Thyroid Ultrasound and Ultrasound-Guided FNA, Second Edition

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Author: H. Jack Baskin | Daniel S. Duick | Robert A. Levine

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Thyroid Ultrasound and Ultrasound-Guided FNA Second Edition

Thyroid Ultrasound and Ultrasound-Guided FNA Second Edition

H. Jack Baskin, M.D., MACE Orlando, FL, USA

Daniel S. Duick, M.D., FACE Phoenix, AZ, USA

Robert A. Levine, M.D., FACE Nashua, NH, USA

Foreword by Leonard Wartofsky, M.D., MACP Washington, DC, USA

Editors H. Jack Baskin 1741 Barcelona Way Winter Park FL 32789 USA [email protected]

Daniel S. Duick 3522 North 3rd Avenue Phoenix AZ 85613 USA [email protected]

Robert A. Levine Thyroid Center of New Hampshire 5 Coliseum Avenue Nashua NH 03063 USA [email protected]

ISBN 978-0-387-77633-0

e-ISBN 978-0-387-77634-7

© 2008 Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper 9 8 7 6 5 4 3 2 springer.com

Foreword Ultrasound has become established as the diagnostic procedure of choice in guidelines for the management of thyroid nodules by essentially every professional organization of endocrinologists. In this, the second edition of their outstanding text on thyroid ultrasound, Baskin, Duick, and Levine have provided an invaluable guide to the application of gray-scale and color Doppler ultrasonography to state-of-the-art diagnostic evaluation of thyroid nodules, and to the management of thyroid cysts, benign thyroid and parathyroid nodules, and thyroid cancer. Differences with, and additions to, the first edition highlight the extraordinary and dramatic advances in applications of ultrasonography that have occurred in the past decade. The high yield of malignancy in ultrasound-guided fine-needle (FNA) aspirates of nondominant nodules in multinodular glands has altered our mistaken complacency in assuming that palpation-guided FNA only of palpable dominant nodules was adequate for diagnosis. Rather, ultrasound has taught us that the commonly held belief that malignancy is less likely in a multinodular gland is incorrect. Utility of ultrasound has gone far beyond just the initial diagnostic approach, as improved highly sensitive probes allow accurate characterization of the nature of thyroid nodules or lymph nodes, setting priorities for FNA and for serial monitoring for changes in size that could imply malignancy. Ultrasound is also informing us as to the frequency and significance of thyroid microcarcinomata. The greater sensitivity of modern ultrasonographic (US) technique has opened a Pandora’s box in facilitating the detection of small nodules, which then mandate FNA (or serial follow-up at a minimum). Awareness that certain ultrasound characteristics of nodules (e.g., hypoechogenicity, microcalcifications, and blurred nodule margins) are associated with malignancy has allowed us to focus our interest in FNA primarily and selectively on nodules with these characteristics. Many such small nodules with these characteristics are found to constitute microcarcinomas, and their natural history teaches us that they can be as aggressive as tumors that are > 1 cm in size. As a consequence, their earlier detection employing ultrasound has facilitated better

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outcomes and potential cures. Thus, modern management of thyroid nodules demands the skilled use of ultrasound to identify all nodules in a given thyroid gland and to more definitively guide the needle for aspiration. The evidence is clear that an ultrasound-based strategy has been shown to be cost-effective in reducing nondiagnostic FNA rates, particularly by targeting those nodules with ultrasonographic characteristics that are more suggestive of malignancy. As a result, unnecessary thyroid surgeries can be avoided and a greater yield of thyroid cancer can be found at surgery. Moreover, in patients with FNA positive for cancer, preoperative baseline neck ultrasound has been shown to be of significant value for the detection of nonpalpable lymph nodes or for guiding the dissection of palpable nodes. Ultrasoundguided FNA of lymph nodes has taught us that anatomic characteristics and not size are better determinants of regional thyroid cancer metastases to lymph nodes. This book is replete with critical assessments of the recent literature on which the above statements are based, and includes the most up-to-date descriptions of newer applications of ultrasound to distinguish benign from malignant nodules such as elastography, as well as practical analytic appraisal of the utility of incorporation of ultrasound to the ablation of both benign and malignant lesions by ethanol instillation, high frequency ultrasound, laser, or radiofrequency techniques. In my view, given the extremely important current and future role of ultrasonography in the diagnosis and management of our patients, endocrinologists, cytopathologists, surgeons, and radiologists are obligated to become familiar with and adopt the approaches and advances described in this volume. Leonard Wartofsky, MD, MACP Washington Hospital Center Washington, DC

Preface to First Edition Over the past two decades, ultrasound has undergone numerous advances in technology, such as gray-scale imaging, realtime sonography, high resolution 7.5–10 Mtz transducers, and color-flow Doppler that make ultrasound unsurpassed in its ability to provide very accurate images of the thyroid gland quickly, inexpensively, and safely. However, in spite of these advances, ultrasound remains drastically underutilized by endocrinologists. This is due in part to a lack of understanding of the ways in which ultrasound can aid in the diagnosis of various thyroid conditions, and to a lack of experience in ultrasound technique by the clinician. The purpose of this book is to demonstrate how ultrasound is integrated with the history, physical examination, and other thyroid tests (especially FNA biopsy) to provide valuable information that can be used to improve patient care. Numerous ultrasound examples are used to show the interactions between ultrasound and tissue characteristics and explain their clinical significance. Also presented is the work of several groups of investigators worldwide who have explored new applications of ultrasound that have led to novel techniques that are proving to be clinically useful. To reach its full potential, it is critical that thyroid ultrasound be performed by the examining physician. This book instructs the physician on how to perform the ultrasound at the bedside so that it becomes part of the physical examination. Among the new developments discussed are the new digital phased-array transducers that allow ultrasound and FNA biopsy to be combined in the technique of ultrasound-guided FNA biopsy. Over the next decade, this technique will become a part of our routine clinical practice and a powerful new tool in the diagnosis of thyroid nodules and in the follow-up of thyroid cancer patients. H. Jack Baskin, MD Editor

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Preface to Second Edition In the eight years since the publication of the first edition of this book, ultrasound has become an integral part of the practice of endocrinology. Ultrasound guidance for obtaining accurate diagnostic material by FNA is now accepted normal procedure. As the chief editor of Thyroid wrote in a recent editorial: “I do not know how anyone can see thyroid patients without their own ultrasound by their side.” The widespread adoption of this new technology by clinicians in a relatively short span of time is unprecedented. While most endocrinologists now feel comfortable using ultrasound for the diagnosis of thyroid nodules, many are reluctant to expand its use beyond the thyroid. Its value as a diagnostic tool to look for evidence of thyroid cancer in neck lymph nodes, or to evaluate parathyroid disease is at least as great as it is in evaluating thyroid nodules. In this second edition, we continue to explore these diagnostic techniques that are readily available to all clinicians. Since the first edition, clinical investigators have continued to discover new techniques and applications for thyroid and neck ultrasound. Power Doppler has replaced color flow Doppler for examining blood flow in the tissues of the neck. Other new advances in diagnosis include ultrasound contrast media, ultrasound elastography, and harmonic imaging. The only ultrasound-guided therapeutic procedure addressed in the 2000 edition was percutaneous ethanol injection (PEI), which had not been reported from the United States but was commonly practiced elsewhere in the world. Today, other ultrasoundguided therapeutic procedures such as laser, radiofrequency, and high intensity focused ultrasound (HIFU) are being used for ablation of tissue without surgery. These innovative procedures are discussed by the physicians who are developing them. We hope that this second edition will inspire clinicians to proceed beyond using ultrasound just for the diagnosis of nodular goiter. The benefits to patients will continue as clinicians advance neck ultrasound to its full potential. H. Jack Baskin, MD Editor, 2008 ix

Contents Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leonard Wartofsky

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Preface to First Edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Jack Baskin

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Preface to Second Edition . . . . . . . . . . . . . . . . . . . . . . . . . . H. Jack Baskin

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Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1

History of Thyroid Ultrasound . . . . . . . . . . . . . . . . . Robert A. Levine

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2

Thyroid Ultrasound Physics . . . . . . . . . . . . . . . . . . . Robert A. Levine

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Doppler Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . Robert A. Levine

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Anatomy and Anomalies . . . . . . . . . . . . . . . . . . . . . . H. Jack Baskin

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Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reagan Schiefer and Diana S. Dean

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Ultrasound of Thyroid Nodules . . . . . . . . . . . . . . . . Susan J. Mandel, Jill E. Langer and Daniel S. Duick

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Ultrasound-Guided Fine-needle Aspiration of Thyroid Nodules . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel S. Duick and Susan J. Mandel

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Ultrasound in the Management of Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 H. Jack Baskin

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Parathyroid Ultrasonography . . . . . . . . . . . . . . . . . . 135 Devaprabu Abraham

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10 Contrast-Enhanced Ultrasound in the Management of Thyroid Nodules . . . . . . . . . . . . . . 151 Enrico Papini, Giancarlo Bizzarri, Antonio Bianchini, Rinaldo Guglielmi, Filomena Graziano, Francesco Lonero, Sara Pacella, and Claudio Pacella 11 Percutaneous Ethanol Injection (PEI): Thyroid Cysts and Other Neck Lesions . . . . . . . . . . . . . . . . . 173 Andrea Frasoldati and Roberto Valcavi 12 Laser and Radiofrequency Ablation Procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Roberto Valcavi, Angelo Bertani, Marialaura Pesenti, Laura Raifa Al Jandali Rifa’Y, Andrea Frasoldati, Debora Formisano, and Claudio M. Pacella 13 High Intensity Focused Ultrasound (HIFU) Ablation Therapy for Thyroid Nodules. . . . . . . . . . 219 Olivier Esnault and Laurence Leenhardt 14 Ultrasound Elastography of the Thyroid . . . . . . . . 237 Robert A. Levine Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

Contributors Devaprabu Abraham, MD, MRCP Salt Lake City, UT H. Jack Baskin, MD, MACE Orlando, FL Angelo Bertani, MD Reggio Emilio, Italy Antonio Bianchini, MD Albano (Rome), Italy Giancarlo Bizzarri, MD Albano (Rome), Italy Diana S. Dean, MD, FACE Rochester, MN Daniel S. Duick, MD, FACE Phoenix, AZ Olivier Esnault, MD Paris, France Debora Formisano, MS Reggio Emilio, Italy Andrea Frasoldati, MD Reggio Emilio, Italy Filomena Graziano, MD Albano (Rome), Italy Rinaldo Guglielmi, MD Albano (Rome), Italy Jill E. Langer, MD Philadelphia, PA

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Laurence Leenhardt, MD, PhD Paris, France Robert A. Levine, MD, FACE Nashua, NH Francesco Lonero, MD Albano (Rome), Italy Susan J. Mandel, MD, MPH Philadelphia, PA Claudio M. Pacella, MD Albano (Rome), Italy Sara Pacella, MD Albano (Rome), Italy Enrico Papini, MD Albano (Rome), Italy Marialaura Pesenti, MD Reggio Emilio, Italy Laura Raifa Al Jandali Rifa’y, MD Reggio Emilio, Italy Reagan Schiefer, MD Rochester, MN Roberto Valcavi, MD, FACE Reggio Emilio, Italy

CHAPTER 1

History of Thyroid Ultrasound Robert A. Levine

The thyroid is well suited to ultrasound study because of its superficial location, vascularity, size and echogenicity (1). In addition, the thyroid has a very high incidence of nodular disease, the vast majority benign. Most structural abnormalities of the thyroid need evaluation and monitoring, but not intervention (2). Thus, the thyroid was among the first organs to be well studied by ultrasound. The first reports of thyroid ultrasound appeared in the late 1960s. Between 1965 and 1970 there were seven articles published specific to thyroid ultrasound. In the last five years there have been over 1,300 published. Thyroid ultrasound has undergone a dramatic transformation from the cryptic deflections on an oscilloscope produced in A-mode scanning, to barely recognizable B-mode images, followed by initial low resolution gray scale, and now modern high resolution images. Recent advances in technology, including harmonic imaging, contrast studies, and three-dimensional reconstruction, have furthered the field. In 1880, Pierre and Jacques Curie discovered the piezoelectric effect, determining that an electric current applied across a crystal would result in a vibration that would generate sound waves, and that sound waves striking a crystal would, in turn, produce an electric voltage. Piezoelectric transducers were capable of producing sonic waves in the audible range and ultrasonic waves above the range of human hearing. The first operational sonar system was produced two years after the sinking of the Titanic in 1912. This system was capable of detecting an iceberg located two miles distant from a ship. A low-frequency audible pulse was generated, and a human operator listened for a change in the return echo. This system was able to detect, but not localize, objects within range of the sonar (3). Over the next 30 years navigational sonar improved, and imaging progressed from passive sonar, with an operator

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listening for reflected sounds, to display of returned sounds as a one-dimensional oscilloscope pattern, to two-dimensional images capable of showing the shape of the object being detected. The first medical application of ultrasound occurred in the 1940s. Following the observation that very high intensity sound waves had the ability to damage tissues, lower intensities were tried for therapeutic uses. Focused sound waves were used to mildly heat tissue for therapy of rheumatoid arthritis, and early attempts were made to destroy the basal ganglia to treat Parkinson’s disease (4). The first diagnostic application of ultrasound occurred in 1942. In a paper entitled “Hyperphonagraphy of the Brain,” Karl Theodore Dussic reported localization of the cerebral ventricles using ultrasound. Unlike the current reflective technique, his system relied on the transmission of sound waves, placing a sound source on one side of the head, with a receiver on the other side. A pulse was transmitted, with the detected signal purportedly able to show the location of midline structures. While the results of these studies were later discredited as predominantly artifact, this work played a significant role in stimulating research into the diagnostic capabilities of ultrasound (4). Early in the 1950’s the first imaging by pulse–echo reflection was tried. A-mode imaging showed deflections on an oscilloscope to indicate the distance to reflective surfaces. Providing information in a single dimension, A-mode scanning indicated only distance to reflective surfaces (See Fig. 2.7) (5). A-mode ultrasonography was used for detection of brain tumors, shifts in the midline structures of the brain, localization of foreign bodies in the eye, and detection of detached retinas. In the first presage that ultrasound may assist in the detection of cancer, John Julian Wild published the observation that gastric malignancies were more echogenic than normal gastric tissue. He later studied 117 breast nodules using a 15MHz sound source, and reported that he was able to determine their size with an accuracy of 90%. During the late 1950s the first two-dimensional B-mode scanners were developed. B-mode scanners display a compilation of sequential A-mode images to create a two-dimensional image (See Fig. 2.2). Douglass Howry developed an immersion tank B-mode ultrasound system, and several models of immersion tank scanners followed. All utilized a mechanically driven transducer that would sweep through an arc, with an image reconstructed to demonstrate the full sweep. Later

HISTORY OF THYROID ULTRASOUND

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advances included a hand-held transducer that still required a mechanical connection to the unit to provide data regarding location, and water-bag coupling devices to eliminate the need for immersion (6). Application of ultrasound for thyroid imaging began in the late 1960s. In July 1967 Fujimoto et al. reported data on 184 patients studied with a B-mode ultrasound “tomogram” utilizing a water bath (8). The authors reported that no internal echoes were generated by the thyroid in patients with no known thyroid dysfunction and nonpalpable thyroid glands. They described four basic patterns generated by palpably abnormal thyroid tissue. The type 1 pattern was called “cystic” due to the virtual absence of echoes within the structure, and negligible attenuation of the sound waves passing through the lesion. Type 2 was labeled “sparsely spotted,” showing only a few small echoes without significant attenuation. The type 3 pattern was considered “malignant” and was described as generating strong internal echoes. The echoes were moderately bright and were accompanied by marked attenuation of the signal. Type 4 had a lack of internal echoes but strong attenuation. In the patients studied, 65% of the (predominantly follicular) carcinomas had a type 3 pattern. Unfortunately, 25% of benign adenomas were also type 3. Further, 25% of papillary carcinomas were found to have the type 2 pattern. While the first major publication of thyroid ultrasound attempted to establish the ability to determine malignant potential, the results were nonspecific in a large percentage of the cases. In December 1971 Manfred Blum published a series of A-mode ultrasounds of thyroid nodules (Fig. 2.1) (5). He demonstrated the ability of ultrasound to distinguish solid from cystic nodules, as well as accuracy in measurement of the dimensions of thyroid nodules. Additional publications in the early 1970s further confirmed the capacity for both A-mode and B-mode ultrasound to differentiate solid from cystic lesions, but consistently demonstrated that ultrasound was unable to distinguish malignant from benign solid lesions with acceptable accuracy (9). The advent of gray scale display resulted in images that were far easier to view and interpret (7). In 1974 Ernest Crocker published “The Gray Scale Echographic Appearance of Thyroid Malignancy” (10). Using an 8MHz transducer with a 0.5 mm resolution, he described “low amplitude, sparse and disordered echoes” characteristic of thyroid cancer

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when viewed with a gray scale display. The pattern felt to be characteristic of malignancy was what would now be considered “hypoechoic and heterogeneous.” Forty of the eighty patients studied underwent surgery. All six of the thyroid malignancies diagnosed had the described (hypoechoic) pattern. The percentage of benign lesions showing this pattern was not reported in the publication. With each advancement in technology, interest was again rekindled in ultrasound’s ability to distinguish a benign from a malignant lesion. Initial reports of ultrasonic features typically describe findings as being diagnostically specific. Later, reports followed showing overlap between various disease processes. For example, following an initial report that the “halo sign,” a rim of hypoechoic signal surrounding a solid thyroid nodule, was seen only in benign lesions (11), Propper reported that two of ten patients with this finding had carcinoma (12). As discussed in Chap. 6 the halo sign is still considered to be one of the numerous features that can be used in determining the likelihood of malignancy in a nodule. In 1977 Wallfish recommended combining fine-needle aspiration biopsy with ultrasound in order to improve the accuracy of biopsy specimens (13). Recent studies have continued to demonstrate that biopsy accuracy is greatly improved when ultrasound is used to guide placement of the biopsy needle. Most patients with prior “nondiagnostic” biopsies will have an adequate specimen when ultrasound-guided biopsy is performed (14). Ultrasound-guided fine-needle aspiration results in improved sensitivity and specificity of biopsies as well as a greater than 50% reduction in nondiagnostic and false negative biopsies (15). Current resolution allows demonstration of thyroid nodules smaller than 1 mm; thus ultrasound has clear advantages over palpation in detecting and characterizing thyroid nodular disease. Nearly 50% of patients found to have a solitary thyroid nodule by palpation will be shown to have additional nodules by ultrasound, and more than 25% of the additional nodules are larger than 1 cm (16). With a prevalence estimated between 19% and 35%, the management of incidentally detected, nonpalpable thyroid nodules remains controversial. Several guidelines have been developed to assist in deciding which nodules warrant biopsy and which may be monitored without tissue sampling. These guidelines are discussed in Chap. 7. Over the past several years the value of ultrasound in screening for suspicious lymph nodes prior to surgery in


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patients with biopsy proven cancer has been established. Current guidelines for the management of thyroid cancer indicate a pivotal role for ultrasound in monitoring for locoregional recurrence (17). During the 1980’s Doppler ultrasound was developed, allowing detection of flow in blood vessels. As discussed in Chapter 3 the Doppler pattern of blood flow within thyroid nodules has an important role in assessing the likelihood of malignancy. Doppler imaging may also demonstrate the increased blood flow characteristic of Graves’ disease (18), and may be useful in distinguishing between Graves’ disease and thyroiditis, especially in pregnant patients or patients with amiodaroneinduced hyperthyroidism (19). Recent technological advancements include intravenous sonographic contrast agents, three-dimensional ultrasound imaging and elastography. Intravenous sonographic contrast agents are available in Europe, but remain experimental in the United States. All ultrasound contrast agents consist of microbubbles, which function both by reflecting ultrasonic waves and, at higher signal power, by reverberating and generating harmonics of the incident wave. Ultrasound contrast agents have been predominantly used to visualize large blood vessels, with less utility in enhancing parenchymal tissues. They have shown promise in imaging peripheral vasculature as well as liver tumors and metastases (20), but no studies have been published demonstrating an advantage of contrast agents in thyroid imaging. Three-dimensional display of reconstructed images has been available for CT scan and MRI for many years and has demonstrated practical application. While three-dimensional ultrasound has recently gained popularity for fetal imaging, its role in diagnostic ultrasound remains unclear. While obstetrical ultrasound has the great advantage of the target being surrounded by a natural fluid interface, 3D thyroid ultrasound is limited by the lack of a similar interface distinguishing the thyroid from adjacent neck tissues. It is predicted that breast biopsies will soon be guided in a more precise fashion by real time 3D imaging (21), and it is possible that, in time, thyroid biopsy will similarly benefit. At the present time, however, 3D ultrasound technology does not have a demonstrable role in thyroid imaging. Elastography is a new technique in which the compressibility of a nodule is assessed by ultrasound as external pressure is applied. With studies showing a good predictive

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value for prediction of malignancy in breast nodules, recent investigations of its role in thyroid imaging have been promising. Additional prospective trials are ongoing to assess the role of elastography in predicting the likelihood of thyroid malignancy. With the growing recognition that real time ultrasound performed by an endocrinologist provides far more useful information than that obtained from a radiology report, office ultrasound by endocrinologists has gained acceptance. The first educational course specific to thyroid ultrasound was offered by the American Association of Clinical Endocrinologists (AACE) in 1998. Under the direction of Dr. Jack Baskin, 53 endocrinologists were taught to perform diagnostic ultrasound and ultrasound-guided fine-needle aspiration biopsy. By the turn of the century 300 endocrinologists had been trained. Endocrine University, established in 2002 by AACE, began providing instruction in thyroid ultrasound and biopsy to all graduating endocrine fellows. By the end of 2006 over 2,000 endocrinologists had completed the AACE ultrasound course. In 2007 AACE and the American Institute of Ultrasound Medicine (AIUM) began a collaborative effort for certification and accredidation in thyroid ultrasound. In the 35 years since ultrasound was first used for thyroid imaging, there has been a profound improvement in the technology and quality of images. The transition from A-mode to B-mode to gray scale images was accompanied by dramatic improvements in clarity and interpretability of images. Current high-resolution images are able to identify virtually all lesions of clinical significance. Ultrasound characteristics cannot predict benign lesions, but features including irregular margins, microcalcifications, and central vascularity may deem a nodule suspicious (3). Ultrasound has proven utility in the detection of recurrent thyroid cancer in patients with negative whole body iodine scan or undetectable thyroglobulin (17, 22). Recent advances including the use of contrast agents, tissue harmonic imaging, elastography, and multiplanar reconstruction of images will further enhance the diagnostic value of ultrasound images. The use of Doppler flow analysis may improve the predictive value for determining the risk of malignancy, but no current ultrasound technique is capable of determining benignity with an acceptable degree of accuracy. Ultrasound guidance of fine-needle aspiration biopsy has been demonstrated to improve both diagnostic yield and accuracy, and will likely become the standard of


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care. Routine clinical use of ultrasound is often considered an extension of the physical examination by endocrinologists. High quality ultrasound systems are now available at prices that make this technology accessible to virtually all providers of endocrine care (3). References 1. Solbiati L, Osti V, Cova L, Tonolini M (2001) Ultrasound of the thyroid, parathyroid glands and neck lymph nodes. Eur Radiol 11(12):2411–2424 2. Tessler FN, Tublin ME (1999) Thyroid sonography: current applications and future directions. AJR 173:437–443 3. Levine RA (2004) Something old and something new: a brief history of thyroid ultrasound technology. Endocr Pract 10(3): 227–233. 4. Woo JSK Personal Communication. 5. Blum M, Weiss B, Hernberg J (1971) Evaluation of thyroid nodules by A-mode echography. Radiology 101:651–656 6. Skolnick ML, Royal DR (1975) A simple and inexpensive water bath adapting a contact scanner for thyroid and testicular imaging. J Clin Ultrasound 3(3):225–227 7. Scheible W, Leopold GR, Woo VL, Gosink BB (1979) Highresolution real-time ultrasonography of thyroid nodules. Radiology 133:413–417 8. Fujimoto F, Oka A, Omoto R, Hirsoe M (1967) Ultrasound scanning of the thyroid gland as a new diagnostic approach. Ultrasonics 5:177–180 9. Thijs LG (1971) Diagnostic ultrasound in clinical thyroid investigation. J Clin Endocrinol Metab 32(6):709–716 10. Crocker EF, McLaughlin AF, Kossoff G, Jellins J (1974) The gray scale echographic appearance of thyroid malignancy. J Clin Ultrasound 2(4):305–306 11. Hassani SN, Bard RL (1977) Evaluation of solid thyroid neoplasms by gray scale and real time ultrasonography: the “halo” sign. Ultrasound Med 4:323 12. Propper RA, Skolnick ML, Weinstein BJ, Dekker A (1980) The nonspecificity of the thyroid halo sign. J Clin Ultrasound 8:129–132 13. Walfish PG, Hazani E, Strawbridge HTG, Miskin M, Rosen IB (1977) Combined ultrasound and needle aspiration cytology in the assessment and management of hypofunctioning thyroid nodule. Ann Intern Med 87(3):270–274 14. Gharib H (1994) Fine-needle aspiration biopsy of thyroid nodules: advantages, limitations, and effect. Mayo Clin Proc 69:44–49 15. Danese D, Sciacchitano S, Farsetti A, Andreoli M, Pontecorvi A (1998) Diagnostic accuracy of conventional versus sonographyguided fine-needle aspiration biopsy in the management of nonpalpable and palpable thyroid nodules. Thyroid 8:511–515

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16. Tan GH, Gharib H, Reading CC (1995) Solitary thyroid nodule: comparison between palpation and ultrasonography. Arch Intern Med 155:2418–2423 17. Cooper DS, Doherty GM, Haugen BR et al (2006) Management guidelines for patients with thyroid nodules and thyroid cancer. Thyroid 16(2)1–33 18. Ralls PW, Mayekowa DS, Lee KP et al (1988) Color-flow Doppler sonography in Graves’ disease: “thyroid inferno.” AJR 150:781– 784 19. Bogazzi F, Bartelena L, Brogioni S et al (1997) Color flow Doppler sonography rapidly differentiates type I and type II amiodaroneinduced thyrotoxicosis. Thyroid 7(4)541–545 20. Grant EG (2001) Sonographic contrast agents in vascular imaging. Semin Ultrasound CT MR 22(1):25–41 21. Lees W (2001) Ultrasound imaging in three and four dimensions. Semin Ultrasound CT MR 22(1):85–105 22. Antonelli A, Miccoli P, Ferdeghini M (1995) Role of neck ultrasonography in the follow-up of patients operated on for thyroid cancer. Thyroid 5(1):25–28

CHAPTER 2

Thyroid Ultrasound Physics Robert A. Levine

SOUND AND SOUND WAVES Some animal species such as dolphins, whales, and bats are capable of creating a “visual” image based on receiving reflected sound waves. Man’s unassisted vision is limited to electromagnetic waves in the spectrum of visible light. Humans require technology and an understanding of physics to use sound to create a picture. This chapter will explore how man has developed a technique for creating a visual image from sound waves (1). Sound is transmitted as mechanical energy, in contrast to light, which is transmitted as electromagnetic energy. Unlike electromagnetic waves, sound waves require a propagating medium. Light is capable of traveling through a vacuum, but sound will not transmit through a vacuum. The qualities of the transmitting medium directly affect how sound is propagated. Materials have different speeds of sound transmission. Speed of sound is constant for a specific material and does not vary with sound frequency (Fig. 2.1). Acoustic impedance is the inverse of the capacity of a material to transmit sound. Acoustic impedance of a material depends on its density, stiffness and speed of sound. When sound travels through a material and encounters a change in acoustic impedance a portion of the sound energy will be reflected, and the remainder will be transmitted. The amount reflected is proportionate to the degree of mismatch of acoustic impedance. Sound waves propagate by compression and rarefaction of molecules in space (Fig. 2.2). Molecules of the transmitting medium vibrate around their resting position and transfer their energy to neighboring molecules. Sound waves carry energy rather than matter through space. As shown in Fig. 2.2, sound waves propagate in a longitudinal direction, but are typically represented by a sine wave

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10 4500

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Bone Muscle Liver

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FIG. 2.1. Speed of sound. The speed of sound is constant for a specific material and does not vary with frequency. Speed of sound for various biological tissues is illustrated

FIG. 2.2. Sound waves propagate in a longitudinal direction but are typically represented by a sine wave where the peak corresponds to the maximum compression of molecules in space, and the trough corresponds to the maximum rarefaction

where the peak corresponds to the maximum compression of molecules in space, and the trough corresponds to the maximum rarefaction. Frequency is defined as the number of cycles per time of the vibration of the sound waves. A Hertz (Hz) is defined as one cycle per second. The audible spectrum is between 30 and 20,000 Hz. Ultrasound is defined as sound waves at a higher frequency than the audible spectrum. Typical frequencies used in diagnostic ultrasound vary between five million and 15 million cycles per second (5 MHz and 15 MHz).

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Diagnostic ultrasound uses pulsed waves, allowing for an interval of sound transmission, followed by an interval during which reflected sounds are received and analyzed. Typically three cycles of sound are transmitted as a pulse. The spatial pulse length is the length in space that three cycles fill (Fig. 2.3). Spatial pulse length is one of the determinants of resolution. Since higher frequencies have a smaller pulse length, higher frequencies are associated with improved resolution. As illustrated in Fig. 2.3, at a frequency of 15 MHz the wavelength in biological tissues is approximately 0.1 mm, allowing an axial resolution of 0.15 mm. As mentioned above, the speed of sound is constant for a given material or biological tissue. It is not affected by frequency or wavelength. It increases with stiffness and decreases with density of the material. As seen in Fig. 2.1, common biologic tissues have different propagation velocities. Bone, as a very dense and stiff tissue, has a high propagation velocity of 4,080 meters per second. Fat tissue, with low stiffness and low density, has a relatively low speed of sound of 1,450 m per second. Most soft tissues have a speed of sound near 1,540 m per second. Muscle, liver and thyroid have a slightly faster speed of sound. By convention, all ultrasound equipment uses an average speed of 1,540 meters per second. The distance to an object displayed on an ultrasound image is calculated by multiplying the speed of sound by the time interval for a sound signal to

FIG. 2.3. Diagnostic ultrasound uses pulsed waves, allowing for an interval of sound transmission, followed by an interval during which reflected sounds are received and analyzed. Typically three cycles of sound are transmitted as a pulse

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FIGS. 2.4–2.6. Most biological tissues have varying degrees of inhomogeneity both on a cellular and macroscopic level. Connective tissue, blood vessels, and cellular structure all provided mismatches of acoustic impedance that lead to the generation of characteristic ultrasonographic patterns. FIG. 2.4. demonstrates the echotexture from normal thyroid tissue. It has a ground glass appearance and is brighter than muscle tissue.

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return to the transducer. By using the accepted 1,540 m per second as the assumed speed of sound, all ultrasound equipment will provide identical distance or size measurements. Reflection is the redirection of a portion of a sound wave from the interface of tissues with unequal acoustic impedance. The greater the difference in impedance, the greater the amount of reflection. A material that is homogeneous in acoustic impedance does not generate any internal echoes. A pure cyst is a typical example of an anechoic structure. Most biological tissues have varying degrees of inhomogeneity both on a cellular and macroscopic level. Connective tissue, blood vessels and cellular structure all provide mismatches of acoustic impedance that lead to the generation of characteristic ultrasonographic patterns (Figs. 2.4–2.6). Reflection is categorized as specular when reflecting off of smooth surfaces such as a mirror. In contrast, diffuse reflection occurs when a surface is irregular, with variations at or smaller than the wavelength of the incident sound. Diffuse reflection results in scattering of sound waves and production of noise. CREATION OF AN ULTRASOUND IMAGE The earliest ultrasound imaging consisted of a sound transmitted into the body, with the reflected sound waves displayed on an oscilloscope. Referred to as A-mode ultrasound, these images in the 1960s and 1970s were capable of providing measurements of internal structures such as thyroid lobes, nodules and cysts. Fig. 2.7a shows an A-mode ultrasound image of a solid thyroid nodule. Scattered echoes are present from throughout the nodule. Fig. 2.7b shows the image from a cystic nodule. The initial reflection is from the proximal wall of the cyst, with no significant signal reflected by the cyst fluid. The second reflection originates from the posterior wall. Fig. 2.7c shows the A-mode image from a complex nodule with solid and cystic components. A-mode ultrasound was capable of providing size measurements in one dimension, but did not provide a visual image of the structure.

FIGS. 2.4–2.6. (Continued) FIG. 2.5. shows the thyroid from a patient with the acutely swollen inflammatory phase of Hashimoto’s thyroiditis. Massive infiltration by lymphocytes has decreased the echogenicity of the tissue resulting in a more hypoechoic pattern. FIG. 2.6. shows a typical heterogeneous pattern from Hashimoto’s thyroiditis with hypoechoic inflammatory regions separated by hyperechoic fibrous tissue

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FIG. 2.7. A-mode ultrasound images. a. shows an A-mode ultrasound image of a solid thyroid nodule. Scattered echoes are present from throughout the nodule. b. shows the image from a cystic nodule. The initial reflection is from the proximal wall of the cyst, with no significant signal reflected by the cyst fluid. The second reflection originates from the posterior wall. c. shows the A-mode image from a complex nodule with solid and cystic components

In order to provide a visual two-dimensional image, a series of one-dimensional A-mode images are aligned as a transducer is swept across the structure being imaged. Early thyroid ultrasound images were created by slowly moving a transducer across the neck. By scanning over a structure and aligning the A-mode images, a two-dimensional image is formed. The twodimensional image formed in this manner is referred to as a B-Mode scan (Fig. 2.8). Current ultrasound transducers use a series of piezoelectric crystals in a linear array to electronically simulate a sweep of the transducer. Firing sequentially, each crystal sends a pulse of sound wave into the tissue and receives subsequent reflections. The final ultrasound image reflects a cross sectional image through the tissue defined by the thin flat beam of sound emitted from the transducer. Resolution is the ability to distinguish between two separate, adjacent objects. For example, with a resolution of 0.2 mm, two adjacent objects measuring 5 millimeters generally indicates thyroid enlargement. A diffusely enlarged gland may be a “simple goiter” due to hyperplasia of normal appearing tissue or due to thyroiditis. Thyroiditis causes inflammation and follicular changes in the parenchyma resulting in the gland losing its characteristic uniform “ground glass” appearance on ultrasound. Various types of thyroiditis and their ultrasound changes are discussed in the next chapter. THYROID ANOMALIES Hemiagenesis of the thyroid is a common anomaly seen with ultrasound. It is usually found when ultrasound is being done for some other cause, such as evaluation of a nodule in the

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FIG. 4.6. Hemiagenesis of the left lobe. Ultrasound done to evaluate the palpable nodule (N) in the right lobe reveals the thyroid ends at the isthmus (arrow). The strap muscles (SM) have filled in the space where the left lobe would be. Physical examination of the left neck was normal

FIG. 4.7. Hemiagenesis in patient with Graves’ disease. The isthmus is intact and ends where the left lobe should be (arrow). The isthmus is present in 50% of patients with hemiagenesis. Note the diffuse enlargement and hypoechogenicity of the gland

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contralateral lobe. The anomaly cannot be detected by physical examination. In the past it was suspected to be related to Graves’ disease because it was often found while doing an isotope scan for hyperthyroidism. However since the introduction of ultrasound, most cases are discovered by this form of imaging, and there is no correlation with hyperthyroidism. The incidence is 1:2,500 with 95% involving hemiagenesis of the left lobe. While the condition is benign and not known to

FIGS. 4.8 and 4.9. Hemiagenesis of the right lobe. Initially, this appeared to be a multinodular goiter, but the physical examination was normal. Doppler revealed a venous plexus occupying the space where the right lobe was absent

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predispose to any type of pathology, knowledge of the condition would be very important to someone undergoing surgery for a thyroid nodule. This is a good reason to always do an ultrasound before sending a patient for neck surgery. Aberrant Thyroid can occur anywhere in the neck. The thyroid gland develops at the base of the tongue and descends to below the larynx where it bifurcates into two lobes connected by an isthmus. Sometimes this descent fails to occur (lingual thyroid) or is interrupted, resulting in a failed bifurcation. This may appear to be a goiter on physical examination, but ultrasound will reveal that the thyroid is above the larynx and undivided but otherwise normal in size. Such “pseudogoiters” function well and do not typically grow, cause problems or require surgery. Conversely, thyroid glands may also descend into the superior mediastinum, as in the case of substernal goiter, and may be difficult to evaluate with ultrasound. However, by using a small transducer and having the patient hyperextend his or her neck and swallow, one can generally visualize a portion of the thyroid. Thyroid tissue can occasionally

FIG. 4.10. Failed bifurcation of the thyroid. This teenage female patient presented with an apparent “goiter” located 1 cm above the larynx. Ultrasound reveals a normal amount of thyroid tissue, and thyroid function was normal


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FIG. 4.11. Failed bifurcation of thyroid with a small cyst (calipers)

be found in the lateral neck. Careful evaluation of this “lateral aberrant thyroid” with ultrasound will often show a pedicle or some type of connection to the thyroid. A fine-needle aspiration (FNA) may be necessary to rule out a metastatic lymph node from a nonvisualized microcarcinoma of the thyroid. NONTHYROIDAL ANOMALIES Thyroglossal Duct is formed of embryonic tissue running from the base of the tongue to the larynx, and portions of the duct near the isthmus may persist as a pyramidal lobe of the thyroid, which can be seen with ultrasound. Sometimes the entire thyroglossal duct persists, and protein material secreted by the lining epithelium may form a thyroglossal duct cyst that manifests itself clinically as a midline mass in the anterior aspect of the neck above the isthmus. Brachial cleft cysts will have a similar appearance except they will be more lateral in the neck. Benign Masses in the neck can be evaluated by ultrasound. A large hypoechoic mass posterior to the left lobe of the thyroid should raise the suspicion of an esophageal diverticulum, and it is important to avoid mistaking it for a thyroid nodule

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FIGS. 4.12 and 4.13. Lateral aberrant thyroid. This patient had a long history of a small mass (calipers) in the right lateral neck that moved up and down with swallowing. FNA of the mass revealed normal thyroid cells. A small pedicle attached the mass to the right lobe on both transverse and longitudinal views (arrows)

needing an FNA. The longitudinal view will reveal that the “mass” is posterior and separate from the thyroid lobe. An undescended thymus gland having echogenicity of thyroid tissue may be seen inferior to the thyroid but attached by a short thyrothymic ligament. By having the patient swallow, the thymus can be seen to move up and down with the


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FIG. 4.14. Thyroglossal duct cyst in the midline. These fluid filled cysts are very superficial. A reverberation artifact in the anterior third of the cyst resembles debris in the fluid (white arrow). Posterior to the cyst is enhancement artifact (black arrow) indicating the sound waves have passed through fluid

FIG. 4.15. This small esophageal diverticulum (arrow) could be mistaken for a posterior nodule in the left lobe

thyroid. Hemangiomas of neck muscles are uncommon, but may present as a hypoechoic heterogeneous mass imbedded in the muscle. Enlarged inflammatory lymph nodes are frequently seen with ultrasound. They can occur in patients

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FIG. 4.16. This series of enlarged inflamed lymph nodes (calipers) beneath the sternocleidomastoid muscle could represent infection or signal the presence of autoimmune thyroiditis

FIG. 4.17. Undescended thymus gland attached to the lower pole of the thyroid by a short thyrothymic ligament (arrow)

having sarcoidosis and are a common finding in patients with Hashimoto thyroiditis. Lymph node enlargement is common with infection. These benign lymph nodes are often prominent in the upper neck (Level II) in patients having upper respiratory


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FIG. 4.18. Muscle anomaly. Patient was thought to have a nodule in the right lobe by physical examination. Ultrasound revealed enlargement of the strap muscle in the right neck (arrow) causing asymmetry; no nodule is present

infections. Although inflammatory lymph nodes can get very large, they maintain their shape and have a short/long axis ratio less than 0.7. They usually have an echogenic hilum running through the center that shows arteriolar blood flow with power Doppler. Malignant Masses may also be found in the neck by ultrasound. Lymphoma frequently presents as enlarged lymph nodes in the neck. While any malignancy may metastasize to the neck, squamous cell carcinoma from an occult primary is the most common nonthyroid cancer. Ultrasound and FNA have been found to complement each other, and the technique of ultrasound-guided FNA has emerged as a powerful diagnostic tool for evaluating thyroid nodules. The technique is equally beneficial in evaluating other masses in the neck, both benign and malignant. When an abnormal mass is found by ultrasound, ultrasound-guided needle placement is essential in obtaining accurate diagnostic material.

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FIGS. 4.19 and 4.20. Hemangioma. This heterogeneous mass imbedded in the left sternocleidomastoid muscle between the thyroid, carotid artery and jugular vein is very vascular on power Doppler, indicating it is a hemangioma. It might be confused with a malignant lymph node except that it is too flat (short/long ratio 0.5, and that do not have a hilar line must have an UG FNA.

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FIG. 8.18. This metastatic lymph node, less than 1cm in size, contains cystic necrosis on the medial side which is hypoechoic (calipers) and shows enhancement. The other side (arrow) is solid and hyperechoic. UG FNA of the hypoechoic area yielded negative cytology, but high levels of Tg in needle washout—a finding not unusual if there is cystic necrosis.

FIG. 8.19. Typical small metastatic lymph node (calipers) near the jugular vein (J). Note the rounded shape with a short/long axis of 1, absence of a hilar line, calcification (white arrow), and enhancement (black arrow), indicating early cystic necrosis.

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FIG. 8.20. Power Doppler of previous lymph node shows chaotic vascularization of the periphery of the node, rather than the normal hilar vascular pattern. Although cytology from the FNA was negative, a high level of Tg was found in the needle washout.

FIG. 8.21. Ultrasound of a 16-year old-female one year post-thyroidectomy. Power Doppler of a small lymph node (arrow) found in the central compartment between the trachea and the left carotid shows chaotic vascularization.

UG FNA of a suspicious lymph node in the neck is carried out in the same manner as an UG FNA of a thyroid nodule with aspirate slides prepared and sent for cytology interpretation.


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FIG. 8.22. Larger lymph node found in the lateral compartment of the same patient. Power Doppler again shows an abnormal pattern with recruitment of vessels into the cortex of the lymph node.

FIG. 8.23. 2cm nonpalpable lymph node (calipers) in 47-year-old male seven years post-thyroidectomy. Enhancement distal to the node (arrow) indicates cystic necrosis has started. FNA found negative cytology, but very high levels of Tg in the needle washout.

Lymph node cytology is sometimes difficult to interpret (10). However, thyroid cancer metastases contain Tg, which can be measured and used as a tissue marker. Therefore, the biopsy

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FIG. 8.24. Ultrasound of 54-year-old female 36 years after her thyroidectomy reveals a paratrachael lymph node (arrow) in the right central compartment. Note that the short/long axis is >1 and several calcifications are seen, indicating malignancy. FNA showed positive cytology, but Tg in needle washout was negative, demonstrating the need to do both tests when lymph nodes are biopsied.

FIG. 8.25. A 1cm lymph node (1) and a 0.5cm lymph node (2) in the lateral neck are both rounded without a hilar line. Both nodes had papillary cancer at surgery.

needle(s) is then washed with 1cc normal saline and the washout sent for Tg assay (11, 12). A normal saline control is also sent for Tg assay. Since most patients are on thyroid hormone suppression, serum Tg is usually low or non-detectable, and


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FIG. 8.26. Ultrasound of a 57-year-old female 13 years after a thyroidectomy shows a small oval node (calipers) in the left central compartment that is suspicious.

FIG. 8.27. Power Doppler of previous lymph node shows a malignant vascular pattern. Cytology was negative on FNA, but Tg in needle washout was high, confirming malignancy.

the material in the needle is diluted approximately a hundredfold to a thousandfold; therefore finding a Tg >10 in the needle washout is considered positive for malignancy. Because the intracellular Tg is not exposed to circulating anti-TgAB, a positive test for anti-TgAB in the serum does not interfere with

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FIG. 8.28. This lymph node (calipers) was suspicious because of its borderline short/long axis of 0.5 and absent hilum. Surgery confirmed metastatic papillary cancer.

FIG. 8.29. Metastatic lymph node (calipers) in left central compartment with short/long axis >1 and no hilar line.

the measurement of Tg obtained from lymph nodes, as it does with serum Tg (13). Either a positive cytology report, or finding Tg present in the needle washout, confirms the lymph node is malignant. Using either positive cytology or the presence of Tg as proof of recurrent cancer, Lee et al. reported 100%


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FIG. 8.30. Another lymph node (calipers) less than 0.5cm that was biopsied because of its shape and location. FNA cytology showed papillary carcinoma.

FIG. 8.31. Ultrasound of 50-year-old female 18 years after total thyroidectomy revealed a paratrachael lymph node (calipers) in the central compartment with a short/long axis of 1.

sensitivity and specificity of UG FNA in detecting recurrent thyroid cancer (14). Studies have found the Tg in the needle washout to be more sensitive than cytology in detecting malignancy (15). This is probably due to poor cellular material in lymph nodes having cystic necrosis (see Fig. 18–20).

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FIG. 8.32. Power Doppler of previous lymph node showed peripheral vascular pattern of malignancy. FNA cytology was positive and Tg in the needle washout was >10,000.

Any suspicious lymph nodes should be mapped using the surgical areas defined by the American Joint Commission on Cancer, even if no FNA is done. This will allow one to go back and restudy the node at a later date to see if any changes have occurred. Mapping of malignant lymph nodes is particularly important when FNA is performed, in order that the surgeon can be directed to the site of the recurrence and plan the surgery appropriately. A modified lateral neck dissection, rather than removing a few nodes, is usually necessary to return an elevated serum Tg to a nondetectable level. Routine isotope scanning is no longer an acceptable method of following patients for recurrent thyroid cancer. Extrapolating from the Chernobyl experience, early detection using ultrasound offers our best hope of eradicating residual or recurrent disease. Ultrasound in conjunction with sensitive Tg monitoring provides endocrinologists with the tools to do this. Since 90% of recurrent cancer is initially in the neck, ultrasound of this area is essential. Searching for small hypoechoic lymph nodes or masses in the neck using ultrasound is not difficult, but it does require some effort and patience that is quickly rewarded. Annual ultrasound for at least 5 years after surgery, and ultrasound on all patients with detectable serum Tg or with positive anti-TgAB seems a minimum requirement if we are to make a significant reduction in the mortality rate of thyroid cancer.


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ULTRASOUND OF THE PREOPERATIVE NECK Obviously, if ultrasound is helpful in the management of thyroid cancer patients after surgery, it should be equally beneficial before surgery. Patients who have been selected for thyroidectomy because of FNA of a nodule or other reasons should be brought back prior to surgery and undergo ultrasound of the lateral neck and central compartment in a search for suspicious lymph nodes. Confirming a malignant lymph node(s) in the lateral neck will extend the surgery beyond a simple thyroidectomy to a modified lateral neck dissection. Likewise, finding a malignant lymph node in the central compartment assures the surgeon that a total thyroidectomy and central node dissection is required. At surgery, well differentiated thyroid cancer involves lymph nodes in 20–50% of patients. Using preoperative ultrasound, suspicious lymph nodes are found in 20–30% of patients. This discrepancy is in part due to ultrasound not being as sensitive as surgery in detecting micrometastasis. Ultrasound may also be unable to see enlarged lymph nodes in the central compartment because they are hidden by the thyroid gland or pushed behind the trachea. Nevertheless, ultrasound will detect most lymph node involvement prior to the initial thyroid surgery. One may question the significance of finding preoperative lymph node involvement in these patients. Ito studied 560 patients who underwent ultrasound prior to having a thyroidectomy for thyroid cancer, and he followed the patients for an average of ten years (16). The recurrence rate of thyroid cancer was 3.1% in the ultrasound negative patients, but the recurrence rate in the ultrasound positive patients was 24.8%. This indicates that recurrence-free survival is definitely worse if lymph node involvement is present on ultrasound at the time of the initial surgery. One may still question the need to perform a lateral neck dissection on such patients, unless it can be shown to improve long-term survival. Noguchi reported on a series of patients found to have macroscopic lymph node involvement at the time of surgery, who were followed for an average of 40 years (17). The long-term survival rate of the group that underwent a modified lateral neck dissection (MLND) was 84%, while that of the group not having MLND was only 66%. Therefore it appears that MLND does alter the outcome in patients known to have lateral lymph node metastasis at the time of surgery. Evidence of the value of preoperative ultrasound of the central compartment is less conclusive. It may be less important

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FIG. 8.33. Preoperative ultrasound of a patient seen for a thyroid nodule in the right lobe (N) revealed a large cystic lymph node in the right lateral neck (box). Note the short/long axis >0.5, absent hilum, and abnormal vascularity. Although FNA of the lymph node had negative cytology, Tg in needle washout was positive.

FIG. 8.34. Preoperative ultrasound of patient with a thyroid nodule (N) whose FNA was positive for papillary cancer shows a suspicious lymph node (calipers) adjacent to the lower pole of the thyroid. A central node dissection at the time of surgery revealed that this was metastatic papillary cancer.


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because many endocrine surgeons now routinely perform a central node dissection at the time of the thyroidectomy. Preoperative ultrasound of the central compartment is much less sensitive than it is in the lateral neck, for the reasons mentioned above. Preoperative FNA of central compartment lymph nodes is fraught with the risk of contamination if the needle inadvertently passes through the thyroid, which might cause a false positive cytology and/or Tg in the washout. It is generally recommended that the central compartment be examined at the time of lateral neck ultrasound. Because 70–90% of positive lymph nodes in the central neck are not seen by ultrasound before the thyroid is removed, a “negative” ultrasound examination is of no value. Suspicious lymph nodes should be reported to the surgeon, but FNA is not recommended. SUMMARY The critical importance of ultrasound in thyroid cancer management is recognized in the 2006 Management Guidelines for Patients with Thyroid Cancer published by the American Thyroid Association. Recommendation 21 is that all patients undergoing surgery for thyroid cancer have a preoperative ultrasound of the neck for lymph nodes. Recommendations 46 and 48 are that routine whole body scans be abandoned, and that periodic ultrasound of the neck be used for the followup of thyroid cancer patients. Implementation of these recommendations by endocrinologists may ultimately lead to a reduction in the rate of recurrence of thyroid cancer and to an increase in the long-term survival of patients. References 1. Pineda J, Lee T, Ain K et al (1995) Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab 80:1488–1492 2. Schumberger M, Arcangioli O, Piekarski J et al (1988) Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest x-ray. J Nucl Med 29:1790–1794 3. Torre E, Carballo M, Erdozain R, Lienas L, Iriarte M, Layana J (2004) Prognostic value of thyroglobulin and I-131 whole-body scan after initial treatment of low –risk differentiated thyroid cancer. Thyroid 14:301–306 4. Pacini F, Lari R, Mazzeo S (1985) Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol 23:405–411

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5. Park H, Perkins O, Edmondson J (1994) Influence of diagnostic radioiodines on the uptake of ablative dose of iodine-131. Thyroid 4:49–54 6. Frasoldati A, Presenti M, Gallo M, Coroggio A, Salvo D, Valcavi R (2003) Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma. Cancer 97:90–96 7. Ahuja A, Ying M, Phil M, King A, Yuen HY (2001) Lymph node hilus—gray scale and power Doppler sonography of cervical nodes. J Ultrasound Med 20:987–992 8. Ahuja A, Ying M, Yuen H, Metreweli C (2001) Power Doppler sonography of metastatic nodes from papillary carcinoma of the thyroid. Clinical Radiology 56:284–288 9. Ahuja A, Ying M (2002) An overview of neck node sonography. Investigative Radiology 37:333–342 10. Ballantone R, Lombardi C, Raffaelli M, Traini E, Crea C, Rossi E et al (2004) Management of cystic thyroid nodules: the role of ultrasound-guided fine-needle aspiration biopsy. Thyroid 14:43–47 11. Frasoldati A, Toschi E, Zini M, Flora M, Caroggio A, Dotti C et al (1999) Role of thyroglobulin measurement in fine-needle aspiration biopsies of cervical lymph nodes in patients with differentiated thyroid cancer. Thyroid 9:105–111 12. Pacini F, Fugazzola I, Lippi F, Ceccarelli C, Centoni R, Miccoli P, Elisei R, Pinchera A (1992) Detection of thyroglobulin in the needle aspirates of nonthyroidal neck masses: a clue to the diagnosis of metastatic differentiated thyroid cancer. J Clin Endocrinol Metab 74:1401–1404 13. Baskin HJ (2004) Detection of recurrent papillary thyroid carcinoma by thyroglobulin assessment in the needle washout after fine-needle aspiration of suspicious lymph nodes. Thyroid 14:959–963 14. Lee M, Ross D, Mueller P, Daniels G, Dawson S, Simeone J (1993) Fine-needle biopsy of cervical lymph nodes in patients with thyroid cancer: a prospective comparison of cytopathologic and tissue marker analysis. Radiology 187:851–854 15. Cignarelli M, Ambrosi A, Marino A, Lamacchia O, Campo M, Picca G (2003) Diagnostic utility of thyroglobulin detection in fine-needle aspiration of cervical cystic metastatic lymph nodes from papillary thyroid cancer with negative cytology. Thyroid 13:1163–1167 16. Ito Y,Tomoda C, Uruno T et al (2005) Ultrasonographically and anatomopathologically detectable node metastases in the lateral compartment as indicators of worse relapse-free survival in patients with papillary carcinoma. World J Surg 29:917–920 17. Noguchi S, Murakami N, Yamashita H et al (1998) Prognostic factors in patients with differentiated thyroid carcinoma. Eur J Surg 166:29–33

CHAPTER 9

Parathyroid Ultrasonography Devaprabu Abraham

INTRODUCTION Primary hyperparathyroidism (PHPT) is a common endocrine condition affecting approximately 100,000 new patients each year in the United States (1). An apparent increase in the incidence of PHPT can be traced to the wide availability and use of multi-channel analyzers leading to earlier detection of the disease since 1970 (2). In more than 85 percent of these cases, a solitary adenoma is the cause of the problem. Accurate preoperative localization of the adenoma allows minimally invasive surgery to be performed, leading to shorter hospitalization and recuperative times (3). ANATOMY OF THE PARATHYROID GLANDS Precise understanding of the normal location and the anatomical variations of the parathyroid glands is the cornerstone to successful identification of parathyroid adenomas. Normal parathyroid glands are ovoid, or bean-shaped, and measure approximately 3 by 5 mm in size with the superior glands being smaller than the inferior glands. They have an anatomically distinct vascular supply from that of the thyroid gland. Normal parathyroid glands are enveloped in a pad of a fibro-fatty capsule, and are seldom seen on ultrasound (4). However, this capsule may become compressed when the parathyroid enlarges, and is often seen on ultrasound as a hyperechoic line between the thyroid gland and the parathyroid adenoma. Post-mortem examination reveals that four glands are found in 91% of subjects, three glands are found in 5%, and five glands in 4% (5). More supernumerary glands appear to be a rare occurrence (6). The anatomic location of parathyroid glands varies widely due to the embryonic origin of the glands from the 4th and 3rd pharyngeal pouches with eventual migration to the lower neck. The superior parathyroid glands

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FIG. 9.1. Inferior parathyroid adenoma in transverse view.

develop in the 4th pharyngeal pouch, and migrate caudally to situate along the upper two thirds of the posterior margin of the thyroid lobes. The superior parathyroid glands are more constant in their location in relation to the thyroid gland due to their common developmental origins. The third pharyngeal pouch gives rise to the inferior parathyroid glands and the thymus gland and, together, they migrate to the lower neck. Fortyfour percent of these glands are located within 1 cm of the inferior pole of the thyroid gland, 17% are in close proximity to the inferior margin of the thyroid gland, 26% are found in relation to the superior portion of the thymus along the thyrothymic ligament, and 2% remain within the mediastinum portion of the thymus (7). Unusual variations in the location of the parathyroid glands include the carotid bifurcation, within the carotid sheath, intrathyroidal and retropharyngeal locations. Due to these anatomical variations, accurate preoperative localization becomes crucial for the success of minimally invasive parathyroid surgery. LOCALIZATION STUDIES It is important to remember that the diagnosis of PHPT is made by chemical tests (i.e., elevated serum calcium and parathormone levels, after ruling out hereditary hypocalcuric hypercalcemia and other causes of hypercalcemia). Localizing studies are not useful for diagonising PHPT and should be obtained after the diagnosis of PHPT has been confirmed. The two most

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FIG. 9.2. Inferior parathyroid adenoma seen in longitudinal view.

FIG. 9.3. Superior parathyroid adenoma seen in transverse view. Note thyroid nodule in anterior lobe.

widely used studies for locating abnormal parathyroid gland(s) have been 99 Tc MIBI—which is a functional study—and ultrasonography—an anatomical study. The respective studies have their strengths and weaknesses. To a practicing endocrinologist, the use of ultrasonography to study a patient with a suspected parathyroid adenoma poses several advantages. These include the ease of availability of ultrasound equipment, the lack of ionizing irradiation, the short duration of the procedure, and the

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FIG. 9.4. Superior parathyroid adenoma seen in longitudinal view.

potential cost savings realized by the patient. Unfortunately, not all parathyroid adenomas can be visualized by ultrasound. Very small adenomas and those located in aberrant locations, such as the mediastinum or posterior to the trachea, are not amenable to ultrasound examination. The limitations of parathyroid localization using ultrasonography also include operator variability—however, an experienced sonographer can be expected to identify 85% of parathyroid adenomas. Similar results have been reported using 99 Tc MIBI scans (60–94%), but they are equally operator dependent. While false positive results are sometimes seen with 99 Tc MIBI scans due to thyroid nodules that trap the isotope, UGFNA of parathyroid adenomas seen with ultrasound have 100% specificity. One should also keep in mind that isotope scans lateralize the adenoma while ultrasound studies localize the lesion. TECHNIQUE OF PARATHYROID ULTRASOUND There are many good reasons to perform an ultrasound on a patient having surgery for hyperparathyroidism. Several investigators have shown a 2% incidence of thyroid cancer in patients with a parathyroid adenoma. Not infrequently, a preoperative ultrasound will reveal an unsuspected coexisting thyroid nodule, which, after FNA, may alter the entire surgery. Finally, ultrasound allows localization of the parathyroid adenoma in most patients, thereby facilitating minimally invasive surgery.


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Proper positioning of the patient is critical to the successful visualization of enlarged parathyroid glands. The subject should be made to lie flat on a firm table with one or two pillows placed under the shoulders to enable full extension of the neck. The linear probe (3–5 cm) is placed along with the coupling gel close to the skin and the thyroid gland is located first. The structures of the neck should be carefully studied in two or more axis at multiple levels of the neck. Most clinicians use multifrequency probes (5–15 MHz) for the study of parathyroid glands. Although high frequency increases resolution, the lower frequency probes are more effective at visualizing the deeper reaches of the neck. The most common locations (posterior border of the thyroid lobes, tracheoesophogeal groove, thyroid-thymic ligament) are searched first, looking for a hypoechoic mass with the features of a parathyroid adenoma. The following are the most distinctive sonographic features of parathyroid adenomas. 1. Extrathyroidal Location: The majority of parathyroid adenomas are located adjacent to, but separate from, the posterior aspect of the thyroid. It is common to see an indentation made by the parathyroid adenoma on the posterior capsule of the thyroid gland (Figures 9.4 and 9.10). Look for the echogenic line separating the adenoma from thyroid tissue. This represents the compressed fibro-fatty capsule surrounding the enlarged parathyroid. Parathyroid adenomas are completely embedded within the thyroid gland in about 2–5% of cases (9, 10). The incidence of intraglandular location is higher in patients with multigland disease—in one series, 3% in patients with single-gland disease versus 15% in those with hyperplasia (10). 2. Hypoechoic and Homogeneous Appearance: The most typical imaging characteristic of parathyroid adenomas is the homogeneously hypoechoic echogenicity in relation to the thyroid gland (11). 3. Oval, Elongated, Triangular, or Oblong Shapes: Parathyroid adenomas conform to the pressures of surrounding anatomical structures and therefore variation in the shapes is common. An excellent method of learning to recognize enlarged parathyroid glands is by performing ultrasound on patients with renal failure. These patients frequently have very enlarged parathyroid glands that are easily seen with ultrasound. This exercise will allow the beginner to become acquainted with the endless variety of shapes and locations of parathyroid glands.

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4. Vascular Pedicle and Blood Flow Seen with Doppler: The presence of an extrathyroidal artery (polar artery) feeding an adenoma may be found in 83% of parathyroid adenomas (12). Besides the visualization of the polar artery, other patterns such as the vascular arc pattern and diffuse flow within the adenoma have also been described (13). PARATHYROID INCIDENTALOMA Subclinical parathyroid tumors can be incidentally discovered during neck ultrasonography. The frequency of observing these incidental tumors is 1.5 cm


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FIG. 9.12. Double inferior parathyroid adenoma in panoramic view. The findings were confirmed during surgery.

FIG. 9.13. Cystic PA.

with obvious ultrasound features of a parathyroid adenoma may not need biopsy confirmation. FNA confirmation is most useful when multiple lesions are identified, in which case the lesion with the least identification characteristics of a parathyroid adenoma should be sampled. FNA also allows one to differentiate a parathyroid adenoma from coexistent posterior thyroid nodules (15). (See Fig. 9.X) Other situations that are candidates for FNA include suspected parathyroid masses in patients with: 1) prior failed surgery, 2) negative 99 Tc MIBI scans, 3) atypical location, or 4) coexistent multinodular goiter.

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Elevation of intact PTH in syringe washings provides confirmation with virtually 100% specificity. Parathyroid cytology has a very limited role in the diagnosis of parathyroid adenomas (15). The technique of parathyroid FNA is similar to that of thyroid FNA. One or two passes using 27 G needles is recommended. Due to the location depth of these lesions, longer needles may be necessary to enable a biopsy to be performed. Parathyroid tumors can be mobile and may need a sharp, brief, and abrupt jab to penetrate the capsule. Parathyroid lesions provide bloody aspirates and the fluid should enter the hub of the needle. Absence of bloody aspirate during FNA is typically encountered with non parathyroid lesions. The syringe aspirate can be processed as follows: 1. Make one slide and rinse the remainder of the specimen in 2 ml of normal saline. 2. Centrifuge the specimen, remove and freeze the supernatant before transporting to the laboratory. 3. Do not submit the slide for cytological evaluation until the syringe-washing PTH results become available.

GRAPH. 1. Parathyroid hormone (PTH) levels in syringe washing specimens obtained after fineneedle aspiration of parathyroid adenomas of study subjects and proven thyroid nodules as controls, represented in log scale. Findings in the 2 groups were significantly different (p 50% reduction of thyroid cyst size, varies from 72 to 95% (27). More importantly, the recurrence rate of thyroid cysts is significantly reduced (< 20%) after PEI therapy (27). Therefore, PEI is currently regarded as the first-line and definitive treatment for cystic lesions causing local discomfort and/or cosmetic concern to patients. PEI OF THYROID CYSTS: TECHNICAL ASPECTS Disposable echoic Chiba needles (18–22 gauge) are inserted through a sterile needle pointing device, and connected to a 20 ml syringe held by a Cameco® pistol (The Business Village, London, U.K.) (Fig. 11.5). Sterility of the maneuver is ensured by a sterile cover for the probe, sterile gel, and sterile gloves for operators. After complete fluid extraction,

FIG. 11.5. The set of materials needed for performing PEI procedure. All the materials should be prepared in advance and be readily available during the maneuver. This way, PEI can be easily performed by two skilled operators (e.g., one physician plus one nurse)

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95% sterile ethanol is immediately injected into the cyst. Ethanol is contained in 10 ml syringes connected to the needle by 20–25 cm. pipes—allowing precise and gentle repositioning of the needle during the maneuver. (Fig. 11.6) The infused ethanol can be seen on US as a hyperechoic material progressively refilling the cyst (Fig.11.7). The operator should carefully monitor the correct positioning of the needle tip during ethanol infusion, avoiding major trauma to the cyst wall. The amount of ethanol injected is usually equal to 50–70 % of the fluid extracted. Before needle extraction, the pipeline and the needle are rinsed with normal saline to minimize ethanol reflux into subcutaneous tissues, thus preventing a potential cause of pain to the patient. In the procedure adopted at our hospital, the injected ethanol

FIG. 11.6. PEI procedure in a 35-year old male patient: view of the operating field. The 20 ml ethanol-containing syringe is connected to the pipe, and ethanol is injected into the lesion (upper panel). At the end of the maneuver, the pipe is clamped, the ethanol-containing 20 ml syringe is disconnected, and a 5 ml saline-containing syringe is connected to the line (lower panel). The saline rinse prevents ethanol leakage through the superficial tissues—a potential cause of intense pain to the patient

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Fig. 11.7. (Continued)

is not evacuated and is left within the lesion. Some authors claim that complete evacuation of infused ethanol avoids the risk of ethanol leakage and any related complications. Available data comparing the two different options, however, apparently do not show any differences in term of successful results (28).

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Fig. 11.7.

(Continued)

SIDE EFFECTS OF PEI Relevant side effects of PEI are rare. The most frequently reported complaint (10–20%) refers to pain at the injection site. Pain, which may irradiate to the ears and jaw, is often quite intense but self-limiting—usually lasting for a few seconds. In a minority of patients, pain may be followed by neck tenderness


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FIG. 11.7. (a) PEI procedure in a large (44 × 32 × 52 mm) empty body thyroid cyst. Phase 1: Fluid extraction followed by disappearance of the cystic lesion (b) Phase 2: Ethanol injection and refilling of the cystic lesion. Ethanol spreading within the cyst walls is immediately visualized as the popping-up of hyperechoic inhomogeneous material. Shortly afterwards, the cyst reassumes its typical anechoic appearance (c) PEI procedure results at a 6-months control ultrasound examination. The lesion volume showed a 90% decrease (from 38.8 to 3.8 ml). A single PEI session was performed. The amount of the extracted fluid was 32 ml, while 16 ml of ethanol were injected. The entire procedure lasted 10 min. No side effects were noted

that generally recedes within some hours. In most cases, pain is due to leakage of ethanol into subcutaneous tissue during needle extraction—therefore, it can be prevented by rinsing the needle tip with a small amount of saline before extracting the needle. Alternatively, local anesthesia can be used to minimize the local discomfort that may occur during and/or immediately after PEI. The most serious complication of PEI is unilateral cord paralysis—usually transient—due to the toxic action of

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absolute ethanol on the recurrent laryngeal nerve. In a series of autonomous hyperfunctioning nodules treated with PEI, unilateral cord palsy has been reported in up to 3.9% of patients (10). Occasionally, other severe complications—such as permanent ipsilateral facial dysesthesia or jugular vein thrombosis—have also been described (10,16). Relevant side effects are far less frequent, if not anecdotic, in PEI therapy of thyroid cystic lesions (13). The presence of a fibrous capsule surrounding the cyst allows direct control on ethanol infusion and acts as a barrier against its uncontrolled spreading. This makes the PEI procedure of cystic nodules safer compared to solid nodules. In addition, PEI of cystic lesions usually requires one to two sessions, while PEI of autonomous functioning nodules is a more complex procedure—demanding many sessions—therefore, the risk of side effects is proportionally increased. PEI OF PARATHYROID CYSTS AND OTHER NECK LESIONS Parathyroid Cysts Parathyroid (PT) cysts (29) are commonly regarded as rare lesions of the neck and superior mediastinum (less than 300 cases reported in the literature). However, their occurrence is probably underestimated, as PT cysts are often mistaken for thyroid cysts (30). PT cysts may have different origins. Only in a minority of cases do they represent functioning lesions—seemingly pseudocystic changes of parathyroid adenomas—whereas, most PT cysts are non-functional derivates from embryological remnants (31). Furthermore, microcystic changes are frequently (40–50%) detected at autopsy in otherwise normal parathyroid glands, and it has been suggested that some PT cysts may arise from a gradual retention of secretions (31). Ultrasound-guided, fine-needle aspiration and parathyroid hormone (PTH) assay in the fluid within the cyst (32,33) are the main tools for diagnosis of PT cysts. The finding of a water-clear fluid in a neck cyst strongly suggests a PT origin and should prompt measurement of PTH in the fluid sample, as intra-cystic PTH levels are usually elevated many times above serum PTH levels (32,33). As with thyroid cysts, PT cysts tend to recur after fine-needle aspiration—therefore, injection of ethanol or other sclerosing agents (e.g., tetracycline) has been proposed as an alternative to surgery (34,35,36,37). In line with reports from the literature, while neck pain and recurrent nerve palsy have been reported after tetracycline injection (37), ethanol injection therapy of PT cysts has proved in our experience to be safe and effective (75.0% mean volume


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reduction; 84.6% cure rate in a series of 13 PT cysts, unpublished data) (Fig.11.8). Larger series are necessary to more accurately define the pros and cons of PEI of PT cysts. Other Neck Lesions In case of thyroglossal duct cysts (Fig. 11.9), PEI effectiveness seems lower in comparison to the results obtained with thyroid and parathyroid cysts (38,39). Besides, a higher risk of infectious

FIG. 11.8. Parathyroid (PT) cyst located at the inferior pole of thyroid right lobe before (upper panel) and after (lower panel) PEI procedure. PT nature of the lesion was suggested by the water-clear appearance of the fluid during diagnostic fine-needle aspiration. As expected, PTH levels in the needle wash-out were exceedingly high (> 1600 pg/ml). The PT cyst was nonfunctional (serum PTH levels = 23 pg/ml; serum calcium levels 9.5 mg/dl). After PEI, the volume of the lesion showed a 90% decrease (from 2.6 ml to 0.25 ml). No side effects were observed

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FIG. 11.9. Thyroglossal duct cyst before (upper panel) and after (lower panel) a single session of PEI procedure (1.5 ml of ethanol injected). The cyst volume decreased from 1.8 to 0.05 ml. No side effects were observed

complications is to be taken into account in treating these lesions by PEI. For these reasons, PEI cannot be considered the first-line treatment for thyroglossal duct cysts, and should rather be viewed as a therapeutic option in patients not amenable to surgery. PEI has been used for treating parathyroid adenomas in high surgical risk patients with primary hyperparathyroidism with partial success (40,41). Furthermore, in patients with chronic renal failure suffering from secondary or tertiary hyperparathyroidism, PEI of hyperplastic PT glands has gained the role of an established and powerful adjunct to medical therapy (42,43). In patients with ultrasound evidence of neck recurrences from papillary thyroid carcinoma, ethanol injection has been


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proposed as a conservative alternative treatment to radio-iodine therapy (often unsuccessful) and to surgical neck exploration (sometimes regarded as overly aggressive). According to two large published series (44,45). PEI treatment is effective in decreasing the volume of most metastatic lymph nodes, with 4.5% of treated lesions disappearing during the follow-up period and no relevant side effect observed. Therefore, in experienced hands, percutaneous ethanol injection seems a valuable option for patients who are not candidates for second surgery and/or radio-iodine therapy.

References 1. Bean WJ (1981) Renal cysts: treatment with alcohol. Radiology 138:329–331 2. Bean WJ, Rodan BA (1985) Hepatic cysts: treatment with alcohol. Am J Radiol 144:237–241 3. Solbiati L, Giangrande A, DePra L, et al (1985) Percutaneous ethanol injection of parathyroid tumors under US guidance: treatment for secondary hyperparathyroidism. Radiology 155:607–610 4. Livraghi T, Giorgio A, Mario G, et al (1985) Hepatocellular carcinoma and cirrhosis in 746 patients: long term results of percutaneous ethanol injection. Radiology 197:101–108 5. Rossi R, Savastano S, Tommasselli AP, et al (1995) Percutaneous computer tomography-guided ethanol injection in aldosteroneproducing adrenal adrenocortical adenoma. Eur J Endocrinol 132:302–305 6. Livraghi T, Paracchi A, Ferrari C, et al (1990) Treatment of autonomous thyroid nodule with percutaneous ethanol injection: preliminary results. Radiology 175:827–829 7. Martino E, Murtas MI, Liviselli A, et al (1992) Percutaneous intranodular ethanol injection for treatment of autonomously functioning thyroid nodules. Surgery 112:1161–1165 8. Papini E, Panunzi C, Pacella CM, et al (1993) Percutaneous ultrasound-guided ethanol injection: a new treatment of toxic autonomously functioning thyroid nodules? J Clin Endocrinol Metab 76:411–416 9. Livraghi T, Paracchi MA, Ferrari C, et al (1994) Treatment of autonomous thyroid nodules with percutaneous ethanol injection – a 4 year experience. Radiology 190:529–533 10. Lippi F, Ferrari C, Manetti L, et al (1996) Treatment of solitary autonomous thyroid nodules by percutaneous ethanol injection. Results of an Italian multicenter study. J Clin Endocrinol Metab 81:3261–3264 11. Monzani F, Caraccio N, Goletti O (1997) Five year follow-up of percutaneous ethanol injection for the treatment of hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol 46:9–15

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12. Lee SJ, Ahn I-M (2005) Effectiveness of percutaneous ethanol injection therapy in benign nodular and cystic thyroid disease: long-term follow-up experience. Endocr J 52:455–462 13. Pacini F (2003) Role of percutaneous ethanol injection in management of nodular lesions of the thyroid gland. J Nucl Med 44:211–212 14. Zingrillo M, Modoni S, Conte M, et al (2003) Percutaneous ethanol injection plus radioiodine versus radioiodine alone in the treatment of large toxic thyroid nodules. J Nucl Med 44:207–210 15. Bennedbaek FN, Nielsen LK, Hegedus L (1998) Effect of percutaneous ethanol injection therapy versus suppressive doses of l-thyroxine on benign solitary solid cold nodules: a randomized trial. J Clin Endocrinol Metab 83: 830–835 16. Bennendbaek FN, Hegedus L (1999) Percutaneous ethanol injection therapy in benign solitary cold thyroid nodules: a randomized trial comparing one injection with three injections. Thyroid 9:225–233 17. Kim JH, Lee HK, Lee JH et al (2003) Efficacy of sonographically guided percutaneous ethanol injection for treatment of thyroid cysts versus solid thyroid nodules. AJR 180: 1623–1726 18. Alexander EK, Heering JP, Benson CB, et al (2002) Assessment of nondiagnostic ultrasound-guided fine needle aspirations of thyroid nodules. J Clin Endocrinol Metab 87:924–927 19. De Los Santos ET, Keyhani-Rofagha S, Cunningham JJ, et al (1990) Cystic thyroid nodules the dilemma of malignant lesions. Arch. Intern. Med 150:422–427 20. Sheppard MC, Franklyn JA (1994) Management of the single thyroid nodule. Clin Endocrinol 41:719–724 21. Clark OH, Okerlund MD, Cavalieri RR, et al (1979) Diagnosis and treatment of thyroid parathyroid and thyroglossal duct cysts. J Clin Endocrinol Metab 48:983–988 22. Jensen F, Rasmussen SN (1976) The treatment of thyroid cysts by ultrasonographically-guided fine needle aspiration. Acta Chir Scand 142:209–211 23. Monzani F, Lippi F, Goletti O, et al (1994) Percutaneous aspiration and ethanol sclerotherapy for thyroid cysts. J Clin Endocrinol Metab 78:800–802 24. Verde G, Papini E, Pacella CM, et al (1994) Ultrasound guided percutaneous ethanol injection in the treatment of cystic thyroid nodules. Clin Endocrinol 41:719–724 25. Zingrillo M, Torlontano M, Chiarella R, et al (1999) Percutaneous ethanol injection may be a definitive treatment for symptomatic thyroid cystic nodules not treatable by surgery: five-year follow-up study. Thyroid 9:763–767 26. Valcavi R, Frasoldati A (2004) Ultrasound-guided percutaneous ethanol injection therapy in thyroid cystic nodules. Endocr Pract 10:269–275 27. Bennedbaek FN, Hegedus L (2003) Treatment of recurrent thyroid cysts with ethanol: a randomized double blind controlled trial. J Clin Endocrinol Metab 88:5773–5777


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28. Kim DW, Rho MH, Kim HJ et al (2005) Percutaneous ethanol injection for benign cystic thyroid nodules: is aspiration of ethanolmixed fluid advantageous? AJNR 26:2122–2127 29. Clark OH (1978) Parathyroid cysts. Am J Surg 35:395–402 30. Ujiki MB, Nayar R, Sturgeon C, et al (2007) Parathyroid cyst: often mistaken for a thyroid cyst. World J Surg 31:60–64 31. Ippolito G, Palazzo F, Sebag F, et al (2006) A single institution 25-year review of true parathyroid cysts. Lagenbecks Arch Surg 391:13–18 32. Silverman JF, Khazanie PG, Norris HT, et al (1986) Parathyroid hormone (PTH) assay of parathyroid cysts examined by fine-needle aspiration biopsy. Am J Clin Pathol 86:776–780 33. Pacini F, Antonelli A, Lari R, et al (1985) Unsuspected parathyroid cysts diagnosed by measurement of thyroglobulin and parathyroid hormone concentration in fluid aspirates. Ann Intern Med 102:793–794 34. Akel M, Salti I, Azar ST (1999) Successful treatment of parathyroid cyst using Ethanol Sclerotherapy. Am J Med Sci 317:50–52 35. Baskin HJ (2004) New applications of thyroid and parathyroid ultrasound. Min Endocrinol 29:195–206 36. Okamura K, Ikenoue H, Sato K, et al (1992) Sclerotherapy for benign parathyroid cysts. Am J Surg 163:344–345 37. Sanchez A, Carretto H (1993) Treatment of a nonfunctioning parathyroid cysts with tetracycline injection. Head Neck 15:263–265 38. Fukumoto K, Kojima T, Tomonari H, et al (1994) Ethanol injection sclerotherapy for Baker’s cysts, thyroglossal duct cysts, and branchial cleft cysts. Ann Plast Surg 33:615–619 39. Baskin HJ (2006) Percutaneous ethanol injection of thyroglossal duct cysts. Endocr Pract 12:355–357 40. Harman CR, Grant CS, Hay ID, et al (1998) Indications, technique and efficacy of alcohol injection of enlarged parathyroid glands in patients with primary hyperparathyroidism. Surgery 124:1011–1020 41. Cercueil JP, Jacob D, Verges B, et al (1998) Percutaneous ethanol injection into parathyroid adenomas: mid- and long-term results. Eur Radiol 8:1565–1569 42. Solbiati L, Giangrande A, Pra LD, et al (1985) Ultrasound-guided percutaneous fine-needle ethanol injection into parathyroid glands in secondary hyperparathyroidism. Radiology 155:607–610 43. Fugakawa M Kitaoga M Tominaka Y, et al (2003) Guidelines for percutaneous ethanol injection therapy of the parathyroid glands in chronic dialysis patients. Nephrol Dial Transplant 18:(Suppl 3):31–33 44. Lewis BD, Hay ID, Charboneau JW, et al (2002) Percutaneous ethanol injection for treatment of cervical lymph node metastases in patients with papillary thyroid carcinoma. AJR 178:699–704. 45. Lim CY, Yum JS, Lee J, et al (2007) Percutaneous ethanol injection therapy for locally recurrent papillary thyroid carcinoma. Thyroid 17:347–350

Chapter 12

Laser and Radiofrequency Ablation Procedures Roberto Valcavi, Angelo Bertani, Marialaura Pesenti, Laura Raifa Al Jandali Rifa’Y, Andrea Frasoldati, Debora Formisano, and Claudio M. Pacella

INTRODUCTION Several ultrasound-guided interventional procedures have been proposed to treat benign thyroid nodules without open surgery. The basic principle is to destroy thyroid nodular tissue by physical means. Percutaneous ethanol injection (PEI) was introduced in 1990 (1) and it has since proven to be very helpful in cystic benign thyroid nodules, whereas it is poorly effective in solid lesions (2,3) and is discussed in Chapter 11. HIFU (High Intensity Focused Ultrasound) is a promising new interventional US-guided technique for solid nodules (4), illustrated in Chapter 13. RADIOFREQUENCY Ultrasound-guided radiofrequency (RF) ablation is a method utilizing high frequency (3.8 to 4 MHz) radio wave energy to coagulate tissues. As RF energy is applied, frictional heating of tissues results, with cell death occurring at temperatures

Endocrinology Division, §Statistics & Clinical Epidemiology Unit, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy *

Department of Radiology and Diagnostics Imaging, Ospedale Regina Apostolorum, Albano Laziale, Rome, Italy Correspondence: Dr. Roberto Valcavi Director, Endocrinology Unit Arcispedale Santa Maria Nuova 42100 Reggio Emilia, Italy [email protected]

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between 60 and 100° C. RF is receiving increased attention as an effective minimally invasive approach for the treatment of patients with a variety of primary and secondary malignant neoplasms; liver tumor ablation has been the subject of most published reports (5). Some authors reported that RF may be effective and safe in treating thyroid nodules (6). However, as RF is based on the use of large needle electrodes (G 14–18), multiple needles, or hook-needles (Fig. 12.1A, B, C), RF may be too invasive for the thyroid gland, a small and delicate organ anatomically adjacent to neck vital structures. Large breaches of thyroid capsule and parenchyma caused by outsized needles may increase the risk of bleeding with sudden neck swelling and potential airway obstruction. This complication has been reported even using Fine Needle (G 22–27) Aspiration (FNA) biopsy (7). We decided not to use this method. PERCUTANEOUS LASER ABLATION (PLA) LASER is an acronym of Light Amplified Stimulated Emission of Radiation. Optical fibers deliver high energy laser radiation to the target lesion. Neodymiun:yttrium aluminum garnet lasers (Nd:YAG), with a wavelength of 1064 nm, are used for PLA because penetration of light is optimal in the nearinfrared spectrum. In recent years, diode lasers with suitable wavelength have also been used. The penetration of laser light is only a few millimeters as a result of scattering and absorption. Scattering results in a relatively uniform distribution of absorbed energy, and heat is produced by conversion of absorbed light (8, 9). Temperatures greater than 60° C result in rapid coagulation necrosis. Irreversible cell death, without preceding coagulation, also occurs at lower temperatures (40–45° C), but requires duration of treatment that inversely correlates with temperature (8, 9). The first report of percutaneous laser ablation (PLA) on human thyroid tissue is by Pacella, et al. (10). In Reggio Emilia, we started to use PLA in patients with benign thyroid cold nodules in 2002. Since then, several studies have been published confirming effectiveness and safety of this new technique (11–19). Fig. 12.2 shows macroscopic changes occurring in a thyroid nodule resected one month after laser ablation. Nodule section shows tissue degeneration and necrosis with tissue carbonization (arrows). Vaporization and charring are consequences of tissue overheating. Plane-cut tip fibers achieve temperatures up to 180–200° C where fibers are in direct contact with tissue. Microscopically (Fig. 12.3), laser ablated areas are characterized

LASER AND RADIOFREQUENCY ABLATION PROCEDURES

FIG. 12.1. Needle electrodes used for percutaneous ultrasound-guided radiofrequency (RF) ablation. Multiple needle (A), needle with four retractable lateral hooks (B), needle with multiple lateral hooks resembling an open umbrella (C)

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FIG. 12.2. Macroscopic changes in a thyroid nodule resected one month after laser ablation. Nodule section shows tissue degeneration and necrosis with tissue carbonization (arrows)

FIG. 12.3. Microscopic section of laser ablated tissue. Typical changes include: central cavity due to tissue vaporization (A) surrounded by a thin layer of carbonized tissue (B), coagulative necrotic area (C), and transition zone (D) that separates necrotic from viable tissue


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by a central cavity due to tissue vaporization (A) surrounded by a thin layer of carbonized tissue (B). Coagulative necrosis develops in the outer stratum of tissue (C) surrounded by a rim of metabolic damage (transition zone, D) that separates necrotic from viable tissue. Flat tip technique, proposed and developed by Pacella, et al. (10), is based on the insertion of a 300 µm plane-cut optic fiber through the sheath of a 21 G Chiba needle, exposing the nude fiber in direct contact with thyroid tissue for a length of 7–10 mm, according to the size of the lesion (Fig. 12.4). Fiber lockers allow us to expose the tip of the fiber within the lesion for the appropriate length (Fig 12.5). A single optic fiber, maintained in a still position, destroys only a small amount of tissue (16–18 mm in length, 8–10 mm in width, 8–10 mm in thickness, i.e., about 1 ml volume) when an energy of 1,600–1,800 Joules with an output power of 2–4 Watts is delivered (10). Therefore, simultaneous insertion of multiple fibers is generally

FIG. 12.4. 21 G Chiba needle with 300 µm plane-cut optic fiber inserted through the sheath, exposing the nude fiber for 10 mm

FIG. 12.5. Nude optic 300 µm plane-cut optic fibers. Fiber lockers allow precise fiber exposure into tissue out of needle tip

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needed. Fiber pullback from the bottom to the upper part of the nodule, along the cranio-cadual axis, achieve further tissue destruction. A square configuration with four fibers has been used by Pacella for round shaped liver lesions (Fig. 12.6) (20). Parallel insertion of two to four fibers allows an ellipsoid ablation, suitable for ellipsoid shape of most benign thyroid nodules (Fig. 12.7). Using this latter technique, we obtained

FIG. 12.6. Multiple fiber technique for laser ablation volume increase. A square configuration with four fibers is used for round shaped lesions in large organs like the liver

FIG. 12.7. Multiple fiber ellipsoid configuration, suitable for ellipsoid shape of benign thyroid nodules. Needles are inserted along the craniocaudal nodule axis, at a distance of about 10 mm. Two to four fibers may be simultaneously inserted, achieving up to 40–45 mm wide, and 18–22 mm thick ablation diameters


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up to 40–45 mm wide, 18–22 mm thick ablation diameters. Combining multiple fiber placement, fiber pull-back, and energies up to 6,000 Joules per fiber, nodules up to 50–70 mm in length may be treated with PLA. Number of fibers, number of pull-backs and total energy delivered are tailored to nodule volume. A maximum amount of about 30 ml nodular tissue may be destroyed in a single session (21). PLA INTERVENTION PLA is an office-based intervention. We established careful precautions for patient safety. A sterile operative setting is arranged (Fig. 12.8). The operator stands on the left side of the patient, while US equipment is used by the ultrasonography assistant who sits on the right side. A sensitive color-Doppler/ power color US system is required. Power color images are important during PLA procedure and follow-up (see below). An auxiliary monitor permits direct US vision by the operator while the assistant looks in the US machine monitor. Usually we do imaging by multifrequence linear probes (7.5–13 MHz) with a footprint of 3.5 or 4.5 cm. Convex probes with 6–7.5 MHz frequency are used only for large nodules. A cardiac monitor with defibrillator is connected to the patient showing continuous ECG. A venous catheter is inserted in a peripheral forearm vein before starting the procedure to ensure continuous venous access. Emergency care facilities and materials are on hand in

FIG. 12.8. Sterile PLA operative setting

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the operating room. An anesthesiologist is not present during PLA. However, should an emergency occur, an anesthesiologist is immediately available in our hospital. The patient is placed in the supine position with hyperextended neck with a pillow under her/his shoulders. Eyes are protected by special glasses. The laser machine is placed behind the patient’s head. There is room for the operator to move around the patient’s head between the bed and laser appliance (Fig. 12.9). Delimitation of the nodule by palpation with a marker pen helps to find the point of needle insertion and plan optimal needle trajectory (Fig. 12.10). Light conscious sedation is obtained by IV diazepam (2–3 mg, repeatable during procedure if necessary). Local anesthesia with lidocaine subcapsular and subcutaneous infiltration is performed under US assistance (Fig. 12.11). US visualization of needle used for local anesthesia allows correct tissue lidocaine infiltration. In addition, multiplanar scans of this non-traumatic, thin needle

FIG. 12. 9. Patient placement with hyperxtended neck. The laser machine is in the back of patient’s head. There is room for the operator to move between the bed and laser machine


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(G 29–30) help in planning subsequent 21 G Chiba PLA needle point of insertion and trajectory (Fig. 12.12). Guidance attachment may be used for 21 G Chiba needles insertion (Fig. 12.13). We prefer manual needle placement as it permits to fit needles according to variable anatomy of the nodule (Fig. 12.14). US images show 21 G Chiba needle introduced into the nodule. Longitudinal scans allow clear vision of the tip of the needle (Fig. 12.15 A, arrow). The inserted optic fiber is

FIG. 12.10. Nodule delimitation with a marker pen

FIG. 12.11. US-assisted local anesthesia with lidocaine infiltration

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FIG. 12.12. Linear 12.5 MHz probe, 4.5 cm footprint. Longitudinal (A) and axial (B) US scans of a left lobe colloid thyroid nodule. Needle (29–30 G) US visualization during tissue lidocaine infiltration. Needle is inserted through prethyroid muscles (arrow)

FIG. 12.13. 21 G Chiba needle insertion with guidance attachment

FIG. 12.14. Needle manual placement. Needles are fit along the longitudinal, cranio-caudal, nodule axis

FIG. 12.15. Linear 12.5 MHz probe, 4.5 cm footprint. Longitudinal US scans of a left lobe colloid thyroid nodule. 21 G Chiba needle is placed into the nodule. Tip of the needle (arrow) (A). Optic fiber exposed (B). Arrows mark needle and fiber tips

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then thoroughly seen (Fig. 12.15 B). The distance between needles is checked by US images and external measurements (Fig. 12.16). Accurate needle placement is critical for procedure success. Sedation and local analgesia reduce patient anxiety, swallowing, cough or other untoward movements that could impede precise needle insertion. After needle placement, fibers are inserted through the needle sheath into the nodule (Fig. 12.17) and laser firing is started (Fig. 12.18). US images through continuous axial, longitudinal and multiplanar scans are performed by the assistant throughout laser illumination duration (10–30 minutes), allowing real time visual control of each fiber. A highly echogenic area due to tissue heating and vaporization slowly enlarges over time (Fig. 12.19). The hyperechoic image gradually increases until coalescence between fibers is observed (Fig. 12.20). Figure 12.21 demonstrates an example of a typical 2-fiber session in a 9.5 ml (40 mm long × 17 mm thick × 27 mm wide) benign nodule of the left thyroid lobe. Panel (A) shows fiber placement with a distance of 1 cm between needles and laser firing. Oval shaped, hypoechoic area, close to nodule margins, shows presumed tissue ablation produced by 2-fiber coalescence (panel B). Binocular anechoic spots with hyperechoic halo, corresponding to cavitation and charring produced by two laser fibers, surrounded by hypoechoic tissue, are clearly seen one week (B) and one month (C) after PLA intervention. Peripheral capsular

FIG. 12.16. External measurement of distance between 21G Chiba needles (10 mm)


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FIG. 12.17. Fibers inserted through 21 G Chiba needle sheath. Lockers ensure exact fiber exposition into nodular tissue

vascularization is preserved, while no blood flow is observed inside the nodule. The nonvascular, hypoechoic necrotic tissue will be reabsorbed over several months following PLA with consequent nodule shrinkage. PLA: CLINICAL RESULTS AND INDICATIONS From 2003 to 2005, we studied 119 patients, average age 56 years, who had benign hypofunctioning thyroid nodules with an average pretreatment volume of 24.8 ml (range 1.3–104 ml). In Reggio Emilia, we developed PLA technique originally proposed by Pacella, et al. (12). In order to achieve maximum ablation in a single session, optimize time and costs, avoid multiple sessions, and increase patient satisfaction and compliance (21), we built up energies, used up to four fibers simultaneously in the ellipsoid configuration, and the pull-back procedure. Table 12.1 shows the characteristics of population studied and technical parameters. At variance with other authors using mean energies of 3,000 Joule per session (12) or less (14, 15, 22), we delivered remarkably higher energies with a mean 7,060 Joule per fiber. Output power was 2–4 Watts. US features, size (ml), presumed necrosis (ml), lab tests (TSH, fT3, fT4,

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FIG. 12.18. Axial US scan, linear 12.5 MHz probe. Left lobe solid isoechoic benign nodule (width 25 mm, thickness 19.5 mm) before fiber insertion (A). Two hyperechoic spots correspond to needles (arrows) before (B) and a few seconds (C) after laser illumination start. Initial tissue vaporization enhances echogenic areas around needles (arrows)


FIG. 12.19. PLA fiber illumination. Longitudinal US scans, 12.5 MHz probe. Highly echogenic area due to tissue heating and vaporization (A). Color Doppler images show laser firing (B)

FIG. 12.20. PLA treatment. Axial US scans, 12.5 MHz probe. Hyperechoic areas due to tissue vaporization enlarge and coalesce (A) during laser illumination. At the end of PLA treatment (C) nodule is filled by hyperechoic images due to tissue infiltration by gas

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FIG. 12.21. PLA 2-fiber session. Axial US scans, linear 12.5 MHz probe, 9.5 ml left thyroid lobe benign nodule. Laser firing (A), one week (B), and (C) one month changes after PLA. Binocular images are due to laser fiber cavitation surrounded by charring. Nonvascular hypoechoic area corresponds to necrotic tissue. Initial nodule shrinkage is visible (C)

Thyroglobulin, anti-Thyroglobulin and anti-Thyroperoxidase antibodies), side effects, compressive symptoms and cosmetic scores were recorded before and at days 1, 7, 30, 90, 180, and 365 after PLA. Mean nodule volume slightly increased to 25.2 ml after a week, then gradually decreased to 12.1 ml after one year (Fig. 12.22). Figure 12.23 shows the mean percent change in nodule volume during the observation period, with a final 55.5% decrease after one year. Mean ablation volume was estimated at 10.6 ml, while the actual volume decrease was


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TABLE 12.1. PLA procedure in 119 patients (Reggio Emilia, years 2003–2005) Patients Age Cytology No. of optic fibres Energy delivered Output power Treatment time Pre-treatment volume

119 (M 23 F 96) 55.8 ± 13.3* years Benign hyperplasia 1–4 7,060 ± 4,299* Joule (1,062–22,000 J) 2 – 4 Watts (2.9 ± 0.5 W) 19 ± 8* min 24.8 ± 21.1 ml* (1.3–104 ml) *mean ± SD

FIG. 12.22. Mean nodule volume before and at several time intervals up to one year, following PLA intervention in 119 patients

FIG. 12.23. Mean percent changes in nodule volume (Delta %) following PLA procedure in 119 patients

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greater after one year (12.5 ml), possibly due to necrosis volume underestimation (Fig. 12.24 A). A significant correlation was observed between energy delivered and necrosis volume (Fig. 12.24 B). To study relationships between PLA effects and nodule volume, patients’ population was stratified into quartiles. Overall, 30 patients had small class 1 nodules (volume 1.3–9.6, mean 6.3 ml), 30 medium to small class 2 nodules (9.8–18.0 ml, mean 13.4 ml), 30 medium to large class 3 nodules (18.1–33.7 ml, mean 24.6 ml), and 29 large class 4 nodules (33.8–104.2 ml, mean 55.3 ml). Data demonstrate that nodules up to 18 ml volume (class 1 and class 2) are best candidates for PLA treatment, with a percent decrease in volume one year after PLA of −66% and −61%, respectively. However, size-tailored energy delivery technique developed in Reggio Emilia also obtained good results in larger nodules. One year after PLA, the percent volume change was − 47% for class 3 and − 50% for class 4 nodules (Table 12.2). Figures 12.25 and 12.26 show the cases of medium-small (10.7 ml), and medium-large (24 ml) nodules treated with proportional energies (3,600 and 8,000 Joules, 3 and 4 watts, respectively). In both cases PLA was successful. After one year, volume decreased by −81% and −85%, respectively. Other representative cases are shown in Fig. 12.27 and Fig. 12.28. In the latter patient, PLA has been preceded by PEI. Some authors claim that combined aspiration and PLA may be beneficial in cystic benign nodules (23). However, in nodules that are

FIG. 12.24. Mean nodule volume, necrosis volume, and final (Delta at 12 months) volume in 119 patients treated with PLA (A). Correlation between energy delivered and necrosis volume (B)

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TABLE 12.2. PLA effects on mean nodule volume and necrosis, according to mean nodule size Baseline

Class 1 – small N = 30 Class 2 – small to medium N = 30 Class 3 – medium to large N = 30 Class 4 – large N = 29

12 Months ∆%

Volume ml

Necrosis ml Volume ml

6.3 13.4

3.7 7.2

2.2 5.6

− 66.0 − 61.3

24.6

10.2

13.2

− 46.8

55.3

23.4

27.4

− 49.9

FIG. 12.25. PLA treatment, 3,600 Joules, 3 Watts, two fibers. Axial US scans, linear 12.5 MHz probe. Mixed, isoechoic 9.5 ml right thyroid lobe benign nodule. Nodule structure before PLA (A) and immediately after PLA intervention (B). Volume was 2.0 ml (−81%) after 12 months (C)

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FIG. 12.26. PLA treatment 8,000 Joules, 4 Watts, two fibers. Axial US scans, linear 12.5 MHz probe. Solid isoechoic 24 ml right thyroid lobe benign nodule. Hyperechoic spots due to tissue vaporization develop around optic fibers (arrows) (A). One month after PLA intervention, large hypoechoic, avascular, necrotic area is visible. Nodule volume is 15.7 ml (−34.6% of the initial volume) (B). One year after PLA intervention, nodule volume is 3.5 ml (−85% of the initial volume). Hyperechoic spots with acoustic shadow due to tissue carbonization correspond to initial fiber placement (arrows) (C)


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FIG. 12.27. PLA treatment 6,000 Joules, 3 Watts, two fibers. Axial US scans, linear 12.5 MHz probe. Solid isoechoic 6.7 ml right lobe benign nodule with mixed areas before PLA procedure (A). Longitudinal scan during PLA intervention with inserted needle (B). Two months after PLA: nodule turned hypoechoic, with dark halo and a few hyperechoic spots due to tissue carbonization. Volume is 3.5 ml (−48%) (C)

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FIG. 12.28. PLA treatment 14,400 Joules, 3 Watts, three fibers. Axial US scans with linear 12.5 MHz probe. Solid isoechoic, large (34.6 ml) isthmus and left thyroid lobe benign nodule, previously treated with PEI. Dense hyperechoic areas are due to prior PEI (A). One month after PLA. Volume is 21.9 ml (−7%) (B). One year after PLA: nodule shows hyperechoic spots with acoustic shadow due to remnants of tissue carbonization and gross calcification. Volume is 7.6 ml (−78%) (C)


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more than 20% liquid, we perform PEI treatment prior to PLA intervention. This induces fluid reabsorption with nodule shrinkage, improving the efficacy of subsequent PLA procedure. SIDE EFFECTS There were no side effects in 76 patients (63.9%). Thirty-six complained of cervical pain (30.3%), slight in 33 cases (27.7%), and intense in three cases (2.5%), requiring anti-inflammatory drug medication. Four patients (3.3%) had fever (38–38.5° C) for two to three days, one patient (0.8%) had subcapsular hematoma with spontaneous reabsorption in two weeks, and one patient (0.8 %) had skin burn. No patient had vocal palsy or other severe side effects. More recently, we introduced routine medication as follows. Immediately after PLA procedure patients receive 20 mg IV methylprednisolone and IV 100 mg ketoprofene infusion. The day after PLA they start on prednisone 25 mg for three days, 12.5 mg for three days, and 5 mg for four days. Pump inhibitors are simultaneously administered (lansoprazole 30 mg p.o.) for 10 days. This medication protocol greatly enhances tolerance, reducing pain, tenderness, and occasional fever. Mean TSH and FT4 values slightly varied immediately after PLA (peak at day 1: TSH 1.23 ± 0.88 µU/ml vs. 0.79 ± 0.79 µU/ml, p < 0.001; fT4 11.52 ± 1.91 pg/ml vs. 12.81 ± 3.52 pg/ml, p < 0.05) and returned to baseline within three months. FT3 did not change after PLA. A large thyroglobulin (Tg) peak occurred at day 1 (4657 ± 7595 ng/ml vs. baseline 75.4 ± 83.4 ng/ml, p < 0.001), and gradually returned to baseline within three months. AntiTg and anti-TPO antibodies were slightly, but not significantly, increased following PLA. Six patients (5%) with baseline negative Anti Tg antibodies became positive at 12 months (normal levels < 100 U/ml). Laboratory changes were not symptomatic. Fig. 12.29 shows clinical results of benign thyroid nodule PLA intervention after one year (21). Compressive symptoms disappeared in 57.5% of patients, improved in 17%, and were unchanged in 25.5%. Cosmetic concerns disappeared in 43%, improved in 43% and did not change in 23%. PLA IN AUTONOMOUS THYROID NODULES Autonomously functioning thyroid nodules (AFNT) have also been treated with PLA (22, 24–26). Scinti scan of a representative case is shown in Fig. 12.30. The nodule was small (2.5 ml). Almost total ablation was obtained in this case.

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FIG. 12.29. Effects of PLA treatment on compressive and cosmetic symptoms after one year. Results are expressed as percent changes (disappearance, improvement or no change) in 119 patients

FIG. 12.30. Scinti scan of a small autonomous adenoma of the left thyroid lobe before and six months after PLA treatment. The hot spot disappeared and normal thyroid uptake was restored


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TABLE 12.3. Advantages 1. New therapeutic option in benign thyroid nodule management 2. Effective: thyroid nodule shrinkage > 50% in a single PLA session 3. Office-based procedure 4. High patient satisfaction 5. Safe: no major side effects Limitations 1. Restricted to specialized centers 2. Operator-dependent 3. Long-term effects unknown 4. More studies needed

However, in larger nodules, ablation may be insufficient without complete disappearance of AFNT. Moreover, recurrence is frequent. Combined reduced radioiodine doses and PLA has been proposed (27). However, this modality does not attain the basic objective of PLA, which is patient cure without other therapies such as radioactive iodine. Further studies are needed in AFNT. CONCLUSIONS PLA is a new, office-based, safe, highly effective technique in benign thyroid nodule treatment. Nodule shrinkage > 50% may be obtained with a single PLA session in variably sized nodules. Small to medium size nodules (< 18 ml, i.e., maximum 40–50 mm in length, maximum 25–35 mm in width, and maximum 15–20 mm in thickness) are best candidates for PLA procedure. Large nodules (18–50 ml) may also be treated. Multiple PLA sessions may be required in outsized nodules. Conscious sedation with IV benzodiazepines and local analgesia with lidocaine permit compliant, well tolerated, PLA intervention. Post-ablation corticosteroid administration minimizes pain and other side effects. Patient satisfaction is greatly enhanced by this method. PLA may be an alternative choice to surgery in the clinical management of benign thyroid nodules. At present, PLA technique is restricted to specialized centers, should to be performed in safe conditions (i.e., hospital setting), and is operator-dependent. Long-term effects are unknown (Table 12.3). Technological improvements, technique standardization, medium-to long-term multicentric, controlled, clinical trials are needed.

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Acknowledgment. Authors thank Sara Lenzi for her invaluable assistance in editing the manuscript and figures. References 1. Livraghi T, Paracchi A, Ferrari C, Bergonzi M, Garavaglia G, Raineri P, Vettori C (1990) Treatment of autonomous thyroid nodules with percutaneous ethanol injection: preliminary results.Work in progress. Radiology 175:827–9 2. Valcavi R, Frasoldati A (2004)Ultrasound-guided percutaneous ethanol injection therapy in thyroid cystic nodules. Endocr Pract 10:269–75 3. American Association of Clinical Endocrinoligists and Associazione Medici Endocrinologi (2006) Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 12:63–102 4. Esnault O, Franc B, Monteil JP, Chapelon JY (2004) High-intensity focused ultrasound for localized thyroid-tissue ablation: preliminary experimental animal study. Thyroid 14:1072–6 5. Gazelle GS, Goldberg SN, Solbiati L, Livraghi T (2000) Tumor ablation with radio-frequency energy. Radiology 217:633–46 6. Kim YS, Rhim H, Tae K, Park DW, Kim ST (2006) Radiofrequency ablation of benign cold thyroid nodules: initial clinical experience. Thyroid 16:361–7 7. Roh JL (2006) Intrathyroid hemorrhage and acute upper airway obstruction after fine needle aspiration of the thyroid gland. Laryngoscope 116:154–6 8. Jacques SL (1992) Laser-tissue interactions: photochemical, photothermal, and photomechanical. Surg Clin North Am 72:531–558 9. Thomsen S (1991) Pathologic analysis of photothermal and photomechanical effects of laser-tissue interactions. Photochem Photobiol 53:825–835 10. Pacella CM, Bizzarri G, Guglielmi R, Anelli V, Bianchini A, Crescenzi A, Pacella S, Papini E (2000) Thyroid tissue: USguided percutaneous interstitial laser ablation—a feasibility study. Radiology 217:673–7 11. Dossing H, Bennedbaek FN, Karstrup S, Hegedus L (2002) Benign solitary solid cold thyroid nodules: US-guided interstitial laser photocoagulation-initial experience. Radiology 225:53–7 12. Pacella CM, Bizzarri G, Spiezia S, Bianchini A, Guglielmi R, Crescenzi A, Pacella S, Toscano V, Papini E (2004) Thyroid tissue: USguided percutaneous laser thermal ablation. Radiology 232:272–80 13. Papini E, Guglielmi R, Bizzarri G, Pacella CM (2004) Ultrasoundguided laser thermal ablation for treatment of benign thyroid nodules. Endocr Pract 10:276–83 14. Dossing H, Bennedbaek FN, Hegedus L (2005) Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules— a randomised study. Eur J Endocrinol 152:341–5


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15. Amabile G, Rotondi M, Chiara GD, Silvestri A, Filippo BD, Bellastella A, Chiovato L (2006) Low-energy interstitial laser photocoagulation for treatment of nonfunctioning thyroid nodules: therapeutic outcome in relation to pretreatment and treatment parameters. Thyroid 16:749–55 16. Dossing H, Bennedbaek FN, Hegedus L (2006) Effect of ultrasound-gGuided iInterstitial laser photocoagulation on benign solitary solid cold thyroid nodules: one versus three treatments. Thyroid 16:763–768 17. Gambelunghe G, Fatone C, Ranchelli A, Fanelli C, Lucidi P, Cavaliere A, Avenia N, d’Ajello M, Santeusanio F, De Feo P (2006) A randomized controlled trial to evaluate the efficacy of ultrasoundguided laser photocoagulation for treatment of benign thyroid nodules. J Endocrinol Invest 29:RC23–6 18. Cakir B, Topaloglu O, Gul K, Agac T, Aydin C, Dirikoc A, Gumus M, Yazicioglu K, Ersoy RU, Ugras S (2006) Effects of percutaneous laser ablation treatment in benign solitary thyroid nodules on nodule volume, thyroglobulin and anti-thyroglobulin levels, and cytopathology of nodule in 1 yr follow-up. J Endocrinol Invest 29:876–84 19. Papini E, Guglielmi R, Bizzarri G, Graziano F, Bianchini A, Brufani C, Pacella S, Valle D, Pacella CM (2007) Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up. Thyroid 17:229–35 20. Pacella CM, Bizzarri G, Francica G, Bianchini A, De Nuntis S, Pacella S, Crescenzi A, Taccogna S, Forlini G, Rossi Z, Osborn J, Stasi R (2005) Percutaneous laser ablation in the treatment of hepatocellular carcinoma with small tumors: analysis of factors affecting the achievement of tumor necrosis. J Vasc Interv Radiol 16:1447–1457 21. Valcavi R, Pesenti M, Bertani A, Frasoldati A, Formisano D (2006) Percutaneous laser ablation (PLA) in 119 benign thyroid nodules. RSNA Annual Meeting SSC 15–04 22. Barbaro D, Orsini P, Lapi P, Pasquini C, Tuco A, Righini A, Lemmi P (2007) Percutaneous laser ablation in the treatment of toxic and pretoxic nodular goiter. Endocr Pract 13:30–6 23. Dossing H, Bennedbaek FN, Hegedus L (2006) Beneficial effect of combined aspiration and interstitial laser therapy in patients with benign cystic thyroid nodules: a pilot study. Br J Radiol 79:943–7 24. Dossing H, Bennedbaek FN, Hegedus L (2003) Ultrasound-guided interstitial laser photocoagulation of an autonomous thyroid nodule: the introduction of a novel alternative. Thyroid 13:885–8 25. Spiezia S, Vitale G, Di Somma C, Pio Assanti A, Ciccarelli A, Lombardi G, Colao A (2003) Ultrasound-guided laser thermal ablation in the treatment of autonomous hyperfunctioning thyroid nodules and compressive nontoxic nodular goiter. Thyroid 13:941–7

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26. Dossing H, Bennedbaek FN, Bonnema SJ, Grupe P, Hegedus L (2007) Randomized prospective study comparing a single radioiodine dose and a single laser therapy session in autonomously functioning thyroid nodules. Eur J Endocrinol 157:95–100 27. Guglielmi R, Papini E, Pacella CM, Todino V, Bizzarri G (2006) Combined treatment of large toxic nodular goiter by percutaneous laser ablation and radioiodine 131I: a pilot study. American Association of Clinical Endocrinologists 15th Annual Meeting & Clinical Congress Abstract Book: 72

Chapter 13

High Intensity Focused Ultrasound (HIFU) Ablation Therapy for Thyroid Nodules Olivier Esnault and Laurence Leenhardt

INTRODUCTION AND RATIONALE High Intensity Focused Ultrasound (HIFU) is a unique process that delivers a large amount of heat energy to a confined space. HIFU can coagulate tissue at a distance. The effect of HIFU on tissues and tumors was first established in the early to mid1950s (1,2), and more recently partial or complete destruction of tumor (3–8) was shown in the animal; HIFU is already being used to treat localized prostate cancer. This technique has been shown to lower costs, shorten hospitalization stays and represents a valuable alternative for patients for whom surgery is contraindicated. Thyroid nodules are frequently discovered during routine physical examinations or during investigations for other purposes (cervical ultrasonography, carotid duplex exams, cervical scans). Recently, systematic ultrasonographic exploration of a French large adult cohort indicated that 14.5% of the subjects had nodular thyroid structures (9). In the United States, 40% of the female population age 50 or older presented with thyroid nodules at ultrasonography, and the prevalence of thyroid nodules increases throughout life (10). Fortunately, more than 95% of thyroid nodules are the result of benign disease processes and the incidence of thyroid cancer is low. Fine needle aspiration biopsy (FNAB) is considered the most reliable test for the diagnosis of malignant thyroid nodule. In large published series, adequate cytological material is classified as benign, malignant, or suspicious in 69%, 4% and 10% of cases, respectively (11). Benign cytological results correspond to colloid or macrofollicular adenomas, nodular and/or cystic goiters, 219

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or thyroiditis. Patients presenting with such benign nodules are subjected to long follow-up. However, the best therapeutic strategy after the discovery of such nodules is still a matter of debate (12). Some nodules are treated with thyrotropin (TSH)suppressive levothyroxine (LT4) therapy. Unwanted effects of thyroxine treatment on the skeletal and cardiovascular systems (13) lead physicians to take a wait-and-see policy that is often preferred (12, 14). Moreover, the effectiveness of suppressive thyroxine therapy in reducing the volume of benign thyroid nodules is controversial (13, 15). Despite reassuring cytological results, some physicians advise removing them, especially in cases of increases in a nodule’s volume, pressure symptoms or cosmetic complaints. Then the goal of the physician is to delay the time of surgery, or even to switch to another treatment which could represent an alternative to surgery. Ideally a new method must be minimally invasive and be done in an ambulatory setting. HIFU meets these requirements. Compared to other alternative treatments such as percutaneous laser ablation, radiofrequency or ethanol injection, HIFU represents a promising non-invasive procedure that patients would favor. The project’s aim is four-fold: - firstly, to assess the feasibility of using HIFU to obtain localized ablation of thyroid tissue without affecting neighboring structures on sheep’s thyroid, - secondly, to evaluate the safety, feasibility and efficacy of HIFU for the destruction of thyroid nodules in patients who are indicated for thyroid surgery, - thirdly, to confirm safety of HIFU treatment and study ultrasonographic nodule changes after HIFU in non-operated patients (the hypothesis is that HIFU treatment would delay surgery and should, therefore, represent an alternative treatment for patients with benign nodular disease) - lastly, to study other applications of HIFU as treatment of toxic adenomas, primary or secondary hyperparathyroidism, treatment of recurrent thyroid cancer and define indications of HIFU treatment in the management of thyroid diseases. HIFU TECHNOLOGY Principle of HIFU High Intensity Focused Ultrasound (HIFU) is a unique process of delivering a large amount of heat energy to a confined space. The acoustic energy is produced by an ultrasonic transducer and concentrated on the tissue to be treated. The energy heats

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the tissue to therapeutic levels, producing necrosis by a thermal effect, with minimum effect on surrounding structures. Simply stated, power ultrasound can coagulate tissue at a distance. A piezoelectric transducer emits a beam of convergent ultrasonic wave towards a tissue target. When ultrasound waves enter the tissue interface (the skin and the muscles) the beam is wide so the power density is low, ensuring that no damage is done to these superficial structures. However, as the beam converges into the target, the power density becomes so high that the tissue heats to over 85° C and coagulates in a few seconds. During an HIFU treatment, the computer controlled device will cause small adjacent lesions (2 mm diameter by 10 depth) to chosen portions of the thyroid gland, while preserving the surrounding structures. A typical treatment lasts less than half an hour, as the treatment head traverses the treatment zone. The imaging and targeting is carried out by a standard linear array included in the device. APPLICATIONS HIFU is intended to control localized tumors in patients with Stage T1–T2 prostate cancer. The focused energy is delivered from an endorectal probe containing an ultrasound treatment transducer and an imaging transducer. This medical device received CE Mark in 2000 for its prostate application. In Europe, Ablatherm® Treatment System (Technomed Medical Systems, Lyon, France), is used in daily practice for the treatment of prostate cancer (16–20). Prior experience (21) with the early development of the Ablatherm device for the prostate

FIG. 13.1. Principle of HIFU

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FIG. 13.2. Principle of HIFU, dose delivery

served as a guide for the following studies: in patients presenting with a T1–2 N0 M0 prostate carcinoma, HIFU treatment was performed under general anesthesia seven to 12 days prior to radical prostatectomy. Only the lobe in which carcinoma was confirmed was treated. The radical prostatectomy specimen was examined histopathologically, and the changes were compared with the targeted zones. In all cases complete necrosis was seen in the treated region. It was shown that extensive coagulative necrosis can be obtained in the treated areas; however, exact targeting is crucial and a prerequisite for extended clinical application of HIFU. Long-term experience with Ablatherm confirmed the early results (16–20) Other potential applications of HIFU for benign prostate hypertrophy, gynecological tumors, and renal cell carcinoma are currently under investigation. In a logical way, we assessed the feasibility of HIFU for the localized ablation of thyroid tissue and conducted experimental and humans trials for the treatment of thyroid diseases, especially thyroid nodules. ANIMAL TRIALS The sheep model proved to be the best choice because of its cervical anatomy. The sheep’s thyroid gland is easily accessible with ultrasound. It is located in the middle of the animal’s neck, is rather superficial and its size is comparable to humans’. As


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sheep do not develop thyroid nodules the treatments involved plain, healthy thyroid tissue. These trials have been supported by a grant from Fondation de l’Avenir pour la Recherche Médicale Appliquée, INSERM, and industrial support by EDAP-Technomed SA. FIRST TRIALS: PROVE FEASIBILITY The first series of trials was carried out with the same Ablatherm™ device (EDAP, Vaulx en Velin, France) as used for the prostate clinical treatments. The endorectal probe featured a 7.5 MHz sector scan imaging probe and a 3 MHz power transducer. Nonetheless the probe was attached to a gantry for positioning above the neck of the animal (Fig. 13.3). To target the lesions, the author overlaid a computer generated pattern which simulated the lesions over the ultrasonic image of the target. The ultrasound power parameters were the same as for human prostate. In the first animal trial both thyroid lobes of eight animals were treated (22). The trachea was hit four times on three animals, the oesophagus once, and the skin once. In all the remaining cases (nine last lobes) the lesion was confined to the gland and no adjacent tissue was damaged. The goal of the initial trials was to prove feasibility and to justify the development of a device for human use. This first study roughly defined the energy parameters, and the subsequent trials were carried out using several devices progressively adapted to the human thyroid.

FIG. 13.3. Positioning above the neck of the animal

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FIG. 13.4. Macroscopic examination

FIG. 13.5. On the left-hand side, the dark treated tissue demonstrates HIFU precision near the trachea.On the right, a bird’s eye view shows the magnified destroyed thyroid tissue

SECOND TRIAL: ADJUSTMENT OF TREATMENT PARAMETERS HIFU treatment was carried out on 27 additional animals to confirm our preliminary results. In a second series of experi-


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ments, typical lesions were coagulative necrosis around the targeted area. The sacrifice of three animals at 30 days showed that the coagulation necrosis is later replaced by fibrosis. Macroscopic examination of adjacent organs revealed mainly skin lesions and muscle injuries. In a third series, the safety of the method was evaluated by repeated firings at the thyroid lobes’ periphery to explore consequences of the surrounding structures’ injuries. Macroscopic examination revealed a tracheal lesion, superficial oesophagus lesions and recurrent nerve lesions. When the recurrent nerves were damaged bilaterally we observed dysphagia and the ewe died three days after HIFU damage. Finally, the repeatability of the method was evaluated using an HIFU prototype designed specifically for human use. The desired thyroid lesions were obtained in the treated lobes. No damage to the nerves, trachea, oesophagus or muscle was observed. At this stage, the use of the HIFU device on sheep thyroid demonstrated several points: ●

●

●

●

●

● ● ●

It is possible to coagulate thyroid tissue at a distance without side effects In the weeks following the treatment fibrosis replaces the coagulated tissue Subject to minor improvements, the prototype was ready for clinical use The limitations of the animal models should be kept in mind when extrapolating those data to the human situation: In the sheep the dimensions of the gland and the distances to surrounding structures are about two-thirds of those in men The anterior part of the neck is flatter in men than in sheep No nodes can be found in sheep thyroids Many immuno histo chemical markers cannot be used in the animal, and must be tested in the next human trials

HUMAN TRIALS A modified device was built to treat the thyroid gland. Animal studies showed that thyroid tissue could be accurately targeted, with no damage to surrounding structures, and that the observed pathologic lesions were typical of HIFU effect (necrosis, haemorrhage and aspects of mummified tissue). The prototype device (Theraclion, Paris, France) was designed to deliver precise high intensity focused ultrasound (HIFU) to the thyroid, resulting in thermal destruction of thyroid tissue. The focused energy is delivered from an external probe containing both ultrasound

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treatment and imaging transducers. INSERM and industrial partner Theraclion SAS have supported these trials. HUMAN FEASIBILITY STUDY The first human study was performed to evaluate the safety, feasibility and efficacy of HIFU for the destruction of thyroid nodules in patients who are indicated for thyroid surgery. Twenty-five patients scheduled for thyroidectomy were treated by the device. Ultrasound (US) examination was performed before and after HIFU treatment. The HIFU treatment lasted approximately 15 minutes per patient. Thyroidectomy was performed at two weeks followed by histopathological examination. During this study, the HIFU device was optimized and the acoustic energy was gradually increased in order to reach the goal of the complete destruction of the nodules, while minimizing complications. For the sake of caution this was done very progressively. Mild adverse events occurred, such as small skin burns and mild local pain during the HIFU shots. The skin burns resolved quickly and without any medication in all patients but one, who kept a punctiform scar. After adaptation of the treatment head no further skin lesions were observed. Local pain caused by HIFU shots increases with the intensity of the energy, ceasing immediately as the treatment is interrupted. As the energy density was increased, adapted analgesia using oral and local medications was given for pain relief during treatment. Post-HIFU US examination showed changes in echogenicity, a decrease of vascularization at power Doppler examination. Macroscopic and histological lesions were observed, and were precisely located in the targeted nodule without affect to the neighboring structures. Lesions in the treated nodule were thrombosis, diffuse lesion with cavitations, coagulative necrosis, hemorrhage and disappearance of the nuclei (data not shown). The extent of the damage varied among the patients according to the delivered energy. The histological assessment after two weeks is only preliminary evidence of the effect. These studies confirmed the feasibility and safety of the HIFU procedure. No serious adverse event was observed, particularly no affect to the recurrent nerves or to the trachea. Likewise the parathyroid remained untouched.


FIG. 13.6. Operator’s interface

FIG. 13.7. HIFU lesion, macroscopic

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FIG. 13.8. HIFU lesion microscopic

ONGOING HUMAN STUDIES Benign Thyroid Nodules The objectives of this ongoing study are to evaluate the efficacy and safety of the ENT HIFU device for the destruction of thyroid nodules in patients presenting with at least one thyroid nodule with no signs of malignancy and who wish to avoid or to delay surgery. The primary objective is the evaluation of the nodule’s volume change following ENT HIFU treatment, as assessed by ultrasonography (US) performed at six-month follow-up (M6), compared with baseline results, and to describe the nodule volume change between M6 and baseline in the observation group. Toxic Nodules The effectiveness and safety of the ENT HIFU device in treating patients who present with at least one autonomous hyperfunctioning thyroid nodule is studied. The primary objective is to assess the proportion of patients with TSH normalization three months after the first course of treatment with HIFU. HIFU’S ROLE IN THE MANAGEMENT OF THYROID DISEASES In 2006, the American Thyroid Association (ATA) published treatment guidelines for patients with thyroid nodules and thyroid cancer (14). Recommendations pointed out that if the nodule is benign on cytology, further immediate diagnostic


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FIG. 13.9. Ultrasound features before treatment

study or treatment is not routinely required. Nevertheless, it seems that the majority of benign non-functioning nodules grow, particularly those that are solid. Then, thyroid surgery is often indicated in such cases, even for benign nodules. The annual rate of evolution of a solitary functioning nodule into a hyperfunctioning nodule is as high as 6%. The risk is positively related to the size of the nodule and negatively related to the serum thyrotropin level. There is controversy as to whether a nodule should be treated and, if so, how. Figure 13.3 from Hegedus, et al. (23) shows a management algorithm that highlights the place of alternative treatments that contrasts with the ATA algorithm. These differences are probably explained,

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FIG. 13.10. Ultrasound features after treatment

in part, by differences in iodine intake in populations that lead to significant differences in natural history and management of thyroid nodules. The therapeutic strategy for treating benign nodules includes several options. Standard therapeutic approaches comprise surgery, radioiodine treatment and levothyroxine therapy. Surgery is the most effective therapy for symptomatic thyroid nodules and should be regarded as standard treatment (23). Nevertheless, thyroidectomy is an invasive and expensive treatment option for a benign condition, which requires an expert surgeon to avoid major complications. Postoperative hypocalcemia or injury to the laryngeal nerve can occur in 1% and 1%–3%,


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FIG. 13.11. Current prototype

respectively. Disadvantages include hospitalization, general anesthesia, postoperative scar formation and iatrogenic hypothyroidism. Still, the need for an effective alternative exists, especially if surgery is declined or the patient is a poor surgical risk. In these situations a nonsurgical approach may be indicated. Radioiodine is a simple, cost effective, safe procedure in the treatment of autonomously hyperfunctioning thyroid nodules. In a prospective study (24) there was a 45% decrease in the total thyroid volume within three months after radioiodine treatment, and 75% of patients with no previous antithyroid drug treatment normalized for thyroid function within three months. In another recently published prospective study (25) there was a decrease in hot nodules volume assessed by US of 28.8% three months, 46.2% six months and 54% 12 months after radioiodine treatment, and 66.7% of patients were euthyroid at three months, 71.8% at six months, and 76.9% at 12 months. Radioiodine may also be recommended to treat large nontoxic multinodular goiters in patients who decline surgery or who are at high surgical risk. When radioiodine treatment is proposed, physicians must follow regulations and

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FIG. 13.12. Patient positioning

policies on 131I in Europe and the United States. The European Union recently adopted the main international commission on radiological protection (ICRP) recommendations on radiation protection. Such regulations may raise a number of practical problems for 131I treated patients. With the exception of a few countries like Germany and Switzerland, there often is no legislation defining the maximal dose of radioiodine that can be administered on an ambulatory basis. Policies and recommendations have been proposed to reduce the radiation hazards for the public or the family living around the radioiodine-treated patients. Therefore, because of these radioprotection recommendations, and because of contraindication to surgery and to radioiodine in some cases, an alternative treatment for toxic nodular nodules may be suggested. Levothyroxine therapy is still a common approach to the management of thyroid nodules in euthyroid patients with inducing thyroid suppression. However, only a subset of patients has a clinically significant reduction of nodule size (13, 15), and recurrence is seen after cessation of therapy. Moreover, LT4 treatment may cause adverse effects such as atrial fibrillation or reduced bone density. These limita-


(HIFU)

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Thyroid nodule

History, physical examination, and serum thyrotropin test

Low thyrotropin level

Scintigraphy

Normal or high thyrotropin level

Functioning nodule Strong suspicion of cancer

Clinical evaluation

Surgery

Radioiodine; alternatives include no treatment, surgery, ethanol injection, and laser treatment (experimental)

Ultrasonographically guided FNAB

Diagnostic results

Nondiagnostic results

Malignant

Suspicious

Benign

Surgery

Surgery

No treatment with clinical follow-up; alternatives include surgery, levothyroxine therapy, ethanol injection, and laser treatment (experimental)

Repeat ultrasonographically guided FNAB

Nondiagnostic results

Surgery

FIG. 13.13. Algorithm for the Cost-Effective Evaluation and Treatment of a clinically Detectable Solitary Thyroid Nodule

tions of standard therapeutic approaches raised interest for alternative treatments. Recently, several publications reported results of interstitial laser photocoagulation (26–29), percutaneous ethanol injection (30–31) and radiofrequency ablation (RF) (32). In a series published by Papini, et al. comparing clinical and ultrasound changes induced in cold nodules by US-guided percutaneous laser ablation (PLA) versus follow-up or LT4 suppressive therapy, PLA was more effective than LT4. A nodule reduction > 50% was found in 33.3% of cases in the PLA-treated group and was not significantly observed in LT4 group. Age, sex ultrasound pattern, pre-treatment volume, number of PLA treatments and total energy delivered did not show any significant correlation with therapeutic outcome (27). Therapeutic efficacy of RF ablation was reported (32). Nevertheless, thermal injury to

234


the recurrent laryngeal nerve was the most serious complication in this study (3.3%). Ethanol injection was reported to be more effective in cystic nodules. These side effects and invasiveness of such procedures raise questions and lead to proposed HIFU treatment in solid or mixed nodules. CONCLUSION The technical treatment parameters leading to a precise necrosis of the targeted nodule by HIFU were determined in feasibility studies. The ultimate goal of HIFU treatment is to induce a significant reduction in the volume of thyroid nodules, perhaps leaving scarring in longer term. Since other thermal therapies such as laser show that the decreases in nodule volume are fully visible after three months, it can be expected that a similar result will be obtained with HIFU technology. Ongoing studies are underway to confirm the efficacy and safety of HIFU treatment of thyroid nodule, parathyroid adenoma, cervical lymph nodes and thyroid cancer recurrences. References 1. Fry WJ, Barnard JW, Fry FJ, Brennan JF (1955) Ultrasonically produced localized selective lesions in the central nervous system. American Journal of Physical Medicine 34(3):413–23 2. Fry WJ, Mosberg WH, Jr., Barnard JW, Fry FJ (1954) Production of focal destructive lesions in the central nervous system with ultrasound. Journal of Neurosurgery 11(5):471–8 3. Fry FJ, Johnson LK (1978) Tumor irradiation with intense ultrasound. Ultrasound in Medicine & Biology 4(4):337–41 4. Moore WE, Lopez RM, Matthews DE, et al (1989) Evaluation of high-intensity therapeutic ultrasound irradiation in the treatment of experimental hepatoma. Journal of Pediatric Surgery 24(1):30– 3; discussion 3 5. Yang R, Reilly CR, Rescorla FJ, et al (1991) High-intensity focused ultrasound in the treatment of experimental liver cancer. Arch Surg 126(8):1002–9; discussion 9–10 6. Chapelon JY, Margonari J, Theillere Y, et al (1992) Effects of highenergy focused ultrasound on kidney tissue in the rat and the dog. European Urology 22(2):147–52 7. Chapelon JY, Margonari J, Vernier F, Gorry F, Ecochard R, Gelet A (1992) In vivo effects of high-intensity ultrasound on prostatic adenocarcinoma Dunning R3327. Cancer Research 52(22):6353–7 8. Margonari J, Chapelon JY, Gelet A, Cathignol D, Bouvier R, Gorry F (1992) Tumor ablation with focalized ultrasound. In vivo


9.

10. 11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

(HIFU)

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experiment with prostatic adenocarcinoma R3327 Mat-Ly-Lu. Prog Urol 2(2):207–19 Valeix P, Zarebska M, Bensimon M, et al (2001) Ultrasonic assessment of thyroid nodules, and iodine status of French adults participating in the SU.VI.MAX study. Ann Endocrinol (Paris) 62(6):499–506 Mazzaferri EL (1993) Management of a solitary thyroid nodule. The New England Journal of Medicine 328(8):553–9 Gharib H, Goellner JR, Johnson DA (1993) Fine-needle aspiration cytology of the thyroid. A 12-year experience with 11,000 biopsies. Clinics in Laboratory Medicine 13(3):699–709 Bennedbaek FN, Perrild H, Hegedus L (1999) Diagnosis and treatment of the solitary thyroid nodule. Results of a European survey. Clinical Endocrinology 50(3):357–63 Castro MR, Caraballo PJ, Morris JC (2002) Effectiveness of thyroid hormone suppressive therapy in benign solitary thyroid nodules: a meta-analysis. J Clin Endocrinol Metab 87(9):4154–9 Cooper DS, Doherty GM, Haugen BR, et al (2006) Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16(2):109–42 Wemeau JL, Caron P, Schvartz C, et al (2002) Effects of thyroidstimulating hormone suppression with levothyroxine in reducing the volume of solitary thyroid nodules and improving extranodular nonpalpable changes: a randomized, double-blind, placebocontrolled trial by the French Thyroid Research Group. J Clin Endocrinol Metab 87(11):4928–34 Poissonnier L, Chapelon JY, Rouviere O, et al (2007) Control of prostate cancer by transrectal HIFU in 227 patients. European Urology 51(2):381–7 Beerlage HP, Thuroff S, Debruyne FM, Chaussy C, de la Rosette JJ (1999) Transrectal high-intensity focused ultrasound using the Ablatherm device in the treatment of localized prostate carcinoma. Urology 54(2):273–7 Rebillard X, Gelet A, Davin JL, et al (2005) Transrectal highintensity focused ultrasound in the treatment of localized prostate cancer. Journal of Endourology / Endourological Society 19(6):693–701 Blana A, Walter B, Rogenhofer S, Wieland WF (2004) Highintensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 63(2):297–300 Thuroff S, Chaussy C, Vallancien G, et al (2003) High-intensity focused ultrasound and localized prostate cancer: efficacy results from the European multicentric study. Journal of Endourology / Endourological Society 17(8):673–7 Beerlage HP, van Leenders GJ, Oosterhof GO, et al (1999) Highintensity focused ultrasound (HIFU) followed after one to two weeks by radical retropubic prostatectomy: results of a prospective study. Prostate 39(1):41–6

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22. Esnault O, Franc B, Monteil JP, Chapelon JY (2004) High-intensity focused ultrasound for localized thyroid-tissue ablation: preliminary experimental animal study. Thyroid 14(12):1072–6 23. Hegedus L (2004) Clinical practice. The thyroid nodule. The New England Journal of Medicine 351(17):1764–71 24. Nygaard B, Hegedus L, Nielsen KG, Ulriksen P, Hansen JM (1999) Long-term effect of radioactive iodine on thyroid function and size in patients with solitary autonomously functioning toxic thyroid nodules. Clinical Endocrinology 50(2):197–202 25. Erdogan MF, Kucuk NO, Anil C, et al (2004) Effect of radioiodine therapy on thyroid nodule size and function in patients with toxic adenomas. Nuclear Medicine Communications 25(11):1083–7 26. Dossing H, Bennedbaek FN, Hegedus L (2005) Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules - a randomised study. Eur J Endocrinol 152(3):341–5 27. Amabile G, Rotondi M, Chiara GD, et al (2006) Low-energy interstitial laser photocoagulation for treatment of nonfunctioning thyroid nodules: therapeutic outcome in relation to pretreatment and treatment parameters. Thyroid 16(8):749–55 28. Dossing H, Bennedbaek FN, Hegedus L (2006) Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules: one versus three treatments. Thyroid 16(8):763–8 29. Papini E, Guglielmi R, Bizzarri G, et al (2007) Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up. Thyroid 17(3):229–35 30. Zieleznik W, Kawczyk-Krupka A, Barlik MP, Cebula W, Sieron A (2005) Modified percutaneous ethanol injection in the treatment of viscous cystic thyroid nodules. Thyroid 15(7):683–6 31. Lee SJ, Ahn IM (2005) Effectiveness of percutaneous ethanol injection therapy in benign nodular and cystic thyroid diseases: long-term follow-up experience. Endocrine Journal 52(4):455–62 32. Kim YS, Rhim H, Tae K, Park DW, Kim ST (2006) Radiofrequency ablation of benign cold thyroid nodules: initial clinical experience. Thyroid 16(4):361–7

Chapter 14

Ultrasound Elastography of the Thyroid Robert A. Levine

It has long been recognized that palpably hard thyroid nodules are suspicious for cancer (1). Conventional ultrasound provides information regarding characteristics shown to be correlated with risk of cancer, such as shape, echogenicity, edge definition, calcification, and vascular flow. However, it does not provide direct information corresponding to the hardness of a nodule. Elastography is a newly developed technique that utilizes ultrasound to analyze the stiffness of a nodule by measuring the amount of distortion that occurs when the nodule is subjected to external pressure. The technique was first described ten years ago, but has only recently been tested on thyroid nodules. Preliminary results have shown an excellent correlation between the hardness of a nodule determined by elastography and subsequent pathology determined by biopsy or excision. Two techniques have been employed to provide external pressure and strain to a nodule. The most common technique is to apply external pressure using the transducer. After placing a linear transducer over the region of interest, the ultrasonographer manually applies light pressure with the transducer. Multiple sites within and around the nodule are analyzed, and the ultrasound software compares the deformation of the nodule to the surrounding tissue (strain index). The relative stiffness is shown on a color display, superimposed on a B-mode image. An alternative technique uses pulsation from the carotid artery as the compression source. This may be useful, particularly when the nodule is in the lateral aspect of the gland, near the carotid. One preliminary study has indicated that carotid pulsation can be used as the pressure source for elastography (2). On the other hand, artifacts introduced by carotid pulsation have been reported to adversely affect image quality on real-time elastograms (3). 237

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Ultrasound elastography has been used to analyze nodules and predict malignant potential in breast, prostate (4), pancreas, and lymph nodes (5). It has been used to measure liver fibrosis (5), as well as stiffness of cardiac tissue following myocardial infarction. It remains an ancillary technique in these organs with clinical application still predominantly in the research setting. Early experience with breast nodules has shown great promise for elastography in prediction of malignant potential. Early reports showed close to 100% sensitivity and specificity for this technique. However, as discussed below, this may be misleading and due to a bias in sample selection. A large study looking at breast elastography has shown a sensitivity of 86% and a specificity of 90% (7). These values suggest that the technique may be useful in selecting which nodules require biopsy. However, as with all ultrasonographic characteristics, the sensitivity may not be sufficient to eliminate the need for biopsy of a nodule. In 2007, there were only two published studies regarding thyroid elastography. Both reported extremely promising results. Lyshchik et al. (8) performed a prospective study involving 52 thyroid nodules in 31 consecutive patients. Of the 52 nodules, 22 were malignant and 30 were benign. They utilized both real-time elastography, and off-line processed ultrasound elastograms. The strain of the nodule was compared to the strain of the surrounding normal thyroid tissue. The results for the off-line analysis were far superior to the real-time studies. They reported that the off-line processed elastogram was the strongest independent predictor of thyroid gland malignancy, with 96% specificity and 82% sensitivity. However, they also report that off-line strain image processing is time-consuming and labor intensive. Rago et al. (9) recently published a study of real-time ultrasound elastography in 96 consecutive patients with a solitary thyroid nodule undergoing surgery for compressive symptoms or suspicion of malignancy on prior fine-needle aspiration biopsy. Tissue stiffness was scored from 1 to 5 based on subjective analysis of the elastogram image. They reported that scores of 1 or 2 were found in 49 cases—all benign lesions. A score of 3 was found in thirteen cases with one case of carcinoma, and twelve from benign lesions. Thirty cases had scores of 4 or 5, and all were carcinomas. They reported a sensitivity of 97% and a specificity of 100% for a score of 4 or 5 being predictive of malignancy. The general applicability of both of the above studies is limited due to selection bias. In the studies, the incidence of

ULTRASOUND ELASTOGRAPHY OF THE THYROID

239

malignancy was 31 – 43%. Most studies show an incidence of malignancy of 2–5% in nodules selected for biopsy, and the incidence of malignancy is much lower in all unselected nodules (1). The predictive value of the test will vary with the incidence of malignancy in the population studied, and will need to be studied in an unselected population with thyroid nodules. A single study has evaluated the utility of elastography in the assessment of cervical lymph nodes suspected of containing metastatic cancer. Lyshchik et al. (5) examined 141 peripheral lymph nodes in 43 consecutive patients referred for surgical treatment of suspected thyroid or hypopharyngeal cancer. By comparing the strain of lymph nodes and surrounding neck muscles, a strain index was calculated. An index cutoff of 1.5 resulted in a 98% specificity and 85% sensitivity. The results were superior to conventional grey-scale ultrasound criteria utilizing the short to long axis ratio. Figs. 14.1 – 14.5 provide illustration of the images provided by elastography. Fig. 14.1 shows a papillary carcinoma of the thyroid with peripheral psammomatous calcification. As would be expected, this nodule was very firm on physical examination. The figure shows that areas of the nodule are very hard, and very suggestive of a malignant nodule. Note the scale at the right edge of the image indicating a color scale ranging from soft (SF) to hard (HD). Fig. 14.2 shows a nodule with soft consistency on the elastogram. Figs. 14.3 and 14.4 are from the same patient. Bilateral nodules were present. The

FIG. 14.1. This nodule has several suspicious features including peripheral microcalcifications, scalloped margins and hypervascularity on power Doppler (not shown). The elastogram shows significant areas indicated as “Hard” (see scale located on the right of the image. HD = Hard, SF = Soft.) The pathology confirmed a papillary carcinoma

240

R.A. LEVINE

FIG. 14.2. This hypoechoic nodule appears very soft on elastography, suggesting a lower risk of malignancy

FIG. 14.3. This 34 year old woman had bilateral nodules. The figure shows the left nodule, which was the larger of the two, and was previously biopsied with benign cytology. The elastogram shows the nodule to be predominately soft

larger left (dominant) nodule had previously demonstrated benign aspiration cytology. It had a soft texture on elastography. The right-sided nodule had more suspicious sonographic features (echotexture, irregular margins, and microcalcifications), as well as a hard testure at elastography, and proved to be a papillary carcinoma. Fig. 14.5 is from a 38-year old male with diffusely multifocal infiltrative tall cell variant of papillary carcinoma—stage T3N1BM0. Multiple areas of hard tissue are shown on the elastogram.


241

FIG. 14.4. In the same patient as Image 14.3, the right nodule was smaller, but had several suspicious features including a heterogeneous echotexture, irregular margins, and microcalcifications. The elastogram shows the nodule to have a hard composition. Fine needle aspiration cytology demonstrated papillary carcinoma

FIG. 14.5. This image is from a 38 year old male with diffusely multifocal infiltrative tall cell variant of papillary carcinoma, stage T3N1BM0. Multiple areas of hard tissue are shown on the elastogram

Not all nodules are amenable to elastography. Due to an inability of the ultrasound beam to penetrate the nodule, elastography cannot be performed on nodules with peripheral rim calcification. Complex nodules with a large cystic component may provide misleading results because the elasticity is more dependent on the liquid content than the solid portion of the nodule. Rago included four cases in which intranodular cysts

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made up less than 20% of the total nodule volume and did not appear to adversely affect the results. Small nodules probably can be measured accurately with elastography, but the limits of acceptable size have not been tested. The impact of background Hashimoto’s thyroiditis or other abnormalities of the thyroid parenchyma has not been adequately assessed. There are two potential roles for elastography in the analysis of thyroid nodules. The first is indicating the need for biopsy in a nodule that otherwise would be considered low suspicion and not be biopsied. Current guidelines state that nodules smaller than 1.5 cm with no suspicious features (indistinct margins, microcalcifications, taller than wide shape, extreme hypoechogenicity, or strong vascular flow) can be monitored without biopsy. However, if the positive predictive value of elastography is high, an otherwise nonsuspicious nodule demonstrated to be hard by elastography should be biopsied. On the other hand, if the negative predictive value of elastography is adequate, it could be used to help determine which nodules can be safely observed without biopsy. Approximately 4% of the population has a palpable thyroid nodule, and over 50% has a small nodule detectable by ultrasound (1). Clearly, all nodules found by physical examination—or as an incidental finding during other neck studies—cannot undergo fine needle biopsy. Any technique used to determine which nodules can be safely monitored without biopsy needs to have a sensitivity close to 100%. In each of the studies reported to date, the prevalence of malignancy far exceeded that found in an unselected population with thyroid nodules. While the initial reports of elastography of thyroid lesions are very exciting, additional large studies on unselected populations with thyroid nodules will be needed to determine whether the technique has sufficient sensitivity and predictive value to obviate the need for biopsy. References 1. Cooper D, Doherty G, Haugen B, et al (2006) American Thyroid Association Guidelines Task force 2006 Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid Feb 2:2–33 2. Bae U, Dighe M, Dubinsky T, et al (2007) Ultrasound Thyroid Elastography Using Carotid Artery Pulsation: Preliminary Study. J Ultrasound Med June 26(6): 797–805 3. Lyshchik A, Tatsuya H, Ryo A, et al (2004) Ultrasound Elastography in Differential Diagnosis of Thyroid Gland Tumors: Initial Clinical Results. RSNA Abstract


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4. Pallwein L, Mitterberger M, Struve P et al (2007) Real-time Elastography for Detecting Prostate Cancer: Preliminary Experience. BJU Int. July 100(1):42–47 5. Lyshchik A, Higashi T, Asato R, et al (2007) Cervical Lymph Node Metastases: Diagnosis at Sonoelastography-Initial Experience. Radiology April 243(1):258–267 6. Friedrich-Rust M, Ong M, Herrman E, et al (2007) Real-Time Elastography for Noninvasive Assessment of Leiver Fibrosis in Chronic Viral Hepatitis. Am J Roentgenol. March 188(3):758–764 7. Itoh A, Venu E, Tohno E et al (2006) Breast Disease: Clinical applications of US Elastography for Diagnosis. Radiology May 239(2):341–350 8. Lyshchik A, Higashi T, Asato R, et al (2005) Thyroid Gland Tumor Diagnosis at US Elastography. Radiology 237(1):202–211 9. Rago T, Santini F, Scutari M, et al (2007) Elastography: New Developments in Ultrasound for Predicting Malignancy in Thyroid Nodules. J Clin Endocrinol Metab Aug 92:2917–2922

Index A A-mode images, 13–15 A-mode imaging, 2, 3, 6 Acoustic enhancement, 15–18 Acoustic impedance, 9 Acoustic shadowing, 15–17 Air microbubbles, 153–158 American Association of Clinical Endocrinologists (AACE), 6 American Institute of Ultrasound Medicine (AIUM), 6 Anesthesia, 102 Anterioposterior-totransverse diameter (A/T) ratio, 89 Attenuation, 22–23 Autoimmune thyroid disease (AITD), 63; see also Thyroiditis diagnosis, 63 Autonomously functioning thyroid nodules (AFNT); see also Nodules percutaneous ethanol injection, 173–174 percutaneous laser ablation, 213–215 Avascular nodules, 30, 31 Azimuthal plane, 104 B B-mode images, 15 B-mode imaging, 2, 3, 6 “Bag of marbles,” 66

Baskin, H. Jack, 6 Benign masses, 53–57; see also Nodules Biopsy; see also Fine-needle aspiration biopsy Doppler imaging prior to, 38, 40 C Calcification(s), 86 eggshell, 18–19 Cancer cystic papillary, 84 testicular (metastatic), 60 thyroid, 111, 133 postoperative surveillance for, 111–112 risk factors, 78–79 ultrasound of postoperative neck, 112–130 ultrasound of preoperative neck, 131–133 Cancer detection, 3–5, 60 commonest areas of detecting cancer, 113 Doppler ultrasound for, 30–33, 40, 41 follicular carcinoma, 30 indications for use of ultrasound for, 78–79 malignant masses, 57 sensitivities of sonographic features, 78 Cat’s eye artifact, 22, 23; see also “Comet tail” artifacts

245

246

INDEX

Closed suction, “free hand” technique, 106, 108 Color-flow Doppler (CFD), 28–30, 87–88 “Comet tail” artifacts, 20–23 Contrast-enhanced ultrasonography (CEUS), 152, 166, 168–169 in assessment of efficacy of thermal ablation treatments, 165–167 clinical use, 159–160 evaluation of nodules with CEUS timeintensity curves, 160–164 technical background, 153–159 Cysts, 53 D Doppler shift, 27, 28 Doppler ultrasound, 39–40 development, 5 for image clarification, 38–39 physical principles, 27–30 prior to biopsy, 38, 40 of thyroid nodules, 30–35 of thyroiditis, 35–38 Dussic, Karl Theodore, 2 E Echogenic strands, 69 Echogenicity, 82–85; see also Hypoechogenicity when it may be challenging to determine, 84 Edge artifacts, 19, 20 Eggshell calcification, 18–19 Elastography, 5–6, 237–242

nodules not amenable to, 241–242 roles in the analysis of nodules, 242 Enhancement: see Acoustic enhancement Esophageal diverticulum, 55 Ethanol injection: see Percutaneous ethanol injection F Fibrosis, 68 Fine-needle aspiration (FNA) of nodules, 78 palpation used to determine accuracy of, 78 Fine-needle aspiration biopsy (FNAB), 152, 219 ultrasound-guided, 4 Follicular carcinoma, 30 G Goiter, diffuse, 48–49 Graves’ disease, 5, 36, 50, 63, 64, 80, 81 Gray scale display, 3–4 “Ground glass” architectural pattern, 66, 67 H Halo, 86–87 Hashimoto’s lymphocytic thyroiditis, 79, 80 Hashimoto’s thyroiditis, 63–67, 71–73, 79 Hashitoxicosis, 36–38 Hemangioma, 58 Hemiagenesis of thyroid, 49–52 High intensity focused ultrasound (HIFU) ablation therapy, 219, 234 animal trials, 222–223

INDEX

first trials (proving feasibility), 223 second trial (adjustment of treatment parameters), 224–225 applications, 221–222 for benign nodules, 228 HIFU lesions, 227, 228 human trials, 225–226 human feasibility study, 226 ongoing studies, 228 operator’s interface, 227 rationale, 219–220 role in management of thyroid diseases, 228–234 technology/principle of, 220–222 for toxic nodules, 228 Hilar line, 114 Hilum, 116 “Honeycomb” pattern, 84 Hypoechogenicity, 64–65; see also Echogenicity Hypoechoic nodules, 90 I Isoechoic nodules, 88 L Levothyroxine therapy, 232–234 Lymph nodes, 38, 40, 115 characteristics, 115 enlarged/inflamed, 56–57, 125 malignant, 41, 117–123, 126–130, 132 Lymphoma, 73 M Mechanical index (MI), 154 Microbubbles, 153–158

247

Modified lateral neck dissection (MLND), 131 Muscle anomaly, 57 N Neck, normal postoperative, 113–114 “Needle only” technique, 108 Needles used for UGFNA, 101 Nodules, thyroid, 77, 132, 151; see also Autonomously functioning thyroid nodules; specific topics algorithm for cost-effective evaluation and treatment of, 233 avascular, 30, 31 evaluation with CEUS time-intensity curves, 160–164 hypoechoic, 90 isoechoic, 88 measuring volume of, 48 palpable, 77–78 treatment of benign, 230–234 ultrasound characteristics, 78, 81–82 calcifications, 86 change in size, 91–92 echogenicity, 82–85 elastography, 89–90; see also Elastography halo, 86–87 margins, 86 taller than wide, 89 vascularity, 87–88 vascular, 30 P Papillary carcinoma, 41 Parathyroid adenomas, 42, 136–138, 142–145, 214

248

INDEX

Parathyroid adenomas (continued) sonographic features, 139–140 Parathyroid glands, anatomy of, 135–136 Parathyroid hormone (PTH), 144, 146–148, 184 Parathyroid incidentaloma, 140, 142 Parathyroid lesions, ultrasound-guided FNA of, 144–148 Parathyroid (PT) cyst, 142, 145 Parathyroid ultrasound, technique of, 138–140 Percutaneous ethanol injection (PEI), 165–167 of cysts, 179–181 of lesions autonomous functioning nodules, 173–174 cold solid nodules, 173–174 cysts, 174–179 of neck lesions, 185–187 of parathyroid cysts, 184–185 side effects, 182–184 technical aspects, 179–181 Percutaneous laser ablation (PLA), 165–167, 192, 194–197, 215 advantages and limitations, 215 in autonomous nodules, 213–215 clinical results and indications, 203, 206–214 changes in nodule volume, 206–209 ellipsoid ablation, 196–197

history, 192 multiple fiber technique for laser ablation volume increase, 196 needle electrodes used for, 192, 193 PLA intervention, 197–206 side effects, 213 Power Doppler (PD), 28–30, 87–88 Primary hyperparathyroidism (PHPT), 135 localization studies, 136–138 Pseudonodules, 68, 70 Pulsed waves, 11 R Radiation exposure, 79 Radiofrequency (RF) ablation (RFA), 165, 191–192 Radioiodine, 231 Reflection, 13 Refraction, 22 Reverberation artifacts, 19–21 Ringdown artifact, 22; see also “Comet tail” artifacts S Shadowing: see Acoustic shadowing Sound and sound waves, 9–13, 25–26 sound wave propagation, 9–10 speed of sound, 9–11, 13 “Spongiform” pattern, 84, 85, 89 Squamous cell carcinoma, 60 Stepladder artifact, 22; see also “Comet tail” artifacts

INDEX

Strepta, 69 “Swiss cheese” appearance of thyroid, 68 T Testicular cancer, metastatic, 60 Three-dimensional (3D) ultrasound, 5 Thymus gland, undescended, 56 Thyroglossal duct, 53, 55 Thyroid; see also specific topics aberrant, 52–53 lateral, 54 anatomy (normal), 45–48 failed bifurcation of, 52, 53 longitudinal view of, 48 in transverse view, 46 Thyroid anomalies, 49–53 Thyroid disorders; see also specific disorders diffuse, 79–81 Thyroid lobe, measurement of, 47 Thyroid nodule (N): see Nodules Thyroidectomy, 124–127, 230–231 Thyroiditis, 63, 73 atrophic, 73 pathology, 64 postpartum, 36, 37 subacute, 37, 38, 81 ultrasonography, 64–73 Doppler ultrasound, 35–38

249

Thyrotoxicosis, 35–36 Tomogram, 3 U Ultrasound, thyroid; see also specific topics history, 1–7 resolution, 4 Ultrasound elastography: see Elastography Ultrasound-guided FNA (UGFNA), 97–98, 109 aspiration and non-aspiration techniques, 106–109 materials, 100–102 of micronodules, 98–99 parallel approach, 104–105 of parathyroid lesions, 144–148 perpendicular approach, 106, 107 preparation, 99 technique, 103–104 Ultrasound image, creation of an, 13–14 Ultrasound imaging, usefulness of artifacts in, 14–26 Ultrasound technique, 45 W Whole body scan (WBS), 111, 112 Z Zajdela technique, 108

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