas (p. E.38). They represented, perhaps, widespread dysplasia of the APUD cell system, of which the neural crest and its derivatives form a part. The parathyroid lesions and the pituitary somatotrophinomas were, however, not readily explicable on this basis. Most were orthoendocrine (entopic), the commonest paraendocrine (ectopic) lesion being a pancreatic gastrinoma (p. G.30). (M.i6) T h e policy of investigating patients w h o presented with one lesion for t h e presence of o t h e r s , of following t h e m all their lives, and of screening their relatives came to be practiced widely by endocrine surgeons in the 1980s (47). Generalized parathyroid hyperplasia and multiple islet cell

Multiple Endocrine Adenopathy (M) • 275 lesions were recognized as indicating MEA I until proved otherwise. Pancreatic polypeptide proved a useful marker for detection of patients with the genetic trait (p. G.56). In these ways increasing numbers of patients were diagnosed and treated effectively. (M.n) Treatment was mainly surgical, and the times at which lesions were tackled depended on the order in which they presented and on their severity. In MEA I, for instance, parathyroidectomy took precedence if hypercalcemia was severe, or, before the introduction of the H2 blockers, total gastrectomy was often required urgently for complicated peptic ulceration. In MEA II many patients died with hypertensive paroxysms, sometimes after operations on the thyroid, when pheochromocytomas had not been recognized (23, 48). It soon became mandatory to search for these tumors and to deal with them first in all patients with MCT(39). (MIS) Interest in the MEA syndromes continued unabated in the 1980s. Prevention by antenatal diagnosis was not yet possible, but genetic counselling, especially for patients with MEA IIA (which includes MCT), was readily available (25). (M.i9) PARAENDOCRINE SYNDROMES There are many varieties of PES but only three are important surgically (1, 49, 50). These are (1) the Z-E syndrome (pancreatic gastrinoma); (2) the watery diarrhea syndrome (pancreatic and adrenal vipoma), both of whose stories are told elsewhere (p. A. 144 & G.29-47); and (3) the ectopic ACTH syndrome (extra-pituitary corticotrophinomas). (M.20) The Ectopic ACTH Syndrome In 1928 Hurst Brown of London described a woman aged 45 with the pluriglandular, polyglandular, or "diabetes of bearded women" syndrome (p. A.25) and a normal pituitary fossa (51). Autopsy revealed a 1-cm oatcelled carcinoma of the lung and enlarged suprarenals. Three years later two more patients who were in hospital together with a similar disease were reported, also from London. One was a boy aged 11, who had a moustache, the other a man of 31; both were found at autopsy to have thymic carcinomas and adrenocortical hypertrophy (52). After Cushing's description of pituitary basophilism in 1932, many patients with the same syndrome were reported. Most had tumors of the pituitary or adrenal cortex, but several had neoplasms at other sites together with adrenal hyperplasia. By 1960 accounts of at least forty such cases were collected (53, 54, 55), and the next year nineteen were reported from the Mayo Clinic, where they comprised 8 percent of patients with Cushing's syndrome studied there since 1932(56). The commonest tumors were carcinomas of the bronchus, thymus, and

276 • History of Endocrine Surgery pancreas. Many patients had hypokalemic alkalosis, and some had Crooke's hyaline changes in the pituitary. The association between carcinoma and Cushing's syndrome seemed too frequent to be coincidental, and it was suggested that the tumors stimulated the adrenals, perhaps by secreting corticotrophin(55). This was soon found to be the case, and Grant Liddle of Nashville, Tennessee, coined the term "Cushing's syndrome due to ectopic 'ACTH'," which was shortened to "ectopic ACTH syndrome" (57, 58,59). (M.2i) Many more patients were soon reported, although often a causal relationship between the tumor and the clinical and metabolic features was not demonstrated(60, 61). John Azzopardi and Dillwyn Williams of London recognized four principal groups of causative lesions, all of which they regarded as endocrine in nature(61). These were: (1) oat-cell carcinoma of the bronchus, an undifferentiated tumor, possibly carcinoid in nature; (2) tumors of foregut origin, including epithelial thymoma, islet cell carcinoma, carcinoids of the bronchus(62), stomach, and pancreas, medullary carcinoma of the thyroid(63), and (in one case) parathyroid carcinoma; (3) adrenal medullary tumors, including pheochromocytoma, neuroblastoma, and ganglioneuroblastoma; and (4) certain ovarian tumors, possibly carcinoids. The ACTH was often abnormal in structure and accompanied by other related peptides (64). Many tumors secreted quite different peptides and amines in addition. These included gastrin, vasopressin, glucagon, norepinephrine, and serotonin, which were often clinically and metabolically silent (65, 66). Most tumors were malignant and ran a rapid course. (M.22) Patients with the ectopic ACTH syndrome tended to differ in several ways from those with the classic Cushing's syndrome. Men were affected more often than women, the history was short and the course rapid, and muscle wasting and pigmentation were more common. Severe hypokalemic alkalosis and impaired glucose tolerance were usual, while production of ACTH and cortisol was very great and usually autonomous. In those with malignant disease the syndrome often developed terminally and passed unnoticed unless it was sought biochemically. (M.23) Treatment was usually unsatisfactory because so many patients were dying(67), but adrenal inhibitors (p. A.60) (68, 69) or venous infarction of the adrenals(70, 71) sometimes gave temporary relief. Surgical operations were employed rarely, and for many years few surgeons treated more than two or three cases(72). One of the first, in 1968, to report more and to discuss the role of surgery was Lawrence O'Neal of St. Louis, Missouri (66, 73). A few benign tumors, especially bronchial carcinoids (62) and pheochromocytomas (74), were resected successfully, and Liddle mentioned nine of ninety-nine patients with the ectopic ACTH syndrome, all operated on by different surgeons, who were cured by removal of their tumors(75). Adrenalectomy was sometimes used for palliation when a slowly growing tumor could not be excised (76) or as an expedient form of treatment when a

Multiple Endocrine Adenopathy (M) • 277 growth could not be found (62, 73). Sometimes the presence of an ectopic corticotrophinoma was not recognized until after adrenalectomy, when a patient in remission from Cushing's syndrome became pigmented and a non-pituitary tumor was found(64, 72, 77). Some other tumors were not recognized until hypophysectomy failed to relieve the syndrome (62). When, in the 1970s, hypophysectomy, without direct evidence of a pituitary tumor, came into regular use for the treatment of Cushing's syndrome (p. A.98-103), recognition of the ectopic ACTH syndrome became vital. By the 1980s several surgeons were able to report sizable series of patients (64, 78).

(M.24)

One lesion presented special diagnostic and therapeutic problems. In 1942 Frank Neff of Kansas City, Kansas, reported the case of a girl aged 16 months with Cushing's syndrome, precocious pseudopuberty, and labile hypertension, who was cured by removal of an adrenal pheochromocytoma (79). The adjacent adrenal cortex was normal. This was a remarkable outcome so many years before steroids and adrenergic blockers had been discovered. Similar patients of all ages were reported from time to time, and in 1977 details of thirty-three were collected (74). About half had both (cortical and medullary) syndromes, but some had clinical evidence of one only, the other being diagnosed from the biochemical or pathological findings. The adrenal cortex was hyperplastic in some cases and apparently normal in others. ACTH was extracted from several tumors (80,81,82), and it seems likely that most of these patients suffered from the ectopic ACTH syndrome. More than half were cured or improved by surgical removal of their tumors. (M.25)

GENERAL SOURCES Ballard et al., 1964. See Ref. 9. Steiner et al., 1968. See Ref. 23. Harrison & Thompson, 1975. See Ref. 7.

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71. Rogove, H.J., Meaney, T.F., and Schumacher, O.P. Cushing's syndrome successfully treated by transcatheter adrenal ablation. Clin Res 1976; 24: 10A. 72. Eugel, F.L., and Kahama, L. Cushing's syndrome with malignant corticotrophin-producing tumor: remission and relapse following subtotal adrenalectomy and tumor resection. Am J Med 1963; 34: 726-34. 73. O'Neal, L.W. Surgery of the adrenal glands. St. Louis: C V . Mosby, 1968: 69-78. 74. Luton, J.-P., Thiebolt, Ph., and Bricaire, H. Assocation syndrome de Cushing-pheochromocytome. La Nouvelle Presse Medicale 1977; 6(43): 4053-57. 75. Liddle, G.W., Orth, D.N., et al. Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog Horm Res 1969; 25: 283-314. 76. MacPhee, I.W. Cushing's syndrome associated with carcinoma of the bronchus. Br J Surg 1959; 46: 456-58. 77. Ratcliffe, J.G., Besser, G.M., Landon, J., et al. Tumour and plasma ACTH concentrations in patients with and without the ectopic ACTH syndrome. Clin Endocrinol (Oxford) 1972; 1: 27-44. 78. Jex, R.K., van Heerden, J.A., Carpenter, P . C , and Grant, C S . Ectopic ACTH syndrome: diagnostic and therapeutic aspects. Am J Surg 1985; 149: 276-82. 79. Neff, F . C , Tice, G., Walker, G.A., and Ockerblad, N. Adrenal tumor in female infant with hypertrichosis, hypertension, over-development of external genitalia, obesity. J Clin Endocrinol 1942; 2: 125-27. 80. Meloni, C.R.J., Tucci, J., Canary, J.J., and Kyle, L.H. Cushing's syndrome due to bilateral adrenocortical hyperplasia caused by a benign adrenal medullary tumor. J Clin Endocrinol Metab 1966; 26: 1192-200. 81. Schteingart, D.E. Conn, J.W., Orth, D.N., Harrison, T.S., etal. Secretion of ACTH and /2-MSH by an adrenal medullary paraganglioma. J Clin Endocrinol Metab 1972; 34: 676-83. 82. Spack, R.F., Connolly, P.B., Gluckin, D.S., et al. ACTH secretion from a functioning pheochromocytoma. N Engl J Med 1979; 301: 416-18.

M.1. M.2.

M.I. Jakob Erdheim. Courtesy of Institut fiir Geschichte d. Medizin der Universitat Wien. M.2. Paul Wermer. Courtesy of S. R. Friesen, M.D.

8 Various Topics

Hormones have long been suspected of playing important roles in diseases that are not primarily endocrine in nature and also in the response of the body to surgical stress. Manipulation of the endocrine environment, initially by the removal of glands and later by the administration of hormones, has been used therapeutically since the nineteenth century. The history of some of these conditions is considered here as they relate to endocrine surgery.

1(C) Cancer of the Breast and Prostate by R.A. Sellwood

The belief that ovarian irritation caused mammary cancer led to the relief of this condition by oophorectomy in the 1890s. Fifty years later orchiectomy was introduced on a firm scientific basis for the treatment of prostatic cancer. The advent of cortisone in 1950 widened the scope of hormonal therapy, including the ablation of endocrine glands for both diseases, and was followed by great activity in this field. It became clear that the growth of these cancers depended on the sex hormones, which influenced the development of the organs from which they arose, and that alteration of the hormonal environment might affect profoundly the course of the disease and often cause remarkable remissions. Today synthetic analogues of hormones and inhibitors of hormonal systems achieve the same results with less trauma and fewer side effects. Operations on the endocrine glands, which played a very important therapeutic and scientific role, have now been largely superseded. (en MAMMARY CANCER—OOPHORECTOMY In 1889 Albert Schinzinger of Freiburg im Breisgau suggested that there was a relationship between the ovaries and cancer of the breast. He had noticed that in older women these cancers often grew more slowly than in younger ones and suggested to the German Surgical Association that bilateral oophorectomy might have a beneficial effect by causing premature ageing(1). Apparently this suggestion was not acted upon at the time, but in 1895 George Beatson of Glasgow (Fig. C.l) performed the first bilateral oophorectomy for cancer of the breast for quite different reasons. While

Cancer of the Breast and Prostate (C) • 285 studying lactation in sheep, he deduced that this process was related to ovarian function and that the effect was not dependent on any nervous connection: "I am satisfied that, in the ovary of the female and the testicle of the male, we have organs that send out influences more subtle and more mysterious than those emanating from the nervous system." He was impressed by the similarity between the histological appearances of hyperplasia and degeneration that occurred during lactation and those observed in mammary cancer, and he wondered if cancer of the breast was caused by ovarian activity: "I often ask myself is cancer of the mamma just an ovarian irritation . . . and if so will cell proliferation be brought to a standstill . . . when the ovaries have been removed." Beatson operated on June 15,1895, on a woman aged 33. She had first discovered a lump in her left breast when nursing her first child, but the tumor did not increase in size until her second lactation twenty months later. After ten more months she sought medical advice because of a large ulcerating cancer. Mastectomy was followed rapidly by recurrence, and she was referred to Beatson with a large mass in the scar and surrounding skin nodules. He administered thyroid extract (p. T.43) for a month before performing bilateral oophorectomy, and then gave more thyroid extract. One month after operation the lesions had diminished in size; at four months they were only just palpable, and at eight months all traces of the disease had gone (2). (c.2) The beneficial effect of oophorectomy was confirmed rapidly by others (3, 4, 5, 6, 7, 8, 9), and in 1900 Stanley Boyd of London reported on fifty-four patients who had been treated in this way by various surgeons (10). Approximately one-third of the patients had benefitted from the operation, and he stressed the need for a method to predict which patients would respond. But by 1905 the operation had fallen into disfavor because remissions of the cancer were often short-lived, recurrence was inevitable, and many patients failed to respond. In this year Hugh Lett, also of London, reported ninetynine patients of whom 36 percent had benefitted from bilateral oophorectomy, 23 percent of them very markedly. He described relief from pain, improvement in health, diminution and disappearance of the growth, healing of ulcers, and prolongation of life. In fifteen patients remission had persisted for more than one year and in four for more than four years, while one patient remained alive and well five years after operation. Lett recognized that the operation was much more likely to be successful in women under 50 than in older ones, but did not realize that success was related to menopausal status. In view of these results he urged that the operation should be given a further trial in women under 50(11). (c.3) Ovarian ablation by radiotherapy was developed in France at about this time by Francois-Victor de Courmelles, and it soon became apparent that results were similar whether castration was achieved by operation or by radiation(12, 13). Surgery had the advantage of acting more rapidly than radiation and of achieving castration more reliably, but in many centers

286 • History of Endocrine Surgery radiotherapy was preferred because oophorectomy failed in so many patients. Whichever method was used, the results were remarkably consistent, and it became clear that worthwhile responses could be obtained in about 30 percent of premenopausal patients(14, 15, 16). Although often dramatic, remissions were always temporary, lasting on average for eighteen months to two years. The striking benefit derived in patients with advanced disease suggested that the development of metastases might be prevented or delayed if bilateral oophorectomy was carried out prophylactically at the time of primary treatment for relatively early disease. Several authors reported enthusiastically on the success of this policy (14, 17), and results from two prospective clinical trials indicated benefit(18,19, 20). But others were more guarded in their assessment, and a large retrospective study suggested that survival after prophylactic oophorectomy was no greater than that following castration when advanced disease became apparent (21). (c.4) PROSTATIC CANCER AND ORCHIECTOMY The course of events in prostatic cancer was similar to that in cancer of the breast. It had been observed by John Hunter in 1786 that bilateral orchiectomy caused atrophy of the prostate (p. E.4), and it was reported by William White of Philadelphia (Fig. C.2) in the nineteenth century that castration reduced the size of the gland and relieved symptoms in benign prostatic hypertrophy (22, 23). Hormone dependence of prostatic cancer was not recognized until much later. During the 1930s Charles Huggins of Chicago (Fig. C3) began a series of experiments on the physiology of the prostate, which led to a wide-ranging study of endocrine-dependent cancers and had a profound effect on the management of prostatic and mammary cancers. In 1941 he found that prostatic cancers could be stimulated by androgens and depressed by both estrogens and castration (24). The next year he reported twenty-one consecutive patients with very advanced cancer of the prostate, fifteen of whom showed noticeable improvement when treated by bilateral orchiectomy(25). He recorded relief of pain from osseous metastases, regression of primary tumors, correction of anemia, and increase in weight. As in cancer of the breast, however, the effect of castration was temporary and was followed by recrudescence of the disease. (c.5) ADRENALECTOMY The association between the temporary nature of the responses to castration and the effects of operation on the concentrations of sex hormones in the blood and urine in both diseases was striking. After bilateral oophorectomy in women the estrogen levels fell dramatically, but gradually rose again. After bilateral orchiectomy in men the fall in androgen concentration

Cancer of the Breast and Prostate (C)

• 287

was also transient, suggesting that the adrenal cortex was another important source of sex hormone production (p. A.46). On December 30, 1942, and January 11, 1943, Huggins removed the adrenal glands in two stages from a patient with advanced metastatic carcinoma of the prostate, using the posterior approach (p. A.13). During 1943 and 1944 he carried out similar operations on three other patients, all of whom had undergone bilateral orchiectomy previously. It rapidly became apparent that, in the absence of adequate replacement therapy, life could not be maintained, and the operation was abandoned for the time being (p. A.34). One patient, however, survived for 116 days, and it was noted that his tumor became smaller and softer during this time. His urinary ketosteroids (p. A.49), which had fallen and risen again after orchiectomy, were reduced persistently after adrenalectomy (26). A similar "dramatic" but temporary improvement was also observed after subtotal adrenalectomy by Henry Cox of Manchester, England (27). In 1947 Hedley Atkins of London performed subtotal adrenalectomy on seven patients with advanced cancer of the breast who had previously undergone bilateral oophorectomy. His impression was that "if sufficient adrenal tissue was removed to have an effect on the cancer, the hazard to life was so great that it was not worthwhile doing" (28). Eventually cortisone replacement therapy enabled Huggins in 1951 to carry out bilateral adrenalectomy by a one-stage procedure with a relatively low operative mortality. In seven patients with advanced cancer of the prostate there was only one postoperative death (29). All patients had previously undergone orchiectomy with remission of the disease and subsequent relapse, and had been treated with estrogens for long periods. Huggins wrote, "Perhaps the most striking observation has been the immediate and persistent relief of crippling pain in the bones." This occurred within two days of operation in five of the six patients who survived, and had persisted at the time of publication in 1952. Huggins considered that three patients had had a "clinical remission of considerable magnitude." A similar and contemporary series of patients treated by Charles West and his colleagues in New York showed similar results. They treated ten patients with advanced prostatic cancer, nine of whom had extensive skeletal metastases. Eight had been treated previously by estrogens and castration. Again relief from bone pain was dramatic, and three patients who had been confined to bed became mobile. There were three postoperative deaths from causes other than adrenal failure, and relief of pain was apparent in all seven survivors. Two showed objective signs of regression (30). (c.6) In advanced cancer of the breast the results of bilateral adrenalectomy were equally impressive. Again Huggins was first in the field, and during 1951 and 1952 he operated on fifty-five patients—fifty-three women and two men. Ten of the women and one man experienced significant and prolonged regression of the disease. There were decrease and disappearance of pain, stabilization or healing of osseous lesions, disappearance of a pleural effu-

288 • History of Endocrine Surgery sion, and regression and healing of recurrent lesions on the chest wall. Estrogens disappeared from the urine (31). Huggins was awarded a Nobel Prize for this work in 1966. Confirmatory reports from both sides of the Atlantic followed rapidly(30, 32, 33, 34, 35). The rates of remission reported varied from 28 to 67 percent of patients treated, and the variation almost certainly reflected the lack of standard methods of assessment and criteria for response. More recently the introduction of such methods has indicated that worthwhile remissions may be expected in 25 to 30 percent of patients(36, 37). The operation did not, however, result in permanent elimination of circulating estrogens in women with cancer of the breast or of androgens in men with cancer of the prostate. This was due in part to stimulation of accessory adrenal tissue by high circulating concentrations of ACTH, and partly to other sources of sex hormone production. (c.7) PITUITARY ABLATION The next rational step was ablation of the pituitary, which would abolish production of ACTH and other trophic hormones that stimulate secretion of sex hormones (p. P.22). The first known hypophysectomy for disseminated cancer of the prostate was performed in 1948 by Earl Warren in Baltimore, but the patient survived for eleven days only, and no further attempts were made until cortisone became available in 1950(38). The first hypophysectomy for cancer of the breast was carried out by Jacques le Beau in Paris on November 29, 1951 (39). No replacement therapy was given and hypophysectomy was probably incomplete, but the patient responded remarkably and gained weight. Herbert Olivecrona (Fig. C.4), working closely with his medical colleague Rolf Luft in Stockholm, was the first to undertake a series of surgical hypophysectomies for advanced cancer (p. P.53). The results, particularly in cancer of the breast, were encouraging. By the end of 1956 he had performed the operation on fifty-nine women and two men with advanced cancer of the breast, and reported benefit in more than half the women and both men (40). In the United States large series were reported with similar striking results. In 1956, 400 patients with a response rate of 34 percent were reviewed (41), and in 1960 Bronson Ray of New York, with his medical colleague Olof Pearson, reported 343 patients with advanced cancer of the breast of whom 144 had derived benefit from the operation. In 123 (36 percent) there was measurable regression of the disease, and in another 21 (6 percent) it appeared to have been arrested. They found that response was most likely in premenopausal women who had responded previously to bilateral oophorectomy. Over 90 percent of these women responded favorably, compared with 7 percent of those who had obtained no relief from castration (42). In cancer of the prostate relief of pain occurred in most patients treated by hypophysectomy, but objective evidence of regression of the typical blastic metastases in bone was more

Cancer of the Breast and Prostate (C) • 289 difficult to obtain than with the lytic lesions that occurred more commonly in cancer of the breast. (c.8) Generally speaking, the results of hypophysectomy appeared to be better than those reported with bilateral adrenalectomy, and this was confirmed by Hedley Atkins (Fig. C.5), Murray Falconer, and their colleagues in London (28). In 1957 they reported a prospective controlled clinical trial to compare the two operations, and the results indicated that hypophysectomy was significantly superior to adrenalectomy in terms of clinical response and survival. This was the first randomized surgical trial of any sort known to have been undertaken. Unfortunately, both operations were major procedures and were carried out on patients who were often elderly and seriously ill. Inevitably, the operative mortality was high (5-10 percent) in most series reported, and this stimulated attempts to ablate the pituitary by less traumatic methods than open operation. Patrick Forrest (Fig. C.6) of Glasgow developed a method of destroying the pituitary with radiation, initially by implantation of radon and later with yttrium-90. Several series of patients with cancers of the breast or prostate were treated by him and by others with rates of remission similar to those reported after surgical hypophysectomy (p. P.65) (43, 44). Whichever method of hypophysectomy was used, the incidence of incomplete ablation of the pituitary was significant, and this was particularly apparent in patients treated by implantation. Many attempts were m a d e to ensure completeness of ablation in the hope that this might achieve a greater incidence and duration of remissions. Particularly good results were obtained by Colin Gleadhill and colleagues in Belfast, Northern Ireland, who packed the pituitary fossa with wax impregnated with yttrium-90 after hypophysectomy (p. P. 57) (45,46). In a controlled trial they obtained 24 percent of objective remissions and a mean survival of nineteen months with hypophysectomy alone, and 57 percent remissions and mean survival of twenty-four months with hypophysectomy plus yttrium. (c.9) PREDICTION OF RESPONSE Although the benefits of surgical ablation of the adrenals and the pituitary were obvious, they were apparent in only a minority of patients, and in most series a majority, often frail and ill, were subjected to major operations without benefit. The need for a method to predict which patients would respond was apparent to Boyd in 1900, and by the 1960s the need was urgent. Richard (Michael) Bulbrook and colleagues in London devised a method based on the measurement of steroids in urine. They found that when the amounts of certain weak androgens were high in relation to the corticosteroids, endocrine ablation was likely to be successful. Conversely, if the relationship was reversed, operations would probably fail. They used these findings to derive a "discriminant function," which enabled the selec-

290


tion of a group of patients who could be spared operations that were unlikely to be of benefit(47). Unfortunately, the methods involved were complex and time-consuming and were not generally applicable. The recognition and measurement of the receptor protein for estrogens in breast cancer cells by Ellwood Jensen in Chicago was a major step. Tumors from which the receptor protein was absent were extremely unlikely to respond to any form of endocrine treatment, whereas about half of those in which it was present derived benefit (48). Measurement of the receptor protein for progesterone further improved the discrimination between responsive and unresponsive tumors. Those that contain both types of receptor are very likely to respond. Regrettably, attempts to use androgen receptors in cancer of the prostate in a similar way have not yet proved successful. (c.io)

ALTERNATIVES TO SURGERY While major advances were taking place in endocrine surgery there were similar developments of more simple forms of endocrine manipulation. Following Huggins' recognition of hormone dependency in cancer of the prostate, many urologists chose estrogens as the primary treatment of choice in order to avoid or delay the psychological problems associated with orchiectomy. In 1944 Alexander Haddow of London had described response to estrogen therapy in postmenopausal women with cancer of the breast (49), and later it was recognized that responses could be obtained with androgens, progestogens, and corticosteroids. By the 1960s and 1970s endocrine surgeons in most major centers had become members of multidisciplinary teams whose therapeutic regimens included both surgery and simple hormonal therapy. Policies varied greatly, but in general ovarian ablation either by surgery or by radiotherapy was preferred as the first line of treatment in premenopausal women with cancer of the breast, while estrogens were used in postmenopausal women and in men with cancer of the prostate. Eventually the side effects of estrogen therapy (water retention and thromboembolic complications) were considered prohibitive, and in cancer of the breast estrogen was replaced by the nontoxic antiestrogen tamoxifen. Aminoglutethimide (p. A.60) and other drugs that interfere with steroid synthesis in the adrenals enabled oncologists to perform an effective "medical adrenalectomy." More recently powerful synthetic analogues of hypothalamic trophic hormone-releasing hormones (p. P.82) have become available and appear to produce the same effects as those of castration in both males and females. It seems likely that surgical ablation of endocrine glands in the treatment of hormone-dependent cancers, which has contributed so much to the understanding of these lesions, has now been superseded by more simple forms of treatment. ecu)

Cancer of the Breast and Prostate (C)

• 291

GENERAL SOURCES Currie, A.R., ed. Endocrine aspects of breast cancer. Edinburgh and London: E. & S. Livingstone, 1958. Stoll, B.A., ed. Breast cancer management—early and late. London: Heinemann Medical, 1977. REFERENCES 1. Schinzinger, A. Uber Carcinoma Mammae. Zbl Org Ges Chir 1889; 29: 55. 2 Beatson, G.T. On the treatment of inoperable cases of carcinoma of the mammae. Lancet 1896; 2: 104-7. 3. Herman, G.E. Recurrent cancer of the breast treated by oophorectomy and thyroid extract. Ibid. 1898; 154: 1612-13. 4. Herman, G.E. A second case in which recurrent mammary carcinoma disappeared after treatment. Ibid. 1899; 156: 1088-89. 5. Herman, G.E. Four cases of recurrent mammary carcinoma treated by oophorectomy and thyroid extract. Br Med J 1900; 2: 1167-68. 6. Eve, F. Recurrent carcinoma of the breast treated by oophorectomy and administration of thyroid extract. Trans Clin Soc London 1900; 33: 210. 7. Thomson, A. Cases in which oophorectomy was performed for inoperable carcinoma of the breast. Br Med J 1902; 2: 1538-41. 8. Power, D'A. Three cases of inoperable cancer of the breast treated by removal of ovaries. Lancet 1902; 163: 933. 9. Paton, E.P. Inoperable scirrhus cancer of the breast treated by oophorectomy; results. Br Med J 1902; 1: 508. 10. Boyd, S. Oophorectomy in cancer of the breast. Ibid. 1900; 2: 1161-67. 11. Lett, H. Ninety-nine cases of inoperable carcinoma of the breast treated by oophorectomy. Lancet 1905; 1: 1227-28. 12. Courmelles, F. de. La radiotherapie combinee du sein et des ovaries contre les tumeurs du sein. CR Acad Sci (Paris) 1922; 174: 503. 13. Courmelles, F. de. Les rayons X et le radium en therapeutique gynecologique. Acta Radiol (Stockh) 1926; 6: 322. 14. Adair, F.E., Treves, N., Farrow, J.H., and Scharnagel, I.M. Clinical effects of surgical and X-ray castration in mammary cancer. JAMA 1945; 128: 161-67. 15. Pearson, O., Li, M . C , McLean, J.P., Lipsett, M.B., and West, C D . Management of metastatic mammary cancer. JAMA 1955; 159: 1701-4. 16. Treves, N., and Finkbeiner, J.A. Therapeutic surgical castration in the treatment of . . . inoperable mammary carcinoma. Cancer 1958; 11: 421-38. 17. Treves, N. Prophylactic castration in the treatment of mammary carcinoma. Ibid. 1957; 10: 393-407. 18. Nissen, Meyer R. Castration as part of the primary treatment for operable female breast cancer. Acta Radiol (Stockh) 1965; Suppl 249. 19. Nissen, Meyer R. Prophylactic castration in the therapy of human mammary cancer. Eur J Cancer 1967; 3: 395-403. 20. Cole, M.P. Suppression of ovarian function in primary breast cancer. In:

292


Forrest, A.P.M., and Kunkler, P.B., eds. Prognostic factors in breast cancer. Edinburgh: Livingstone, 1968: 146. 21. Kennedy, B.J., Mielke, P.W., and Fortuny, I.E. Therapeutic castration versus prophylactic castration in the total treatment of breast cancer. Surg Gynecol Obstet 1964; 118: 52^40. 22. White, J.W. The present position of the surgery of the hypertrophied prostate. Ann Surg 1893; 18: 152-88; 1904; 40: 782-95. 23. Murphy, L.J.T. The history of urology. Springfield, IL: Charles C Thomas, 1972: 386. 24. Huggins, C , and Hodges, C V . Studies on prostatic cancer; effect of castration and of androgen injection on serum phosphatases. Cancer Res 1941; 1: 293-97. 25. Huggins, C. Effect of orchiectomy and irradiation on cancer of prostate. Ann Surg 1942; 115: 1192-1200. 26. Huggins, C , and Scott, W.W. Bilateral adrenalectomy in prostatic cancer. Ibid. 1945; 122: 1031-41. 27. Cox, H.T. Adrenalectomy and prostatic cancer. Lancet 1947; 2: 425-26. 28. Atkins, H.J.B., Falconer, M.A., Hayward, J.L., andMacLean, K.S. Adrenalectomy and hypophysectomy for advanced cancer of the breast. Ibid. 1957; 1: 48996. 29. Huggins, C , and Bergenstal, D.M. Inhibition of human mammary and prostatic cancers by adrenalectomy. Cancer Res 1952; 12: 134-41. 30. West, C D . , Hollander, V.P., Whitmore, W.F., Randall, H.T., and Pearson, O.H. Effect of bilateral adrenalectomy upon neoplastic disease. Cancer 1952; 5: 1009-18. 31. Huggins, C , and Dao, T.L.-Y. Adrenalectomy and oophorectomy in the treatment of advanced cancer of the breast. JAMA 1953; 151: 1388-94. 32. Pyrah, L.N., and Smiddy, F.G. Mammary cancer treated by bilateral adrenalectomy. Lancet 1954; 1: 1041-47. 33. Greening, W.P., and Harmer, M.H. Adrenalectomy in cancer of breast and prostate. Postgrad Med J 1954; 30: 556-70. 34. Cade, S. Adrenalectomy for hormone-dependent cancers. Ann R Coll Surg Engl 1954; 15: 71-107. 35. Block, G.E., Vial, A.B., McCarthy, J.D., Porter, C.W., and Coller, F.A. Adrenalectomy in advanced mammary cancer. Surg Gynecol Obstet 1959; 108: 65168. 36. British Breast Group. Assessment of response to treatment in advanced cancer of breast. Lancet 1974; 2: 38-39. 37. Hayward, J.L., et al. Assessment of response to therapy in advanced breast cancer. Eur J Cancer 1977; 13: 89-94. 38. Warren, E., 1948, quoted by Brendler, H. Adrenalectomy and hypophysectomy for prostatic cancer. Urology 1973; 2: 99. 39. Perrault, P.M., le Beau, J., Klotz, B., Sigard, L, and Clavel, B. L'hypophysectomie totale dans le traitment du cancer du sein. Premier cas franc,ais. Avenir de la methode. Therapie 1952; 7: 290. 40. Luft, R., and Olivecrona, H. Hypophysectomy in the treatment of malignant tumors. Cancer 1957; 10: 789-94. 41. Kennedy, B., French, L.A., and Peyton, W.T. Hypophysectomy in advanced breast cancer. N Engl J Med 1956; 255: 1165.

Cancer of the Breast and Prostate (C) • 293 42. Pearson, O., and Ray, B.S. Hypophysectomy in the treatment of metastatic mammary cancer. Am J Surg 1960; 99: 544-52. 43. Forrest, A.P.M., Blair, D.W., and Valentine, J.M. Screw implantation of the pituitary with yttrium 90. Ibid. 1958; 2: 192-93. 44. Greening, W.P. Irradiation of the pituitary for advanced mammary cancer. Ibid. 1956; 1: 728-29. 45. Edelstyn, G.A., Gleadhill, C.A., and Lyons, A.R. Attempted total hypophysectomy in advanced breast cancer. Br J Surg 1964; 51: 32-40. 46. Edelstyn, G. A., Gleadhill, C A., and Lyons, A.R. Total hypophysectomy for advanced breast cancer. Clin Radiol 1968; 19: 426-32. 47. Bulbrook, R.D., Hayward, J.L., and Thomas, B.S. The relation between the urinary 17-hydroxycorticosteroids and the ll-deoxy-17-oxosteroids and the fate of patients after mastectomy. Lancet 1964; 1: 945-47. 48. Jensen, E.V., Desombre, E.R., and Jungblut, P. Oestrogen receptors in hormone responsive tissues and tumors. In: Wissler, R., Dao, T., and Wood, S., Eds. Endogenous factors influencing host-tumor balance. Chicago: University of Chicago Press, 1967: 15. 49. Haddow, A.L., Watkinson, J.M. Pater son, E., and Roller, P.C. Influence of synthetic oestrogens upon advanced malignant disease. Br Med J 1944; 2: 393-98.

C.1.

C.2.

C.3.

C.4.

C.l. George Beatson. Courtesy of Beatson Institute for Cancer Research, Glasgow. C.2. J. William White. Courtesy of Brooke Roberts, M.D., University of Pennsylvania. C.3. Charles B. Huggins. Courtesy of Charles B. Huggins. C.4. Herbert Olivecrona. Courtesy of Mrs. U. Olivecrona. 294

C.5. C.6.

C.5. Hedley J. B. Atkins. Courtesy of the President and Council of the Royal College of Surgeons of England. C.6. A. Patrick M. Forrest. Courtesy of Sir Patrick Forrest. 295

11(H) Essential and Renal Hypertension

It has been known since the end of the nineteenth century that adrenal disease influences blood pressure. Cortical insufficiency results in hypotension, and excessive secretion of some cortical and medullary hormones causes hypertension. Since the 1920s most physicians have realized that among the large population of patients with supposed essential hypertension there are a few with "suprarenal hypertension" (1). These are discussed in Chapter 4. Some people, however, have suggested that the adrenals are involved in the pathogenesis of essential hypertension itself. The emphasis centered on the medulla at first, and a few had the "beautiful dream" that hyperepinephrinemia was its cause (p. A. 104). At that time, when there was no effective medical treatment, surgical attempts to relieve hypertension were derived from this idea. (HI) In 1910 George Crile of Cleveland, Ohio, proposed that hypertension and certain other diseases were controlled by a "kinetic drive" from the "brainthyroid-adrenal-sympathetic system" and that this could be reduced by unilateral adrenalectomy, cervical sympathectomy and thyroidectomy, or thyroid artery ligation, performed alone or in various combinations(2,3). Eventually he employed adrenal denervation by section of the splanchnic nerves as the operation of choice, and found, surprisingly, that unilateral denervation was more effective than bilateral. In 1934 he claimed excellent results in over 300 patients with "neurocirculatory asthenia," hyperthyroidism, peptic ulcer, diabetes, and "polyglandular disease." Hypertension (sometimes also treated by adrenalectomy), Raynaud's disease, and psychoses were not improved. From 1913 onwards, however, European surgeons, particularly Rene Leriche of Strasbourg and Lyon, undertook various forms of adrenalectomy and sympathectomy, alone and together,

Essential and Renal Hypertension (H)

• 297

for hypertension, Buerger's and Raynaud's diseases, and diabetes, and claimed some good results, especially in hypertension(4). (H.2) Other reports of unilateral adrenalectomy for hypertension were less encouraging (5). Meanwhile Joseph and Cornelius D e Courcy in Cincinnati maintained that medullary hyperplasia was always present in essential hypertension, and treated six patients by removal of two-thirds of each adrenal, describing the effects on hypertension as comparable with those of thyroidectomy on hyperthyroidism. Operations, however, revealed three adrenal neoplasms—one small pheochromocytoma and two unspecified cortical tumors—which were removed. In 1925 Alfred Adson introduced ventral rhizotomy for hypertension at the Mayo Clinic (6), but later used lumbar sympathectomy, splanchnicectomy, and partial bilateral adrenalectomy, which was less traumatic, in a few patients, and described the results as "good" in most of them (7). Thoracic, thoracolumbar, and "total" sympathectomy were undertaken for essential hypertension by other surgeons, particularly Max Peet in A n n A r b o r and Reginald Smithwick in Boston, and comparable results were claimed(8). Interestingly, Smithwick found that pheochromocytomas and aldosteronomas were each present in 0.5 percent of hypertensive patients undergoing sympathectomy (p. A.86, A.117). m\3) By the mid-1930s the role of the adrenal cortex in the hypertension of Cushing's syndrome was recognized, and it was suggested that pituitary basophilic hyperplasia might be the cause of essential hypertension (9). Support came from the observations that the blood pressure fell to normal in hypertensive patients who developed Addison's disease and that hypertension returned after the administration of D O C ( 1 0 ) . Furthermore, adrenalectomy abolished the hypertension induced by experimental constriction of one renal artery (11). Whatever role the adrenal cortex played in essential hypertension, further trials of adrenalectomy seemed justifiable.

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