World Health Orga nization Classifica tion of Tumours Hamilton SR. Aartonen LA (Eds.) : World Health Organization
Classification of Tumours , Patholog y and Genetics of Tumours
of the Digestive System (3rd edition) . IARC Press: lyon 2000 ISBN 92 832 241 0 8
Eble J .N., Sauter G .• Epstein J E., Sesterreon l.A . (Eds.) World Health Organization Classification of Tumours. Pathology and Genetics of
Tumours althe Urinary System and Male Genital Organs (Jrd ed ition) fARe Press : lyon 2004 ISBN 92 832 2415 9 Barnes L , Eveson J .W , Reichart P" Sidransky 0 (Eds.): World Health
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Organization Classification 01 Tumours. Patho logy and Genetics 01 Tumours of Soft Tissue and Bone (3rd edition). IARC Press : lyon 2002 ISBN 92 832 2413 2
Tavassoli F A .. Devilee P. (Eds .): World Health Organization Classification 01 Tumours . Pathology and Genetics of Tumours of the Breast and Female Genital Organs (3rd edition). IARC Press : lyon 2003 ISBN 92 832 2412 4
Travis wo., Brambilla E., Muller· Hermelink H.K ., Harris C .C. (Eds.): World Health Organization Classification 01 Tumours. Pathology and Genetics of Tumours of lung P1eu"a. Thyrrus and Heart (3I"d edi\lon), IARC Press : lyon 2004 ISBN 92 832 2418 3
Delellis A.A., lloyd A.V, Heitz, P.U., Eng C . (Eds.): World Hea lth Organization Classification of TlJTlOUrs. Pathology and Genetics ot TlJTlOUrs of Endocrine Organs (3rd edition). IARC Press : lyon 2004 ISBN 92 832 2416 7
Fletcher C.D.. Unni KK., Mertens F. (Eds,): World Health
leBoit P.E.. Burg G , Weedon D., Sarasm A . (Ed s.): World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumou rs (3rd edition). IA RC Press : lyon 2006 ISBN 92 832 2414 0
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I WH O
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International Agency for Research on Cancer (IARC)
4th Edition
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Edited by
Steven H. Swe rdlow Elias Campo Nancy Lee Harris Elaine S. Jaffe Stefano A. Pileri Harald Stein JOrgen Thiele James W. Vardiman
Intern ational Agency for Resea rch on Cancer Lyon , 2008
World Health Organization Classification of Tumours Series Editors
Fred T. Bosman, M.D. Elaine S. Jaffe. M.D. Sunil R. Lakhani. M.D. Hiroko Onqaki, Ph.D.
WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues Editors
Sleven H. Swerdlow, M.D. Elias Campo. M.D. Nancy Lee Harris, M.D. Elaine S. Jaffe , M D. Stefano A. Pileri. M.D. Harald Stein, M.D. JOrg en Thiele, M.D. James W. Vardi man, M.D.
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This volume was produced with support from the
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University of Chicago Cancer Research Center
The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues presented in this book reflects the views of a Working Group that convened for an Editorial and Consensus Conference at the International Agency for Research on Cancer (fARC), Lyon October 25-27. 2007. Members of the Working Grou p are indicated in the List of Contributors on pages 369-374.
Published by the International Agenc y for Research 00 Cancer (IARC), 150 cou rs Albert Thomas, 69372 Lyon ceoex 08, France
C International Agency for Research on Cancer, 2008 Distributed by WHO Press, World Health Organization , 20 Avenue Appia, 1211 Geneva 27, Switzerland (Tel: +4 1 22 791 3264; Fax: +4 1 22 791 4857; e-mail: bookordersOwholnt). PubliCations Of the World Health Organization enjoy copyright crotectco in accordance with the proviecos of Protocol 2 of the Universal Copyright Coeventoo. All rights reserved .
The designatiOns employed and the presentation ot the material in this publicatiOn do not imply the expression ot any opiniOn whatsoever on the part of the secretarial 01 the WOOd Health OrganiZatiOn concerning the legal status 01 any country , territory. city . or area or 01 its authonltes , or concerning the delimitatiOn 01 its frontiers or ccooca-ee. The mootion ol scecac companies or 01 certain manufacturers' products does not imply that they are encIorned or fecorrmellded by the World Health Organization in preference to others of a smilar nature that are not mentioned Errors and omissions excepted, the rwnes 01 proprietary products are distmguished by initial capnatjetters. The authors alone are responsible fOf the views expressed in this pubhcatlQfl. The copyright of figures and charts remains with the authors (see source 01 charts and photographs. page 376--379)
Format for bibliographic citations: Swerdlow S.H., Campo E., Harris N,L., Jaffe E.S" Pileri S.A., Stein H" Thiele J , Vardiman J.w. (Eds.): WHO Classification of Tumours of Haematopoietic and Lympho id Tissues, IARC: Lyon 2008
IARC Ubrary Cataloguing in Publication Data WHO Classific ation of Tumou rs of Haematopo ietic and Lymp hoid Tissues Edited by Swerdlow S.H.. Campo E., Harris NL , Jaffe E.S.• Piled SA, Stein H., Thiele J .. Vardiman JW.
1. Haematopoie hc System Neop lasms - genetics
2. Haematopoielic System Neop lasms - pathology I. Swerdlow. Steven H. ISBN 978-92-832-243 1-0
Contents WHO Classifjcatioo Summary table Introduction to the classification of tumours of haematopoietic and lymphoid tissues Introduction and overview of the classification of the myeloid neoplasms
2 Myeloproliferative neoplasms
9
10 14 17
31
Chronic myelogenous leukaemia. BCR-ABL 1 positive 32 Chronic neutrophilic leukaemia PoIycythaemia vera Primary myelofibrOsis Essenliallhrombocythaemia
Chronic eosinophilic leukaemia. NOS Mastocytosis Cutaneous mastocytosis Systemic mastocytosis Masl cell leukaemia
Mast cell sarcoma Extracutaneous mastocytoma Myeloproliferative neoplasm, unc lassi fiable
38 40 44
48 51 54
57 58
61 61 61 64
3 Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA.
PDGFRB Of FGFRl
67
4 MyelodysplasticJmyeloproliferative neoplasms 75 Chronic mveiomonocync leukaemia 76 Atypical ctYonic myeloid leukaEmia. BCR-ABL 1 negative 80 Juvenile myelomonocytic leuk aemia MyelodysplastiC/myeloproliferali ve neoplasm , urclasaifiable
5 Myelodysplastic syndromes Myelodysplastic synd romes/n eo plasms , overview Refractory cytope nia with unilineage dysplasia Refractory anaemia with ring side rob lasts Refractory cytopenia with multilineage dysplasia Refractory anaemia with exc ess b lasts Myelodysp lastic synd rome with isolated de l(5q) Myelodysp lastic synd rome, uncrasslttabte Childhood mye lodysp lastic synd rome Refractory c ytopenia of c hild hood
82 85 87 88 94 96 98 100 102 103 104 104
6 Acute myeloid leukaemia (AML) and related precursor neoplasms AML with recurrent genet ic abn or malities AML with t(8:21 )(q22:q22); RUNX1 -RUNX1T1 AML with inv( 16)( p 13.1q22) or 1(16:t6)(p 13.1;q22): CBFB-MYH 11 Acute orornveiocvnc leukaem ia with t(15:17)(q22 :q 12): PML- RARA AML with us.11)(p 22:q 23): MLLT3-MLL AML with t(6:9)(p23 :q34); DEK-NU P2 14 AML with inv(3)( q2 1q26 .2) or t(3;3)( q2 1;q26.2); RPNt ·EVI1 AML (megakaryoblastic) with t( 1;22)(p13;q 13): RBM15-MKL 1
109 11 0 11 0 11 1 11 2 114 115 116 117
AML with mutated NPM 1 AMLwith mutated CEBPA AML with myelo dysplas ia-related changes Therapy -relate d myeloid neoplasms Acu te myeloid leukaemia, NOS AML with minimal diff erentiation AML withOut matu ration AML with maturabon Acute myelomonocytic leukae mia Acute monoblastic and monocytic leukaem ia Acute erythroid leukaemia Acu te megakaryoblastic leukaemia Acute basophilic leukaemia Acu te paomveosrs with myelofibros is Myeloid sarcoma Myeloid proli ferations related 10 Down synd rome Transient abnOrmal myelopoiesis Myeloid leukaemia associated with Dc:rwn syndrome Blastic plasmacytoid dendritic cell neoplasm
7 Acute leukaemiasof ambiguous lineage Acute undlHerentiated leukaemia Mixed phenotype acute leukaemia wilh t(9;22)(q34;q 11.2): BCR-ABL 1 Mixed phenotype acute leukaemia with t(v:11q 23): MLL rear ranged Mixed phenotype acute leukaemia , B/myeloid, NOS Mixed phenotype ac ute leukaemia , T/myeloid , NOS Mixed phenoty pe acu te leukaemia, NOS· rare types Other ambiguous lineage reukaerraes Natura! killer (NK)-celilympho blastic leukaemi a/lymphoma
120 122 124 127 130 130 131 131 132 133 134 136 137 138 140 142 142 143 145 149 151 15 1 152 152 153 154 t 55 155
8 Introduction and overview 01 the c lassification of the lymphoid neoplasms
9 Precu rsor lymphoid neoplasms B lymp hob lastic leukaemia/lymphoma, NOS B lymphob lastic leukaemia/ lymphoma with recu rrent gene tic abn orma lities B lymphob lastic leukaem iallymphoma with t(9 :22)(q 34;q 11.2): BCR-ABL 1 B lymp hoblastic leukaemia/ly mpho ma with l(v:11q 23): ML L rearranged B lympho blastic leukaemiall ymphom a with t(12:2 1)(p1 3;q22 ): TEL-AMLl (ETV6--RUNX 1) B lymphoblastic leukaemia/lymphoma with hyperdi ploi dy B lymphoblastic leukaemiallymphom a with hypodiplOi dy (Hypodiploi d ALL) B lymphoblastic leukaemiallymphoma with t(5; 14)(q31;q32); IL3-IGH B lymphoblastic leukaemiallymphoma with t( 1;19) (q23:P13.3): E2A-PBX1( TCF3-PBXI) T lymphoblastic leukaemiallymphoma
157 167 168 171
171 171 172 173 174 174 175 176
10 Mature B-ceUneoplasms Chronic lymphocytic leukaemia Ismail Iympt'locytic lymphoma :f s-een prolyrT¢lhocytic leukaemia Splenic B-cell marginal zone lymphoma Hairy cell leukaemia Splenic B-cell Iymphomalleukaemia, unclassiliable Splenic diffuse red pulp small B-ceil lymphoma Hairy cenleckaeme-....anent lymphoplasmacytic lymphoma Heavy chain diseases Gamma heavy chain disease Mu heavy chain disease Alpha heavy chain disease Plasma cell neoplasms Monoc lonal gammop athy 01 undetermined significance (MGUS) Plasma ce ll myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Monoclonal immunoglobulin deposition diseases Extranodat marginal zone lymphoma of mucosaassocia ted lymphoid tissue (MALT lymphoma) Nodal marg inal zone lymphoma Follicular lymphoma Primary cutaneous follicle centre lymphoma Mantle cell lymphoma Diffuse large B-celllymphoma (DLBCl), NOS T celilhi stiocyte-rich large B-ce ll lymphoma Primary DlBCL of the CNS Primary cutaneous DlBCl . leg type EBV positive DLBCl of the elderly DLBCL assoc iated with chronic inflammation Lymphomatoid granulomatosis Primary med iastinal (thymic) large B-celilymphoma Intrav escurer large B-celi lymphoma ALK positive large Been lymphoma Plasmablastic lymphoma large a-ceu lymphoma arising in HHV8-associated multicent ric Castleman disease Primary effusion lymphoma Burkitllymp homa B-cel1lymphoma, unclassiliab le, with features intermediate between DLBCL and Burkitllymphoma B-ceillymphoma, unctessmebie. with features intermediate between OLBCl and clas sica l Hodgkin lymphoma 11 Mature T- and NK-cell neoplasms r-cea prolymphocytic leukaemia t- een large granular lymphocytic leukaemia Chronic Iymphoproliferative disorder of NK cells Aggressive NK cell leukaemia Epstein-Barr virus (EBV) positive t-een Iymphoprol ilerative diseases of ch ildhood Systemic EBV+ t-een Iymphoproliferalive disease of childhood Hydroa vacclnrtorrne-uk e lymphoma Adull T-ceil leukaemia/lymphoma Extranodal NK/T-cell lymphoma. nasal type
,
•
179
180 183 185 188 191 191 192 194 196 196 197 198 200 200 202
Enteropathy -associated t-een lymphoma Hepatosplenlc t -een lymphoma Subcutaneous panniculitis-like t-een lymphoma Mycosis fungoi des Sezary syndrome Primary cutaneous CD30 posi tive t-een Iymphoprolilerative disorders Primary cutaneous per ipheral t-een lymphoma s, rare subtypes Primary cutaneous garnna-della T-cen lymphoma Primary cutaneous COB positive agg ressive ep idermotrop ic cytotoxic T-celt lymphoma Primary cutaneou s CD4 positive small/medium T-cell lymphoma Peripheral t-een lymphoma. NOS Ang ioimmunoblastic t -een lymphoma Anaplastic large cell lymphoma. AlK positive Anapla stic large cell lymphoma . ALK negat ive
289 292 294 296 299
300 302 302
303 304 306 309 312 317
208 208 209
214 218 220 227 229 233 238 240 242 243 245 247 250 252 254 256 258 260 262
265
267 269 270 272 274 276 278 278 280 281 285
12 Hod gkin lymphoma Introduction Nodular lymphocyte predominant Hodgkin Iymptuna Classical Hodgk in lymp homa. introduction Nodular sclerosis classical Hodgkin lymphoma Mixed ce llularity classical Hodgkin lymphoma Lymphoc yte-rich classical Hodgkin lymphoma lymphocyte-depleted classical Hodgkin lymphoma
32 1 322 323 326
330 331 332 334
13 1rnmunode ficiency-assoc iated Iymphoproliferative disorde rs 335 Lymp hoproliferative diseases associated with primary immune disorders 336 Lymphomas associa ted with HIV infection 340 Post-nansotanttsmpnooronterauve disorders (PTlD) 343 Plasmacytic hyperp lasia and infectiousrroooo ocieose-uke PTlD 345 Polymorphic PTlO 346 Monomorph ic PTlO 347 Classical Hodgkin lymphoma type PTLO 349 Other iatrogenic immunodeficiency-assoc iated Iymphoproliferative disorders 350 14 Histiocytic and dendritic cell neoplasms Introd uction Histiocyt ic sarcoma Tumours der ived from langerhans cells Langerhans cell histiocytosis Langerhans ce ll sarcoma Interdigitating dendrit ic cell sarcoma Follicular de ndritic ce ll sarcoma Other rare dendritic cell tumours Disseminated juvenile xanthogranuloma
Contributors Clinical advi sory oorrrnittee Source of Charts and photographs References Subject index NOS, no! otherwise specifi ed
353 354 3S6
358
3S8 360 36 1
363 365
366 369 374 376
300 429
WHO Classification 4th Edition
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WHO Classification of tumours of haematopoietic and lymphoid tissues MYELOPROLIFERATIVE NEOPLASMS
MYELODYSPLASTIC SYNDROMES
Chronic myelogenous leukaemia , BCR-ABL 1 positive
987513
Chronic neutrophilic leukaemia
996 3/3
Polycythaemia vera
995 0/3
Primary myelofibrosis
996 1/3
Essential thrombocythaemia
996213
Chronic eosinophilic leukaemia, NOS
9964 /3
Mastocytosis
Cutaneous mastocytosis
9 74011
Systemic mastocytosis
9 74 1/3
Mast cell leukaemia
974 213
Mast cell sarcoma
974 0/3
Extracutaneous mastocytoma
974 0/1
Myeloproliferative neoplasm , unctassitlable
Refractory anaemia
9980/3
Refractory neutropenia
999 1/3
Refractory thrombocytopenia
9992/3
Refractory anaemia with ring sideroblasts
9962/3
Refractory cytopenia with multitineage dysplasia
9965/3
Refractory anaemia with excess blasts
9983/3
MyelodysplasUc syndrome associated with isolated del(Sq)
Myelodysplasticsyndrome, uncJassifiable
9966/3 9969/3
Childhood myelodyspla suc syndrome Refractory cytopenia of childhood
996513
9975/3
MYELOID AND LYMPHOID NEOPLASMS WITH EOSINOPHILIA AND ABNORMALITIES OF PDGFRA, PDGFRB OR FGFRI
ACUTE MYELOID LEUKAEMIA (AML) AND RELATED PRECURSOR NEOPLASMS AML with recurr ent genetic abnormalities
AML with t(6 ;21)(q22;q2 2); RUNXI-RUNX1Tl
9696/3
AML with inv(16)(pI 3.1q22 ) or t(16;16)(pI3.1;q2 2); CBFB-MYHl1
9671/3
Acute promyelccytlc leukaemia with t(15 ;17)(q22 ;qI2); PML-RARA
9666/3
AML with t(9 ;11)(p22 ;q23); MLLT3-MLL
9697/3
AML with 1(6;9)(p2 3;q34 ); DEK-NUP214
986513
MYELODYSPLASTIC/MYELOPROLIFERAnVE NEOPLASMS
AML with inv( 3)(q2 1q26.2) ort(3; 3)(q21;q 26.2); RPNI -EV/1
9869/3
Chronic myetcmonocytic leukaemia
9945/3
Atypical chronic myeloid leukaemia. BCR-ABL 1 negative
AML (megakaryoblastic) with t(I ;22)(p I 3;q I 3); RBMI5-MKLI
9911/3
967613
AML with mutated NPM1
986 1/3
Juvenile myelomonocytic leukaemia
9946/3
AML wrlh mutated CEBPA
9661/3
Myeloid and lymphoid neoplasms with PD GFRA rearrangement Myeloid neoplasms with PDGFRB rearrangement Myeloid and lymphoid neoplasms with FGFR1 abnormalities
9965/3 9966/3 9967/3
Myelodysplasticlmyeloproliferative neoplasm. unclassifiable 9975/3 Refractory anaemia with ring sideroblasts associated WIth marked thrombocytosis
10
Refractory cytopenia with unilineage dysplasia
WHO ctassrtceton
AML with myelodysplasia-related changes 969513 Therapy-re lated myeloid neoplasm s
99 6213
99 2013
Acute myeloid leukaemla",NOS
9861/3
AML with minimal differentiation
987213
AML without maturation
9873/3
AML with maturation
9874 /3
Acute myelomonocytic leukaemia
9867 /3
Acute monob lastic and monocytic leukaemia 9891 /3 Acute erythroid leukaemia
984013
Acute megakaryoblastic leukaemia
99 10/3
Acute basoph ilic leukaemia
987013
Acute panmyelosis with myelofibrosis
9931 13
Myeloid sarcoma
993013
Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis
989811
Myeloid leukaemia associated with Down syndrome
9898/3
Blastic plasmacytoid dendritic cell neoplasm
9727/3
B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities
B lymphoblastic leukaemiaflymphoma with 1(9;22)(q 34;q l 1.2); BCR-ABU
9812/3
B lymphoblastic leukaemiall ymphoma with t(v;11q23); MLL rearranged
981Y3
B lymphoblastic leukaemiall ymphoma with 1( 12;21)(p13;q22); TEL-AMU (ETV6-RUNX1)
9814/3
B lymphoblastic leukaemiallymphoma w ith hyperdiploidy
981513
B lymphoblastic leukaemiallymphoma with hypod iploidy (hypod iploid ALL)
981613
B lymphoblastic leukaemiallymphoma with t(5;14 Xq31 ;q32 ); IL3-IGH
9817/3
B lymphoblastic leukaemia/lymphoma with t(1;19 )(q23 ;p13 .3); E2A-PBXl
(TCF3-PBX1)
9818/3
T lymphoblastic leukaemia/lymphoma
9837/3
MATURE B-CELL NEOPLASMS
ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGE Acute undifferentiated leukaemia
980 1/3
Mixed phenotype ac ute leukaemia with t(9;22)(q3 4;q 11.2); BCR-ABL1
980613 9807/3
Mixed phenotype ac ute leukaemia, B/myeloid, NO S
9808/3
B-cell prolymphocytic leukaemia
983313
Splenic Bccell marginal zone lymphoma
968913
Hairy cell leukaemia
9940/3
Splenic diffuse red pulp small B-cell lymphoma
9591/3
Hairy eel/leukaemia-variant
959 1/3 9671/3
Lymphoplasmacytic lymphoma
9809/3
Natural killer (NK) cell lymphoblastic !euKaemiallymphoma
waldenstrom macroglobulinemia Heavy chain diseases
PRECURSOR LYMPHOID NEOPLASMS B lymphoblastic leukaemiaflymphoma B lymphoblastic leukaemiall ymphoma, NO S
982313
Splenic B-cell fymphomalleukaemia, unclassifiable 959 1/3
Mixed phenotype ac ute leuka em ia with t{v;11q23); MLL rea rranged
Mixed phenotype ac ute leukaemia, Tfmyeloid, NOS
Chronic lym phocytic leukaemia! small lymphocytic lymphoma
98 11/3
9761/3 9762/3
Alpha heavy chain disease
9762/3
Gamma heavy chain disease
9762/3
Mu heavy cha in disease
9762/3
Plasma cell myeloma
9732/3
Solitary plasmacytoma of bone
9731/3
Extraosseous plasmacytoma
9734/3
WHO classification
11
I
~l..
Systemic EBV positive T-celllymphoproliferative disease of childhood 9724/3
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
9699/3
Hydroa vaccin iforme-like lymp homa
972513
Nodal marginal zone lymphom a
9699/3
Adult T-cell ieukaemia/lymphoma
9827/3
9699/3
Extranodal NKIT cell lym phoma, nasal type
9719 /3
9690/3
Enteropamy-associated T-cell lymphoma
9717/3
9690/3
Hepatosplenic T-cell lymp homa
971613
Primary cutaneous follicle centre lym phoma
959713
Mantle cell lymphoma
967313
Subcutaneous panniculitis-like T-cell lymphoma
970813
Mycosis fungoides
970013
Sezary syndrome
970113
Paediatric nodal marginal zone lymphoma
Follicular lymphoma Paediatric folliculaf lymphoma
Diffuse large B-eelllymphoma (OlBCl), NOS 968013 T-ceillhistiocyte rich large B-eelilymphorna
9688/3
Primary DLBCl of the CNS
968013
Primary cutaneous DlBCl. leg type
9680/3
EBV positive OLBCL of the elderly
9680/3
Ol BCl associated with chro nic inflammation 968013 l ymphomatoid granulomatosis
9766 /1 9679/3
Intravascular large B-cell lymphoma
971213
AlK positive large B-cell lym phoma
9737/3
Plasmablastic lymphoma
973 5/3
l arge Bccell lymp homa arising in HHV8associated multicentric Castleman disease 9738/3 Primary effusio n lymphoma
9678/3
Burkitt lymph oma
968 7/3
B-ceillym phom a, uncl assifiable, with feature s intermediate between diffuse large g-ceu 968 0/3 lymph oma and Burkitt lymph oma B-ceil lymph oma , unclassifiable, with feat ures intermediate betwee n diffuse large 8-cell lymphoma and classica l Hodgkin lymphoma 9596/3
MATURE T-CELL AND NK·CELL NEOPLASMS
j-cen prolymphocytic leukaemia
9834/3
'f-celllarqe granular lym phocytic leukaemi a
983 1/3
Chronic Iymphoproliferative disorder of NK..cells
983113
Aggressive NK cell leukaemia
9948/3
WHO
ciassitcenon
lymphomatoid papulosis
9718/1
Primary cutaneous anaplastic large cell lymphoma
9718/3
Primary cutaneous qamma-delta
r -ceuivmpncma
Primary med iastinal (thym ic) large B-celllym phoma
12
Primary cutaneous CD30 positive F-eel! Iymphoproliferative disorders
9726/3
Primary cutaneous COB positive aggressive epidermotropic cytotoxic T-cefl lymphoma
9709/3
Primary cutaneous CD4 positive smalVmedium T-cell lymphoma
9709/3
Peripheral Tccelllympboma, NOS
970213
Angioimmunoblastic 'l-cetl Iyrnphoma
970513
Anaplastic large cell lymp homa, ALK positive 97 14/3 Anaplastic large cell lymphoma, ALK negative
970213
HODGKIN LYMPHOMA Nodular lymphocyte predomi nant Hodgkin lymp homa
9659/3
Classical Hodgkin lymp homa
9650/3
Nodular sclerosis classical Hodgkin lymphoma
9663/3
l ymphocyte-rich classica l Hodgkin lymphoma
965113
Mixed cellularity classica l Hodgkin lymphoma
965213
l ymphocyte-depleted classical Hodgkin lymphoma
965313
_
HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS
Histiocytic sarcoma
9755 /3
l angerhans cell histiocytosis
975 1/3
langerhans cell sarcoma
9756/3
Interdigitating dendritic cell sarcoma
9757/3
Follicular dendritic cell sarcoma
975813
Fibroblastic reticu lar cell tumour
9759/3
Indeterminate dendritic cell tumour
9757/3
Disseminated juvenile xanthogranuloma
POST·TRANS PLANT LYMPHOPROUFERATIVE DISORDERS (PTLO) Early lesi ons
P1asmacytic hyperplasia
9971/1
Infectious mononucleosis-like PTLD
9971 /1
Polymorphic PTLO
9971/3
Monomorphic PTlO (B- and TINK-cell types)' Classical Hodgkin lym phoma type PTLO'"
NOS, not otherwise speci fied . The italicized numbers are provi siona l cod es for the 4th edition of lCD -D . While they are expected to be incorporated in the next ICD -O editi on , they currentty remain
subjectto changes. The italicized histologi c type s are provisional enti ties , for which the WHO Working Group fe ll the re was insufficient evidence to recognize as distinct diseases at this time. "These lesions are classi fied according to the leukaemia
or
lymphoma to which they correspond, and are assigned the respective tCO-G code.
WHO classification
13
.. .
Introduction to the WHO classification of tumours of-haernatopoletlc and lymphoid tissues
NL Harris E. Campo E.S. Jaffe SA Pileri
Why classify? Classification is the lan-
The WHO cl assification of tumours of the
classification , involvement of clinicians is essential to ensure its usefulness and acceptance in daily practice 18971. At the lime of publication of the WHO classi fication (3rd edition), prop onents of other cla ssifications of haematologic neoplasms agreed to use the new cl assification, thus ending decad es of cont roversy over the classification of these tumo urs 147. 478 . t 89. 1B9A, 190, 673,7750 , 1344A. 18198 1,
haematopoietic an d lymphoid system is based on the principles initially d efined in the "Revised Europe an-Amer ican Classifica tion of Lymp hoid Neoplasms" (REAL). from the Interna tiona l Lymphoma Stud y Group (ILSG) 18981. In the WHO classification, these p rinciples have also been appl ied to the class ification of myeloid and his tiocy tic neoplasms, The gu id ing prin cip le of the REAL and WHO cl assific ations is the attempt to define "real" d iseases that c an be recognized by pa tholo gi sts with availabl e techniques. and that appear be distinct clinical entities . There are 3 important com ponents to this p rocess First. recognizing tha t the underlying c auses of these neo plasms are often unknown and may vary, this approa ch to cl assifica tion uses all available information - morpholog y, immunop henotype, genetic features, and cl inical features- to define diseases. The relative impo rtance of eac h of these features varies among diseases, d epend ing upon the state of current knowledge, and there is therefore no one "g old standard ," by which all di seases are defined . Second. rec ognizing that the com plexity 01 the field makes it impossib le for a single expert Of small g roup to be comptet ely authoritative, and that broad agreement is necessary if a classificati on is to be ac cep ted, this cta ssrncanon relies on bu ild ing a consensus among as many experts as possible on the def inition and nomenclatu re of the diseases, We recognize that com promise is essential in orde r to arrive at a consensus, but bel ieve that the only thing worse than an imperfect classification is multiple competing classifi cati ons . Finally. wh ile patholog ists must take pr imary respon sib ility for developing a
As indicated above , there is no one -gold stand ard ," by which all diseases are def ined in the WHO cl assific ation. Morpholog y is alway s important, and many diseases have ch aracteristic or even diagnosti c morphologic featu res, Immunephe notype and genetic features are an important part of the definition of tumours of the naematopolettc and lymphoid tissues , and the av ailability of this information makes arriving at conse nsus definitions easier now than it was when only subjec tive morphologic criteria were available . lrrmunophenotyping studies are used in routine diagnosis in the vast majority of haematolog ic mali gn ancies, both to d etermine lineage in malig nant processes and to dis tinguish be nig n lrom ma lignant processes . Many disea ses have a chara ct eristic immunophenotype. such that one would hesitate to make the diagnosis in the abse nce of the immunep henot yp e, while in others the immunoonenotvpe is only part of the diagnosis, In some lymphoi d and in many myeloid ne0p lasms a speci fic genetic abnorma lity is the key defining criterion, while etters lack specific known genet ic ebnomantes. Some g enetic abnormalities, while characteri stic of one dis ea se, are not specific (such as MYC. CCND 1or BCl2 rearrangements or mutations in JAK2). and others are prognostic factors in several diseases (such as TP53 mutations or FLT3-ITO) , The inc lusion of jr munoohenotvoc leatures and genetic abnormalities to define entities not only provides ob jective criteria for disease recogni tion but has identified antigens, genes or pathways that can be targeted for therapy; the success of rituxima b , an anti-CD20 molecule, in the
guage of medic ine: diseases must be described , defin ed and named before the y
can be diagnosed , treated and stud ied . A consensus on definition s and termin olog y is essent ial for both clinic al practice and investigation . A cl assification should contain diseases thai are clearly defin ed . c linically d istinc tive . norKlVerlappi ng (mutually excllsive) and that together comprise all known entities (collectively e xha ustive).
II should serve as a ba sis lor future investigation . and should be able to incorporate new information as it becomes ava ilab le. Classification has two aspects: clas s discovery - the proces s of identifying categories of diseases, and class pre diction - the process of determining which cere-
gory an individual case belongs to. Pamerogi sts are critical to both processes . The World Hea lth Org anizati on (WHO) Classi fication of Tumours of the Haematopoietic and Lymp hOid Tissues (4th Edition ) was a coll aborative project of the European Association for Haematopathology and the Society lor Hematopatholog y. It is a revision and update of the 3rd Edition 11039 }. which was the first true worldwide consensus c lassific ation of baematoiocic malignancies. The update, which began in 2006, had an a-me mbe r steering committee composed of membe rs of both societies, The Steering Comminee, in a series of meetings and discussions, agreed on a proposed list of diseases and chapters and selec ted authors. with input from both soc ieties. As with the WHO 3fd ed ition 189 71. the advice of clin ical haematologists and oncologists was obtained . in order to ensure that the classifica tion will be clinica lly useful. Two Clinic al Adv isory Committee s (CAG). one for myeloid neoplasm s and other acut e leukaemias and one for lym phoid neoplasms. were convened, The mee tings were org anized aroun d a ser ies of questions, inc luding disease definitions, nomenclature, grading. and clinical relevance. The committ ees were able to reach consensus on mos t of the questions po sed . and muc h of the inp ut of the 14
Introduction to the classification
committees was incorporated into the class ification. Over 130 pa thologists and haem ato logis ts from around the world were involved in writing the chap ters. A consensus meeting was held at the head quarters of the IARC in Lyon, France. to make final d eci sions on the classi ficatio n and the con tent of the book.
H. Stein S.H. Swerdlow J Thiele J w. Vardiman
treatment of. B-cel! neoplasms, and 01 imatinib in the treatment of leukaemias associated with ABL 1 and oth re!lrrangements inv olving tryoene kinase genes are testament to this approach. Finally. some diseases require know ledge of clinical features - age, nodal versus extranodal presentanon. specific anatomic site . and history 01 cytotoxic and other therapies - to make the diagnosis. Most 01 the diseases described in the WHO classification are considered to be distinct enti ties ; howev er. some are not as clearly defined, and these are listed as prov isional entities, In addition . borderline categories ha....e been created in this edition for cases that do not c learly fit into one category, so that well-de fined categories ca n be kept homogeneous, and the borderline cases can be stud ied further. The WHO classification stratifiesneoplasms primarily ac cording to lineag e: myeloid, lymphoid, and histiocyticfdendritic c ell. A normal c ounterpart is postulaled lor each neoplasm. While the goal is to define the lineag e of each neoplasm, lineage pla sticity may occur in precursor or imma ture neoplasms, and has recently been identified in some mature haematotymphoid neoplasms , In addition, genetic atooerreuues suc h as FGFR1, PDGFA and PDGFB rearrangements may give rise to neoplasms 01 either myel oid or lymphoid lineage associated with eosinophilia ; these disorders are now recognized as a separate group. Precursor neoplasms (acute myeloid reukaemes. lymphoblastic Iymphomasfleukaemias, acute reukaerraas 01 amb iguo us lineag e, and blast ic p lasmacytoid de nd ritic ce ll neop lasm ) are considered separately from mo re mature neoplasms [myeloproliferative neoplasms (MPN). myelodysplastic/myeloproliterative neoplasms, myelodysplastic syndromes , mature (peripheral) B-cell and T/NK -cell neoplasms, Hodgkin lymphoma. and hisIiocyteldeodritic-c ell neoplasms] . The mature myeloid neoplasms are stratified according to the ir bi ologica l features (myeIopl'oIiferative, with effective baereiopoiesis. ....ersus myelodysplastic , with ineffective neematcootesfs . as welt a s by genetiC feature s). Within the mature lymphoid neop lasms , the diseases are listed broadly ac cord ing to clinical presentation (disseminated often leukaemi c, extran coat. indolent. aggressiv e). and to some extent according to stage of differentiation when this can be postulated: howe....er the
ord er of listing is in part arb itrary, and is not an integral part of the cl assification. The 4th ed ition of the WHO classification inc orpo rates new information that has emerged from basic and clinic al in....estrgat ions in the interva l since pu b lication of the 3rd edition . It inc ludes new defining criter ia for some disease s, as well as a number of new entities. some def ined by genetic criteria - particul arly among the myeloid neoplasm s- and others by a combination of morpholog y. immunoph eootype . and clinic al features. The frequent application of immunophenotyping and genetic stud ies to peripheral blood, bone ma rrow, and lym ph node samp les has also led to the de tection of small clonal populations in asy mptomatic pe rsons . These include small clones of cells with the BCR-ABL 1 translocation seen in chronic myelogenous leukaemia. small cl ones of ce lls with BCL2-IGH rearrangement. and small populat ions of c ells that have the imm uoopheootype of chronic lymp hocytic leukaemia (e l l ) or folli cu lar lymphoma (mo noc lonal B lymphocytosis, follicular lymphoma-in Situ , paediatric follicul ar hyperplas ia WIth monoclonal B c ells). In man y case s. it is not clear whether these represent earty involvement by a neoplasm, a precursor iesoo. or an inconsequential find ing. These situations have some ana logies to the identification of small monoclonal immunoglobulin components in serum (monoclonal gammopathy of unknown significance), The ch apters on these neoplasms include recommendations for dea ling with these situations. The rec omm end ations of international con sens us group s have bee n co nsidered. with regard to criteria for the d iagnosis of e ll, plasma cell myeloma, Waldenstr6m macroglobulinemia, and new subtypes of cutaneous lymphomas, as well as in the development of new algorithms for the diagnosis of MPN .
the WHO classification has produced a new and exciting degree of cooperation and conmunic ation among patholog ists and oncologists from around the world . which stould facilitate con tinued progress in the understand ing and treatment of haema totog ic manqnaocies . The mulliparameter approach to c lassification, with an emphasis on defining real disease entites. tha t has be en ad opted by the WHO classification, has been shown in inte rnational studi es 10 be reproducible: the disea ses d efined are c linically disttnct iv e. and the uniform definitions and terminology facilitate the interpretation of clinical and translational stud ies 15 1, 791 . In addition, accurate and precise classifi c ation of d isease entities has facilitated the discovery of the genetic bas is of my eloid and lymphoid neoplasms in the ba sic science laboratory
A critic al feature of any class ification of diseases is that it be periodically reviewed and updated to incorpor ate new information. TheSocietyfor Haematopathology and the European Association for Haematopathology now have a more than to-year record of couebceaton and coo pe ration in this effort. The societies are comm itted to updating and revising the classification as needed . with input lrom clinicians and with the collaboration of the WHO . The experience of developing and updating Introdu ction to the cl assification
15
• )
CHAPTER 1 Introduction and Overview of the Classification of the Myeloid Neoplasms
•
-, "
..
Introduction and overview of the classification of the myeloid neoplasms
J.w. Vardiman A.D. Brunning D.A . Arter M.M.Le Beau
The WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissue s (3rd edition) published in 200 1 reflected a pa radigm shift in the approach to c lassification of myeloid neoplasms { 1039). For the first time. genetic information was incor porated into diagnostic algorithms provided lor the vario us en tities. The publicat ion was prefac ed with a comment pred icti ng future revisions nec essitated by rapidly eme rg ing gen el ic information. The cu rrent revision is a commentary on the significant ne w molecular insights mat have bec ome avail abl e since the publication of the last ctass'ncauon . The first entity described in this monograph . chronic myelogenous leukaemia (CML) rema ins the prototype for the identification and c lassific atio n of myeloid neoplasms This leukaemia is recognized
genetic features is used in an anerrctt c define d isease entities , such as CML, that are biolog ically homogeneous and clinically relevant - the same approach used in the 3rd ed ition of the classification. Altho ugh the previous scheme began to open the door to including genetic abnormalities as c riteria to classi fy myeloid neoplasms, this rev ision firmly acknow ledges that as in CML, recu rring ge netic abno rmali ties provi de not onl y objec tive c rite ria for recognition of speci fic entities but also identification of abnormal gene product s or pathways that are potent ial targets for therapy. One example in this revised sc heme is the addition of a new subgroup of mye loid neoplasm s (Tabte 1.01) assoc iated with eos inoph ilia and chromo somal ab normalities that involve the oiateiet-oenved growth factor rece ptor
by its c linic al and morphologic features, and its natural progression is charac terized by an inc rease in blasts of myeloid , lymphoid or m ixed myeloid/lymphoid immunop henotype. It is always associated with the BCR·ABL 1 fusion gen e that results in the production 01 an abnormal protein tyros ine kinase (PTK) with enhance d enzyma tic ac tivity. This p rotein is sut tcrentto ca use the leukaem ia and also provides a targ et for prote in tyrosi ne kinase inhibi tor (PTKI) the ra py tha t has prolonge d the lives of thousands of pa tients with this often tatal illness {6 151. This successful integ ratio n of cl inical , morphologi c and genetic information embodies the goal of the WHO classific ation scheme. In th is revis ion . a combination of c linica l, morpholog ic . imm uno phe noty pic and
.-"""'"
Table 1.01 Themyeloid neoplasms' major sul:9'OUJlS and d\al;U::i tstic features at ~
0.....
MPN
MyeIoidIIymphoid neoplasmswith eosinophilia and abriof· malilies of PDGFRA.
8M ctllularity
'10 MIrf'OW bluts
Usually increased. often normalin ET
tbmaJ or sIighlIy increased: 2ll%.
eQPl in some cases 'l'Illh specific cybJeneIlc abnorrnaIilies or in
some cases of erylhroIeukaemia
Inel!&Cti'Ie
Cytopenia(s)
U_
......
..--
\IariabIe. WBC
Co<m>oo
more myeloid lineage
......,
-......
"",",
May Of may J'IOl be
-...
""""""'"
dyspIaslai'loneor
Moy""Y ......
-
WllC_ ........ ........
or e"ect1ve
.........
"""'-
Mf)N, myeloproliferative neoplasms: MDS, myelod)'spla:slic syndromes; MDSlMf)N, myeIodysplasbcJmyeloprolifefalive neoplasms: AMl, ICIJIe myeloid leukaemia; ET, esseflIlaj Ihfombocylhaemia, JMML. ju¥&nile myelomonocytic leukaemia, wec. wniIe bloocI e&II$.
18
'
Introduction and overview of the c lassif ication of the mye loid neoplasms
]
alpha (PDG FflA) Of platelet de rived growth factor recep tor beta (PDGFRB) genes -a subgroup defined larg er9 by genetic events that lead to consti tutive act ivat ion of the receptor tyrosine kinase, PDGFA, and that respond to PTKI therapy {13 1, 466. 8121 . Similar examples are found througho ut the classification in each major subgroup, and inclu de not only neoplasms assoc iated with rmcroscoprcally rec og niza ble chromosomal abnormalities but also with gene mutations without a cytogenetic correlate as weu. On the other hand . the importance 01 careful clinical, morphological and immunophenotypic characterization of each
myeloid neoplasm and coeretanoo with the genetic findings cannot be over-
emphasized. The discovery of activating JAK2 mutations has revolutionized the approach to the diagnosis of the myeloproliferative neoplasms (MPN) 1163, 1044 , 1186,12681. Yet JAK2mutatiQns are not specific for any single clinical or morphologic MPN phenotype, and are also reported in some cases 01 myelodysplastic syndromes (MDS), myeiooysplasnc/ myeloproliferative neoplasms (MDSlMPN) and ac ute mye loid leu kaemia (AMl). Thus, an integ rate d, multidisciplinary approach is necessary for the classification of myeloid neoplasms. With so muc h yet 10 learn, there may be some 'missteps" as trad itional approaches to categorization are fused with more rrcecuarfy-orentec clessifcaton schemes , Nevertheless, thi s revi sion of th e WHO classification is an attempt by the authors, editors and the c linic ians who served as members of the Clinica l Advisory Committee (CAC ) to p rovide an "evidencebased" c lass ifica tion that ca n be used in daily p ractic e for therap euti c deci sions and yet pr ovide a flexib le framework for integration of new data ,
Prerequisites for classification ofmyeloid neoplasms by WHO criteria The WHO c lassification of myeloid neoplasms relies on the morphologic, cytochemical and immunophenotypic features of the neop lastic cells to esta bl ish thei r lineage and deg ree 01 ma turation and to decide whether cellular p rolife ration is q101ogica lly normal or dysplastic or esecuve or ineffec tive . The classification
is based on cr iteria applied 10 initial specimen s obtained prior to any definitive therapy, includ ing growth lactor therapy, for the myeloid neoplasm. The blast percentage in the per ip her al b lood , bone ma rrow an d other involved tissues remains of p ractica l impo rtance to categorize myeloid neoplas ms and to judge their progression . Cytogenetic and molecular genetic studies are requ ired at the time of d iag nosis not only for recoq r nton 01 specific genetically d efined entities, but for establiShing a baseline against which futu re studies can be judged to assess disease progression. Beca use of the multidisciplinary approach req uired to diagnose and classify myeloid neoplasms it is recomnended thaI the various diagnostic studies be correlated with the clinical findings and reported in a single, integ rated report. If a definitive classification cannot be reached the report should indicate the reasons why and provide guidelines for additional studies that may clarify the diagnosis. To obtain consistency, the following guidelines are recommended for the evaluation of specimens when a myeloid neoplasm is suspected to be present. It is assu me d tha t this evalua tion will be pe rformed with full knowled ge of the clinical history and pertinent laboratory data. Morphology Periphera l blood: A perip heral b lood (PB) smea r sho uld be exa mined and co rrelate d with result s of a co mple te b loo d c ount. Freshly mad e smea rs shou ld be sta ined with May-Gnmwald -Giernsa or Wright-G iemsa and examined for wh ite bloo d ce ll (WBC) , red b lood ce ll (AB C) and plate let abnormal ities It is impo rtant to ascerta in that the smears are we llstained, Evaluation of neutrophil g ranularity is imp ortant when a myelo id d isor der is suspected; de signat ion of neut rophils as abnormal b ased o n hypog ranular cytoplasm alo ne shoul d not be conside red unless the stain is well-controlled . Manual 2OO-cell leukocyte di fferentials of PB smea rs are recommended in patients with a myeloid neoplasm when the WBC count permits. Bone manowaspirate: Bone marrow (BM) as pi rate smears should also be stained with May-G rQnwald-G iemsa or WrightGie msa for optimal visua lization of cytoplas mic g ranules and nuclear chromatin. Because the WHO Classification relies on percentages of blasts and other specific Introduction and overview of the
11111111 111I 1111 1111 111111
456 F'S!. 1.01 Bone marrow tIeI:Me biopsy, Bone marfOW b'ephinebiopsies should be alleast 1.5 em in length and ollt<w1ed at right angles10 the cortical bone. cells to categorize some eoutes. it is recommended that 500 nucleated BM cells be counted on cellular aspirate smears in an area as close to the particle and as undiluted with blood as possible. Countll"lQ from multiple smears may reduce sampling error due to irregular distribution of cells. The cells to be counted include blasts and promonocytes (see definition below) . pronveocvtes. myelocytes, metamyelocytes, band neutrophils, segmented neutrophils, eosiropnns. basophils, fTlQIlOcytes , lymphocytes. plasma cells , erythrOid precursors and mas t cells. Megakaryocvtes. including dysplastic forms. are not inc lude d. If a concomitant non-mye loid neoplasm is present, such as p lasma ceu myeloma, it is reasonable to exclude tho se neo plastic cells from the coun t used to evaluate the myeloid neop lasm. If an aspirate ca nnot be obta ined du e to fibrosis Of ce llular packing, touch preparatio ns of the b iop sy may yield valuable c yto log ic informa tion, but d ifferential co unts from touc h preparations may not be repr esentative . The d ifferential co unts obta ined from marrow aspi rate s should be compared to an estimate of the p ropo rtions of cells o bserved in avai lab le biop sy sections, Bone marrow trephine biopsy: The contribut ion of adequate 8M bio psy sections in the diagnosis of myeloi d neoplasms cannot be overstated. The tre phine biopsy provides information rega rdin g overall cellularity and the to pog raphy, propo rtion and maturation of baematopolenc cells , and allows evalu ation of 8M stroma. The biopsy also provid es material for immunohistochemical studies th at may have diagnostic and prognostic importance. A biopsy is essential whenever there is myelofibrosis, and the classification of sore entities , partiCularly MPN, relies heavily on trephine sections, The specimen must be
ctassncauoo at the myeloid neoplasms
19
adeq uate, Iake n at rig ht angle from the cortica l bone and at least 1.5 cm in length to enable the evaluation of at least 10 partially preserved inter-trabecular areas. It should be well-fixed, thinly sectioned at 3-4 micra, and stained with haematoxylin and eosin and/o r a stain such as Giemsa that allows lor detailed morphologic evaluation . A silver impreg nation method for reticulin fibres is recommended and marrow fibrosis graded according to the European consensus scoring system 122141, A periodic acid-Schitt (PAS) stain may aid in detection 01 megakaryocytes. Immunohistoc hemical (IHe) study of the biopsy is often indispensable in the eva luation of myeloid neoplasms and is discussed belOw, Blas ts: The percentage of myeloid blasts is important for dl8gnosis and ctasstcaton of myeloid neoplasms , In the PB the blast percentage should be derived from a 200-cell leukocyte differential and in the 8M from a 500-cell count of cellular 8 M aspirate smears as described above . The blast percentage derived 'rom the 8 M aspirate should correlate With an estimate of the blast percentage in the trephine biop sy. although large foca l clusters or sheets 01 blasts in the biopsy should be regarded as possible disease progression. Immunohistochemical staining of the BM biopsy for CD34+ blasts often aids in the correlation of aspirate and trephine biopsy findings, although in some myeloid neoplasms the blasts do not express CD34 , Flow cytometry determination of blast percentage should not be used as a substitute for visual inspection. The spec imen for flow c ytometry is otten haemoouute. and may be affected by a number of preanalytic variabl es. and as noted for the
biopsy. not all blasts express CD34 . Myeloblas ts. monoblasts and megakary blasts are included in the blast count. Myeloblasts vary from slightly larger than mature lymphocytes to the size of monocvtes or larger. with moderate to abundant dark blue to blue-grey cytoplasm. The nuclei are round to oval with finely granul ar chromatin and usually several nucleoli. but in some nuclear irregularities may be prominent. The cytoplasm may contain a few azurophil granules (Fig 1,03), Monob lasts are large cells with abundant c ytoplasm that can be light grey to deeply blue and may show pseudopod formation (Fig 1.04 A. S). Their nuc lei are usually round with deli cate , lacy chromatin and one or more large prominent nucleoli.
They are usually strongly positive for n0nspecific esterase(NSE) but have no or only weak myeloperoxidase (MPO) activity, Promonocytes are considered as ' rroooblast equivalents " when the requisite percentage 01 blasts is tallied for the diagnosis of acute monoblastic . acute monoc ytic and acute myerorronocync leukaemia. Promonoc vtes have a delicately convoluted. folded or grooved nucleus with finely dispersed chromatin, a small , indistinct or absent nucleolus, and finely granulated cytoplasm (Fig 1.04 C, 0), Most promonocytes express NSE and are likely to have MPO activ ity. The distinct ion between mono brasts and prornonocvte s is often difficu lt. but because the two cell types are summated
... .,
20
Introduction and overview of the classification of the myeloid neoplasms
•
as rr onootasf s in making the diagnosis of AML, the distinction between a monoblast and promonocyte is not aly,.ogys critical. On the other hand , distinguishin g promonocvtes from mo re matu re b ut abnormal leukaemic monocytes can also be dilficult, but is critical, because the designation 01 a case as acu te monocytic or acute myelomonocytic leukaemia versus chronic myelomonocytic leukaemia olten hinges on this distinclion . Abnormal rrooocv tes have more clumped chromatin than a p romonocyte, variably indented. folded nucl ei and grey cytoplasm with rrore abundant lilac -colored granules . Nucleoli are usually absent or indi stinct (Ftg 1.04 E.F). Abnormal monocytes are rot consider ed as monoblast eouvaeots. Megakaryoblasts are usually 01rreoen to large size with a round , indented or irregular nucleu s with finefy reticular chromatin and one to three nucleoli. The cytOplasm is basophiliC, usually agranular, and may show cytoplasmic blebs (See Chapter 6 on acute myeloid leukaemia, NOS). Small dysplastic megakaryocytes and micrornegalocytasis (RARS-n should not be categorized as MDS/MPN. and in contras t to the criteria used in the 3rd edition of the WHO classification, cases of CMML with PDGFRB rearrangements are also excluded Rationale for diagnosis and classification of MDSlMPN This diagnostic ca tegory was introduced in the 3rd edition amidst controversy as to wl1ether some entities, particularly CMML, would be better categorized as either MDS or MPN depend ing on the extent of mye loprol iferation as evidenced by the WBC cou nt. Some cases of CMML have low neutroph il co unts and only modestly elevated monocyte co unts and resemble MDS clinically and morphologically whereas others have markedly elevated WBC counts and org anomegaly more in keep ing with MPN. yet criteria that clearly distinguish biologiCally relevant subtypes of CMML remain to be defined . To date, a lew cases of CMML and atypical chronic myeloid leukaemia, BCR-ABL1 neg ative (aCML) have been reported to demonstrate JAK2mutations that characterize BCR-ABL 1 negative MPN, but the prol iferative aspec ts of most cases of MPD/MPN are related to aberrancies in the AAS/MAPK signaling p athways. In juvenile myelQmonocytic leukaemia (JMML) nearly 80% of patients demonstrate mutually exclusive mutations 01 PTNPN1', NRAS or KRAS, or NFl 11329. 2096, 21621. all of wl1ich encode signaling proteins in AAS dependent pathways, and approximately 30- 40% of cases of CMML and aCML exhibit NRAS mutations {1686, 231 1, 24171. In view of the lack of any spec ific genetic abno rmality 10 suggest that these entities should be relocat ed 10 another myeloid subgroup, they remainin this "mixed" category which acknowledges the overlap that may occ ur between MDS and MPN. Casesof CMML with eosinophilia associated with PfX3FRB rearrangements are excluded , but rare cases of CMML
with eosinophilia that do not ex hib it such rearrangements sho uld be cJassified in this categOry The most controverstat issue in the su bgroup at MDSIMPN is the provisional entity. refractory anaemia with ring siderob lasts and thrombocytosis (RAR5-T). The ma jority (SO- 60%) 01 cases of RARS-T studied lor JAK2V6 17F carry this mut ation 1234. 354.762 , 1835. 1839. 1969,2081,2139. 23581. This has prompted the notion that RARS-T should be moved to the MPN group of myeloid neoplasms. whereas othershave argued thaI RARS-T is not an entity at all but merely one of the better recogniZed MPN entities, such as PMF or ET. i'l which genetic evolution has led to a dysplastic teanse. ring sideroblasls 11966. 2139. 23581. In a few cases reported. hl:1Never. the cells of patients with RARS-T. when studied by in vitro cul ture techniques, have growth characteristic more in keeping with MOS than MPN 1234, 18351. An additional question is hOw to clearly distinguish RAR5- T from RARS, in which moderately elevated pla telet counts are etten repo rted . This question is morepressing in view of the revised c riteria for RARS-T that lowers the p latele t threshold from ~x lrJl/L to ~450x 1rPlL, in parallel with the revised threshold lor Ef It is important to note that the d iagnostic criteria for RARS-T include not only the Iinding of an elevated platelet coun t in conjunction with anaem ia and ring elderoblasts in the 8 M, but al so mo rp hologicallyabnormal megakaryoc ytes similar to those of ET or PMF. Only a few pat ient s with RARS and plate let counts in the 450,500x W 9/L rang e have be en studi ed for JAK2 mutat ions and in mo st with platelet counts in the lower rang es no mutations have been found . Neverth ele ss, more stud ies are need ed , and we rec ommend to test for JAK2 mutation s in patents who have RARS and pl atelet counts above the normal range . The sum of current information reg arding RAR5-T argu es for its continued placemen t in the MDS/MPN category. but in view of the debate regar ding its precise definition and nature, it is best reg arded as a 'provisional entity" until more data are available, lastly. classification of myeloid neoplasms that carry an isolated isochromosome t 7q and that have less than 20% bl asts in the P8 or BM may prove difficult. Some authOrs suggesl this cytogenetic defect defines a unique disorder characterized
by mixed MOS and MPN features associated with pro minent pseuoo-Percer-Hoet anomaly of me neutroot urs. low 8M blast count, and a rap id ly p rog ressive clinical course. Most c ases rep or ted have a prominent monoc ytic component and meet the c riteria lor CMML, b ut in some, the PB monocyte coun t may not reach the low er threshold fo r that dia gnosis 1708, 14371· In cases that do not fu" ill the c riteria lor CMML or another well de fined myeloid category. desig nation as MOSIMPN. unclassifiable. with isolated isochromosome 17q abnormality, is most ap propriate.
$urTmary of major changes in MDSIMPN 1. Some cases of CMML with eosinophilia are relocated to the category, "Myeloid neoplasms with PDGFRB rearrangement" 2 . The c ategory, "Atypical CML" has been renamed as •Atypical C ML . BCR-ABL 1 negative" to emphasize this disease is not merely a va riant of BCR-ABL 1 positive CM L. 3 . RAR$-T remains as a provisional enlity, classified as MDS/MPN . uncrassiuabre . until furthe r data clarifies its approp riate designation. The crite ria for its recognition have been modified. The platelet threshold has been lowered to ~ 45Ox 1rPll, and meg akaryoc yte s w ith morp hology simil ar to those seen in ETor PMF must be present Myeladysplastic synd romes (MOS) These disorders , usually characterized by the simultaneous prolifer ation and apo ptests of baematopoienc cells that lead to a normal or nvoerceuurar BM bi op sy and PB c ytopenia(s), remain among the most c halleng ing of the myeloid neop lasms for p rope r d iagn osis and class ification , The general fea tures of MOS, as well as specific gu ide lines fo r diagnosis and c lassific ation are outlined in Chapter 5. An impo rtant add ition to the MOS ca tego ry (Table 1.05) is the provision al entity, refractory c ytopenia of c hild hood (RCG), This categ ory is reserved for c hildre n with MOS who have 5011
' 50'
blasts <m d II
"""""
MiKi1I ~celsll
.."
"""""
... """""
Blasts 18.5gJdL., men, 16,5g!31.S C)
"Spent phase"and post·polycythaemic myelofibrosis (oost-Pv MF) During the later phases of PV, e rythropoiesis progressively decreases. As a consequence, the red blood cell mass normalizes and then decreases, and the spleen further enlarges. Usually these Changes are accompanied by corresponding 8M aneranons 1641 . 20711. The most common pattern of disease progression is posf-Pv MF accompanied by myeloid metaplasia which is characterized by a Ieukoerythroblastic PB smear, poikilocy' ioss wil h teard rop-shaped red blood cells. and splenomegaly due to EMH , as defined in Table 203 {143A). The morphological hallmark of th is slage of the disease is overt reticulin aOO collagen fbrosisofthe BM 1641 . 775 , 2203, 22221, The CelkJarity varies in this terminal stage. tu: h'y1:loceIIular specimens are coreroo. CUsters of megakaryocytes, olten with hyperchromatic and very dysmorphic nuclei, are prominent Eryth ropoiesis and granulopoiesis are decreased in amount. and are sometimes foun d . along with megakaryocytes, lying within dila ted marrcw srcsocs 12203 1. Osteosclerosis may also occur 164 1, 775 1, The splenic enlargement is a consequence of EMH , ....nich is characterized by the presence of erythroid. granu locylic and megakaryccvnc elements in the splenic sinuses and cords of Billrot h. An increase in the number of immature cells may be observed in these stages, butme finding of ) 10% blasts in the PB or 8 M or the pre sence of signific ant my e lodysp lasia is unusual, and mosl likely sig nals tran sformation to an acce lerated phase and/or a myelodysplastic synd rome (MD S), Cases inwhich 20% or more blasts are found are AML 11701, 2071, 2203, 2222).
cnsoerec
""""phenotype No abnormal phenotype has been reo
"",eo Go'o'" The mosf frequent genetic ab normality in PV is the somatic qam-ot-tuncnon mut atoo JAK2 V617F. Altho ug h il occurs in >95%of patients with PV, it is not specific and is found in other MPN as well. but in
splerJedoi"r
Fig. 2.19 ~ Ylll'a, ~ rnyelofbosis (pos&-PV MF) and"¥lbd metaplasia , specinen. The splenic enlarvement in the ~ ptIase isdue IlIMlIy b eJb"ameOJlary Ilaema!DpoIesis !hat Cll:X:ln II1 It1e splenic sftlses , as wei 11$Iibrosis.-.d lll1trapmenl d platelets and tIaernalopoieli eels II1lhe splenic
coos iower freq uencvltea. 1044 ,1 186 , 12881. The mutation occurs in a haematopoielic stem cell , and is found in all of the myeloid lineages. Hence cells that utilize JAK2 kinase in the intr acellular signaling path way may be hyp ersen sitive to g rowth fa ct ors a nd other cvtokmes. inc lud ing EPO . A fun ct ionally similar mutat io n in exon 12 of JAK2 has also been reported 11981/. so that virtually all patient s with PV have a JAK2 aber ration , St ill, no ge ne tic defect enti rely specif ic to PV has been ide ntified . At diagnosis, c yto ge ne tic ab normal ities are detectab le in ab out 20% of pa t ients. The mo st c ommon rec urring abnormalities inc lude +8, +9, del(20Q), de l( 13q) and de l{9p) : sometimes +8 and +9 are found tog ether 142, 2394/. There is no Philade lphi a c hromosome or BCR-ABL 1 fusi on g ene . The se c hromosomal ab normalities are seen with increasi ng frequency with d isea se progression and in near ly 80-90% of those w ith post-PV MF 1421, Almost 100 % o f those wh o develop MDS or AMl have cyt ogenetic abnormalities. inclu ding those commonly o bserved in the rapy-related MD S and AMl (See Chapter 6 ).
Postulated cell of ori gi n Heemetopoteuc stem cel l. Prog nosi s and pred ictive fact ors With currently available treatment, median survival li mes > 10 ye ars are commonly repor ted {SO, 1215 , 1548,2071/ . although controversy persists about the risk factors other than olde r age {1215, 1389, 17021 . Most p atients d ie from thrombosis or haemorrhage , but up to 20% succumb to myelodysplasia or acute mye loid leukaemia ISO, 1389, 207 11, The factors tha t p red ict the risk of thrombo sis or haemorrhage are not well d efined 11389, 1700,20711, The incid ence of MDS and ac ute leukaemic transformation is only 2-3% in patients who hav e not been treated with cy totoxic agents , but increases to 10% or more follow ing ce rtai n types of c hemot hera py {704 , 1389 , 1548 , 170 1, 1702 1_
PoIycythaemlCl vera
43
Primary myelofibrosis
J . Thiele H M . Kvasnicka A. Tefferi G. Barosi A. Orazi JW. Vardi man
ICD-O code
Definition Primary myelofibrosis (PMF) 11464 1 is a clonal myeloproliferative neoplasm (MPN) characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow (8M) that in fully developed d isease is associated with reactive deposition of fibrous connec tive tissue and with extramedul lary haematopoiesis (EM H) . There is a step wise evolution from an initial prefibrotic phase 121771 cha rac terized b y a hypercell ular BM wit h absent or minimal reticulin fibrosis to a fibrotic phase with marked reticulin
9961 /3
Synonyms Chronic idiopathic myelofibros is (CIMF); Agnogenic myeloid metaplasia (A MM); Myelofib rosiS/scl erosis with myeloid metaplasia (MMM) ; Id iopathic myelofibrosis .
or collagen ubrosrs in lhe 8M and often
Epidemiology The overt fibrotic pha se is estimated to oc cur at 0.5- 1,5 per 100 000 persons per year {1060,21671. It occur s most C()fTV'TK)ll1y in the sixth 10 seventh decade of life, and both sexes are nearty equally affected 121671. Children are rarely affected 136n
osteosclerosis. This fibrot ic stage of PMF is characterized by ieukoervtbrobiastosis in the booo witll teardrop-shaped red cel ls. and by hepatome galy and sp lenomegaly (Tabl e 2,0 4 ).
Etiology Exposure to benzene or ionizing radi ation has been documented in some cases {5881 Rare familial c ases of 8 M fibrosis
Table 2.114 Diagnos1ic crilefialor primary myelofibrosis: 70 years . Hb
other typ es of haematopoietic and nonhaemat opo ielic neop lasms. The presence of a BCR- ABL 1 fusion gene exc ludes the diagnosis of El
IC[).() code
9962/3
bocytose, haemorrhagic thrcrnbocythaemia.
Sites of inv olvement Bone marrow and blood are the principal sites of involvement. The spleen does not show signilicant extramedullary haematopoesrs (EMH), but is a sequestration site for platelets 1705. 902. 21751. EtiOlogy The etiolog y of ET is unknown.
1. SllSIairled' platelet count ~45Ox 10"1t 2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased nlll'11bers of9l1larged. matul'tl megakaryocytes. No signllical1t increase Of Iefl-sMtofOOlItrophiI glanoopoiesis orer,1IWOpoiests
3. Not meetlng WHO atSerialor poIycyIIlaema vera,· P'JI'Nf'Y myelofIbrosI$.< BCR-ABL f posiWe ct.ror.: myeIogenouIlMaetnia' ormyeIodysplaslic syndrtml" Of oIher myeklid ~ 4. Demonstration 01 JAK2V617F orolher donal maricer. or in !tie absenteofJAK2V617F, no e-.1dence lor reeceve thrombocy1osls'
• Sustatned ooring the W(ri.-up process. • Requires Itle fcMure of iron repIaoement ItIefapy toincrease IIaemoglcOf1 level10I!'oe polyc)1IIaemia "'llfa fange Illhe presence of deaeased serum lerTilin. Ex5 emfrom baseIne (lislance Ircm ltIeleft C05laI margin) orIle appearance 01 newly p.alpable splenomegaly 4. Increased LDH (atloYe reference level) 5, Development 01 >1 of3 CXlIlSlrtlllional s~ : >10% weight bss in 6 month$. right sweats, I,Il8lplBined illver{>37.5-C1
50
MyeloproliferatIVe neoplasms
by long symptom-free intervals, inter, ruptec by occasional ute-mreaten thromboembolic or haemorrhagic episodes 1705, 802, 902, 12 15, 154 9, 2175 Although after many years a few pat with ET may develop 8M fibrosis associ-ated w ith mye loid metaplasia (EMH such progression is uncCll'TYTlOl1 1297, 775. 1189.22201. Precise diagnostic guidelines lor diagnosing post-Ef MF are given in Table 2 .07 . Strict adherence to and other WHO c riteria 1143A . 21771 necessary to prevent diagnostic comus associated with early PMF accompa by thrombocytosis 1365}. Transformation~ ET to ac ute myeloi d leu ka emia or MOO occurs in 1x1r:P1L a diagnosis of chronic mye;o. monocytic leukaemia with eosinoptlU may be more appropriate, but if there are dysplastic features and> 10% neutrophl precu rsor s in the PB and no rnonccytoss. a d iag nosis of atypical chronic myebd leukaemia with eosinophilia should Sifn. larly be considered. The distinction between GEl. NOS. arc idiopattuc HES is important. Idiopattlc HES can be diag nosed onl y in fUlly investigated pa tients and on ly when (i) there, an eosinophil count of
Differential diagnosis D iag nosis re qu ires posi tiv e evidence of the leukaemic nat ure of the co ncnton and exclusion of cases of MPN with rearrangement 01 PDGFRA. POGFRB or FGFR1. The diagnostic process often starts wi th exclusion of reactive eosinophil ia. A d eta iled histor y, physical exam ina tion, b loo d count an d blood film ar e essential. Conditions to be excluded include parasitic otectoo. allergies, pulmonary d iseases such as Loetner's syndrome. cyclical eosinophilia. skin diseases such as anqictymphoid hy perplasia, colla gen vascular d isorders and Kimu ra 's 52
Myeloproliferative neoplasms
1. There iseosinophilia(eosinophil count
3. There is nott.5;12)(q31-35.p13)« ohIr ream1l9B"*~of PDGFRB -4
There is no FlP1l1-PDGFRA fusion gene crotherrearrangement 01 PDGFRA
5, There is noI'88rrangemerlt of FGFR1 5. Theblast cell count in the peripheral blood and bone marrow is less than 20"10 and there is 110
'l\'(15)(p13Q22) IX 1(16;16)(p13;q22) IX oIher lealureGagrlosbc ofAML 7. There is a cbIaI cytol}eneIiC or rnolecaar genetic abnormaIrty, IX bIasleels aremore lhan ~ in !he ~ bk:Jod« men than 5% in !he bone marn:ow ·If apatient haseoiil"lOPhilia bul lhese mlenaare not met !he dial;Joos4S may be reactive eosinopt1ilia,idiOpa1tMc
hypereosinophilia or idiopathic hypereosinophilicsyndrome,
,. e
tiC
1m
Nc
m,
G. No
"'"
;d
a, • Fa lu
ca wit
GEl
con
maO as
•
eosinophilia is excl ude d by appropriate h:lrcxJgh investigatoo ; (iii) AML. MPN, MOS. MPN/MDS and systemic ma stocytosis are excluded; (iv) a cytokine-prod ucmq. ~icalty-aberrant. t-een pop ulation is excluded; (v) and there is tissue damage as a result of hyper eosinophilia . Hcnteria i-iv are met but there is no tissue damage. the app rop riate d iagnosis is ocoamc hyperoosinop hilia . Patl8rlts in whom a diagnosis of idiopathic Itypefeosinophilia or id iopalhic HES is made should be kepi und e r reg ular review since evidence may su bsequently Emel'g8 that the con dition is leukaemic in !'laue, Treatment may also be necessary
e,tlchemstry Cytochemical stains c an be used to identify eosinophils bu t they a re no t essential for diagnosis , Partial degranulaeco can lead to eosinop hils ha ving reduced peroxidase con tent.
-
No specific immuno p henotypic ab nermalily has been reported In CEL.
Geretics No single or spec ific cytogenetic or molecular genetic ab normality has been identified in CEl. NOS . Cases with rearrangement of PDGFRA, PDGFRB or FGFRI are spec ific ally excluded , The detectOO d a Ph cbrcroscre or BCR-ABL 1 fusion gene ind icates one of the rare cases of chronic myelogenous leukaemia wnh dominant eos inoph ilia . rather than eEL. Ellen when eosinophilia occurs in conjunction with a ch romosomal abnormality that is usually mye loid neoplasmassociated, it may be difficult to decide
_.-
F"l9- 2.32 kiopaltiC HES. Ablood smeard a pabertWlth ca-dIaclai.n,1eukot'yt:lsi$ and~ .
whether the eosinop hils are pa rt of the clonal process. since react ive eosi nophilia can occur in patients with myeloid neo-pla sms 17111. However, the linding of a recurring ka ryotypic abnormality that is usually ob served in my elo id d isord er s. suc h as +8 or i( 17q), does suppo rt the d iagnosis of CEl 1128, 1692 ). Occasiona l pat ients have a JAK2 mutat ion 1106 41. x-unkeo polymorphism ana lysis of the PGK or HUMARA genes c an oc ca sionally be used in fema le patients to dem onstrate cionautv 1392, 13501.
Prognosis and predictive factors Survival is quite varia ble. In some series in which pat ient s with idiopathic HES as well as those with probable eosinophilic leukaemia were incl uded. 5-year survival rates ap proached 80% 1443. 19 71,2072, 23821. Marked splen ome g aly. as well as the find ing of b lasts in the b lood or inc reased b lasts in the 8M , cvtcqeneuc abn ormalities and dysplastic features in othe r my eloid lineages have been reported to be unfavourable prognostic find ings [443, 1971. 2072 ,2382].
Postul ated cell of or ig in The ce ll of orig in is a haemopoietic stem cel l, b ut the lineag e potential of the affec ted cell may be var iab le.
Chronic eosocobtc leukaemia. not otherwise specified
.
53
.
Mastocytosis
H ,-P' Horn y'
n.o. Metc alfe J.M . Bennett B,J . Bain
Definition Mastocytosis is due to a c lonal, neoplastic prolife ration of mast cells thai accumulate
in one or more organ systems. It is characterized by the presence of mult ilocal
compact clustersor cohesive aggregates! infiltrates of abnormal mast cells. The d isorder is heterogeneous. ranging from skin lesions that may spontaneously regress to highly aggre ssive neoplasms associated w ith muttiorgan failure and short survival (Table 2.09). Subtypes of mastocytOSis are recog nized mainly by the distribution of the disease and cli nical manifestations . In cutaneous mastocyt osis (eM), the mast cell infiltration remains confined to the
Solitary mastoc ytoma of skin Indolent systemic mastocytosis Systemic mastocytosis withAHNMO" Aggressive systemic mastocytosis Mast cell leukaemia Mast cell sarcoma Extracutaneous mastocytoma
skin, whereas systemic mastocytosis
Synonym Mast cell d isease .
IC[)..() codes Cutaneo us mastocytosis (urtica ria pigmentosa) Diffuse c utaneous mastocytosis
9740/1 9740/ 1
Table 2.09 Classification of mastocytosis. , Cutaneous mastocytosis (CM)
2, Indol&nt s)'5t&mic mastocytoSis (ISM)
3. Sy5temic mastocytosis wittl associatedclonal haematological non-mast-celliineage disease (SM·A.HNMDj
4 AggressiwSy5temic masklc)'toSis (ASM) 5, Mast cellleul25% aremnalln oratypical.
.........
2. Deleclion of an ICtiYaII'lg poI"It rnuta\lI:Wl at c:odor1816 of KIT~ bone manow. blocdor anolher eJ:lraCula.
3. MastOBIs itI bone marrow. blocdor oItler eJhcutaneous organs express CO2 and'orC025 in adl;1itlOII ~ nonnat mast 011 maR-eB. nger recognizable due to 8M fibrosis or bla stic infiltration wou ld be expected to have a poor prognosis.
Myeloproliferative neoplasm, unciasSlfiable
65
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of
PDGFRA,PDGFRBorFGFR1 Myeloproliferative and lymphoid neoplasms associated with rearrangernenl of PDGFRA.
PDGFRB and FGFA1 constitute three rare
B,J . Bain D,G Gilli land
H.-P. Horny JW. Vardiman
,
specific disease groups, which have sore sha red features and some that differ. All result from lormalion of a fusion gene encoding an aberrant tyrosine ki-
nase. Eosinophilia is characteristic but not invariable. II has been established that, in the case 01 POGFRA and FGFR t-related neoplasms. the cell of origin is a mutated plu ripotent (lymphoid-myeloid) stem cell.
It is possible that this is also true for PDGFR~relaled
neoplasms, but this has yet to be established.
All three disorders can present as a chronic myeloproliferatIVeneoplasm (MPN) , but the frequency 01 manifestation as a lymphoid neoplasm varies . The clinical
.. 4,, .'•. .. . '.'
and neen ercoocer features are also influenc ed by the partn er g ene involved . In the c ase of PDG FRA-related disord ers, prese ntation is usua lly as c hronic eo sinop hilic le ukae mia (CEl) with promi nent involve ment of the mast cell linea ge and sometimes of the neutr oph il lineage. l ess often , pr esent ation is as ac ute my eloid leuka emia (AMl ) or precur sor-T lymp hoblastic lymphoma (T-LBL), in both instances with ac companying eos ino philia , In the c ase of PDGFRB-related disea se, the features of the MPN are more va riab le but are often those of c hronic myelomonocytic leukaemia (CMML) with eosinophil ia, Proliferation of aberrant mast c ells can again be a feature. Acute tran sformations that have been d escribed to date have been myeloid . In the case of FGFR r-reteteo disease, a lymphoma tous presentation is COOlmon, pa rticularly T-18L with accompanying T~" 3.01
""
,
.
~
f ig. 3.01 FIP1L 1-PDGFRA-ffllaled etvonic ~leu kaerlia. A PenpheraI blood IilmstIOlWIg Ihree rrlllder*f degranulated eosinopl'lils. Romanowsky stain. B Trephine biopsy section. Abundanl eosinophils and eosI'q)lli precursors, Giemsa stain. C Trephine biopsy S&ClIOO. Abundalll mast cells. many of wI\it:tI are spindle-shaped, Iormingsmalloose dosleB, Masteel tryp\lIS8 staining, 0 Trephinebiopsy section. CD25expression in tilemast CIk
eosinophilia, Other patients have had CEL, precursor-B lym phoblastic leuka emia / lymp homa or AML. The importance of recog nizing these di so rde rs is that the aberrant tyro sine kinase activity can make the d isea se responsive to tyrosine kinase inhibitors, This hope ha s already been reali zed for MPN with rearrangemen t of PDGFRA o r PDGFRB, whic h are resp onsive to imatin ib and some related ty rosine kinase inhibitors . Similar specific therapy has not yet been de ve loped for FGFR 1-relale d disease. Rele va nt c ytogenetic analysis,
Diagnosticctitena of an MPN' wilt1 eoslnophilia associated witt1 FIP1U -PDGFRA.
AmyeloproIlferatMl neoplasm .",111 promnenl eosmoph~ia
molecular genetic analysis or both should be car ried out in all patients in whom MPN w ith eosinop hilia is suspected and also in pat ients presen ting with an acute leukaemia or lymphoblastic lymphoma with eosinophilia. Recognition of PDGFRA related disease usually requires molecular genetic ana lysis, sinc e the majority of cases resu lt from a cryptic deletion, whe reas c ytogenetic anal ysis will reveal the ca usative abnormal ity in the case of PDGFRB- and FGFR1-related d isease.
Myeloid and lymphoid neoplasms with PDGFRA reanangement
AND Presence of a FIPILl-PDGFRA fusion gene'
Definition
• Patients preserUlg witt1 aculemyekidledaema or tyr1lJhDbIastic ~ with8CJSinOPt*l and a FIP1L1.f'OGFRA lusion geneare also aSSlgfllld tobs categoIy. ! II appropnate OI)IeaJar.-.alysis is not 1IYIilable.lhisliagnosis slJ:ll*S be suspected ilU1ere is. Pt\-negalrve MPN lIiIlIh Ihe ~ teahns of chronic eosirq:lhIc leukaemia assooateeI WIfI ~, • marked ~ of 58I0OI YltaJfWI812. eIeYaliort of serum tryplase and incteasecI bone Il'llWI'lM mast llllI!.
The most common MPN assoc iated wll1l PDGFRA rea rrangement is that asSOCIated with F1PIL l-PDGFRA formed as a result of a cryptic de letiorl at 4q 121466l (Table 3.0 1). Presentation is generally as eEL but can be as AM L, T·LBL or bon
68
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities 01 PDGFRA . PDGFRB Of FGFRI
smcuaneously (14691. Acu te transformation can follow presentation as GEL.Organ damage occurs as a result of leukaemic infiltration or the release of cvtokines. en zymes or omer proteins by the eoeropnns and possibly also by mast cells. The peripheral blood (PB) eosinop hil count is markedly elevated (in cases reported to dale it has almost always been ~ 1.5x1rPlL) atthough it should be noted that. in some series of patients . investigation was confined to patients with eosinophilia. There is no Ph chromosome or BCR-ABL 1 fusion gene. Except when there is transformation kl acute leukaemia, there are 65 years , female sex. W8C >50x 1Q91l thrombocytopenia, and Hb nocytb lO'IL 2. Blasts (ird.Jdlng ~)" In 20/ 100 000 amo ng tho se ove r the age of 70 years {109, 7831. App roximately 10 300 inciden t cases of MOS were d iagnosed in 2003 in the USA {1351 1. There is a male predominance . Thera py-related mveioovsptasuc syndromes are discussed in Chapter 6. Cli nic al featu res The major ity of patients present with symptoms related to cvtooentats): most of the patients are anaemic and transfusiondependent. less frequent are neutropenia and/or thrombocytopenia. Organomegaly is infrequ ently observed.
Etiology Prima ry or de novo MOS oc cu rs without a know n history of c hemotherapy or race expos ure. Possible etiolog ies for pre ma ry MOS Include benzene exposure at levels well abo ve the m inima allowed by most government age nc ies. cigarette smoking, exposure to agricultural cherricats or solvents an d family history ci heematoootenc neoplasms 121131. Some inherited haematolog ic al d isorders. SUCll as Fanconi anaemia. dyskeratosis Cl)f\o geni ta. Shwachmann-Diamond evnocre and Diamond-Brackten syndrome are also associated with an increased risk MOS.
non
a
M"",hoIogy The morphological classitication 01 MOO is principally based 00 the percent blasts in the 8M and PB. the type an:!
a
degree of d ysplasia and the pr esence of ring sideroblasts {1 90 I. The cy topen ias generally co rrespond to the d ysp lastic lineage. but discordance may be present (Table 5.0 1) 123271. To determi ne the blast perc entage in the BM, a 500-ceU differential of all nucleated cells in a smear ortrephine imprint is recommended and in the PB, a 2QO.leukocyte cnnerentrat In severely cvtooenrc patients, butfy coat smears of PB may tacuuare performing the Odferential. The charac teristic s of the d ysplasia are relevant when diSlinguishing between the various types 01 MOS and may be important in predictmg biology. In addition , some cytogenetic abnormalities are associated with characteristic d ysplastic features, e.g isolated del(Sq) and hypolobated and non-lobated megakaryocyte
nuc lei and det( 17p ) with hypo lobe ted neutrophil nuclei / 12371 Assessment 01 the deg ree of dysp lasia may be pr ob lematic depending on the quality of the smear preparations and the stain. Poor quali ty smears may result in misinterp retation of the presence or absence 01 dysplasia particularly in assessing neutrophil granula tion . Because of the critical importance 01 recognition of dys pl asia to the diagnosis of an MOS, the necessity 01 high quality slide preparations cannot be overemphasized. Slides for the assessme nt of dysplasia should be made from freshly obtained specimens ; specimens exposed to anticoa gulants for more than two hours are unsatisfactory As a general precaution, no patient should be diagnosed as having MOS without knowledge 01 the clin ical and
"'ReIrDIlyq10perIIas 'III\I1lriineage dysplasia (RCOO) Refraclory anaemia (RA); Relracloryneutropenia (RN);
_ _ IRT)
Retacklry anaemiI WIth nngsidetobltsts (RARS)
drug history and no case of MOS should be reclassified while the patient is on growt h teeter therapy, inclu ding erythropoietin. In add ition, cytopenia(s) in the absence of dys pl asia shoul d not be interpreted as an MOS. A presumptive diagnosis of MOS may be made in the absence of dysplasia il certa in cytogenetic abnormalities are present (See Genetics). Persistent cytopenia without dysplasia and without one of the specific cytogenetic abnormalities c onsidered as presumptive evidence of MOS should be viewed as the recent ly described "idiopathic cytopenia of undetermined siqrufcance" ( leUS), and the patent's haematologic and cytogenetic status should be cerefuny monitared 124221 . In an attempt to more accurately pred ict chnical behaviour, cases of MOS without
8100dMdinp ~ or bicytopenia'
-
t«I or rareblasts « 1%)1
No "''''
Cylopenia(s) No or fare blasts « 1'10)2 NoAlIeI'rods logy The t(9;11)(p22;q23) may occur at any age. but is morecomnor I in child ren. being
Acute myeloid leukaemia and related precursor neoplasms
Molec ular studies have iden tified a t1t.rna'I homologue of the Drosophila trithorax gene design ated MLL (HRX), that results in a fusion gene in translocations invo/Vllg 11q231 1141. The MLL p rotein is a histl)1!! mettwnransterase that assembles in pro. tein complexes tha t reg ulate g ene Iran.
scription via ctuomato remodel ing. The ~9:11)(p22:Q23) involving MLLT3 (AF9 ) is toe most common MLL translocation in AML and appears to represent a distinct enhty. Secondary cytogenetic abnormalities are common with t(9:11) (p22:Q23). with +8 most commonly observed, but do not appear to influence survival [306, 15311. Postulated normal cou nterpart aaenaiopoeuc stem cell with multiJineage
ootennar. Prognosis and pred ictive factors Acute myeloid leukaemia with the . 9:11XP22;Q23) has an intermediate sur.....aI and one that is supefior to AML with e:tner l1Q23 translocations 11531. 18911. Cases with the t(9: 11) and ief 80 different translocalions involving MLL are now described in adult and paediatric acute leukaemia, with over 50 eensiccato n partner genes now cnaraclenzed 11 470. 20081. rrensiccetcoe involving MLLT2(AF4). resuitmq predominantly n acute lymphoblastic leukaemia (ALL). end MLLT3(AF9). resuhing predominan tly n AML, are the most common. Other MLL eensccauons that commonly result in AML rcuoe the MLLT1(ENL). MLLTIO (AF1O), MLLT4 (AF6) and ELL as partner genes, Other than the ML L-ELL fusion resulting Irom the t(1 1:19)(q23:p13,1), which is res often associated with only AML, these fusions occ ur pr edom inantly in AML, but may be seen in ALL as well. Up 10 one third of MLL transiocauons in AML ee not detectable on co nventional karyotype analysis , and FISH or other molecular stud ies may be necessary to dentify these variant translocations 120081. AML with these fusions usually have myelomonocytic or monoblastic rro rpnobgic and immunophenotypic features While in the p ast all of these translocali:lns were encompassed by the category rj AML with 11q23 abnormalities. the diagnosis should now specify the specific abnormality and should be limited to cases with 11q23 balanced translocations fI'o'OIving MLL. For example. a case of AMl with an MLL-ENL fusion would be dl8gnosed as acute myeloid leukaemia dh ~11 ,19)(q23;p13.3): MLL-ENL. 40Jte myeloid leukaemia with cytogenetic
B Fig. 6.09 AML (monoblaslic) WIth t(9;1'Xp22;q23). Bone marrow smears A 5evefall'l'lOl'lllblasts. some WIth very allur'llobated megakaryocytes. Bone marnJo\! cellularity is variable with some cases presenting as hypoc ellular AML Marrow fibrosis is variable.
«30
Immunophenotype Immunophenotypic studies of AML with inv(3)(q21q26.2) or t(3:3}(q21:q26.2) are limited. The blast cells generally express C0 13. C033. HLA-OR. CD34 and C03S Blast cells of some cases also abe rranf express C07 and a subset may express meg akaryocytic markers such as CQ4t and C06 1. Abe rrant expr ession of lym. photo markers other than C07 appears uncommon [20041. Genetics A variety of abnoemauties of the long arm of chromosome 3 occur in myeloid rnalo(t nances. with inv(3)(q21q26.2) and t(3:31 (q21 ;q26.2) being the most common. The abnormalities involve the oncogene EVIl at 3q26.2 . or its longer form MOS1-EV! and RPN7 at 3Q21 APN1 may act as <WI enhancer of EVIl expression resulting increased cell proliferation , and impaireo
cell differentia.lion: it induces naen etoooreticcell transformati on ( 1236, 1609, 21251 . Other cytog enetic aberrations involving 3q26.2, such as t(3:2 1)(q26.2:q 22) res~tting in an EVI1-RUNX 1 fusion and usually seen in therapy-related disease, are not included in this disease ca tegory. Secondary karyoty pic a bnormalities are common with inv(3)(q21 q26.2) and t(3;3) (Q21;q26.2) with monosomy 7 most common, occu rring in approximately half of cases, followed by 5q deletions and com"'" ...",.",..1 1963/. These abroonalrties may precede the development of the 3q262 abnormality 116091. Patents with AMl with inv(3)(q21q26.2) ««3:3Xq2 1;q26.2) show overexpression d EV/1 and GATA2, bulthese fIndings do ro appear to be specific for the genetic aonormality 11236,16091 . Patients with chronic myelogenous leu-.aemia may acquire inv(3)(q21q26.2) or (3:3kq21;q26.2), and such a finding usually portends accelera ted or blast pha se of !heir disease , Cases with both t(9 :22) (Q34;q11.2) and inv(3 )(q 21q 26.2) or t(3;3 ) (q21;q26.2) are best considered as ag g-essive phases 0 1 ch ronic myelogenous leukaemia. rather than AMl with inv(3) (q2tq26.2) or t(3;3)( q2 1;q26.2). PosllJlated normal counterpart tiaematopoietic stem cell with multilineage POtential. Prognosis and predictive factors AML with inv{3)(q 2 1q26 .2) or t(3;3) (q21:q26.2) is an aggressive di sease with sort survival 171 5 , 1834, 1983 1. Two patients with AMl with inv(3)(q2 1q 26.2) were reported to show a response to a rsen ic trioxide with thalidomid e, w ith one act uevi'19 complete rem ission 11 824 j , Cas es lI,ttl inv(3)(q2 1q2 6 ,2) or t(3:3)(q 21;q2 6 .2) and cvtrc cells 1186, 1084, 1880 1. In some unusual cases of AML with minimal ditter· ennanon there may be a residual norma population of maturing neutroo nue. These c ases ma y resemb le AML with maturenon. but are distingui shed by the absence of MPO or SBB positivity in the b lasts and the abse nce of Auer rods, The BM sections are usually markedly hvoerceuuie with poorly differentiated blasts. With sensitive ultrastructural studies, MPO, CAE ac tivity may be demonstrated in sma
•
granules. endoplasmic reticulum, Goigi area and/or nuclear membranes.
1",,,,,,,OP" 011Otype Most cases express earty, heernetoooetcassociated antigens (such as CD34, CD38 and HLA-DR) and lack antigens associated with myeloid and monocyti c maturation. such as CD 11b. C01S , CD14, CD64 and CD65 Biasi ce lls usually express CD13 and/or CO l 17 while expression of CD33 is found in approximately 60% of cases, Blasts are negative tor Band T-assoc iated cytoplasmic lymphoid markers cCD3, cCD79a and cCD22 . MPO is neg ative by cytochemistry. but may be positive in a fraction 01 blasts by flow cytometry Of immunohistochemistry. Nuclear terminal oeoxvnocieonoyttransterase (Td T) is positive in approximately
50% of cases. Expression of CO? has been reported in approximately 40% of cases, while expression of o ther membfane,lympood-associated markers is rare. Genetic s No unique chromosomal abnormality has been identi fied in AM L with minimal differentiation. The most co mmon abnormalities previously reported are complex karyotypes and unbalanced abnormalities, such as -5/del(Sq), -7/del(7q), +8 and del( 11ql , but the presence of some 01 these abnormalities would now pl ace the case in the category of AML with myelodysplasia-related changes. Mutations of RUNX 7 (AML 7) occur in 27% of cases and 16-22% of cases have FLT3 mutations. Differential diagnosis The differential diagnosis incl udes ALL, acute megakaryoblas!ic leukaemia, mixed phenotype acute leukaemi a and more rarely. the leukaemic phase of large cell lymphoma. Immunophenotyping studi es are essential to dis tinguish these condi-
oons Acute myeloid leukaemia without maturation Definition Acute myeloid leukaem ia without maturation is characterized by a high percentage o! 8M b la.''-.ts »l~I,~\1 $~":li~ic.5\'71· evidence of maturation to more matur e neutrophils. Blasts constitute ~% of the roo-erythroi d cells. The myeloid nature of
Fill.6.2" Acute myeloid leukaem ia without maturation. Bone marrow smear. AThecellsarepredominanlty myelobIasts: OCC3S;onal myeloblasts contain azllrophilic grarlules or Aller rods. There is rIO e'o'i Oenc41 01 maturation beyornllhe myeloblast stage. B Myeloperoxidase reaction showing OOmertlUSmyeIoblasls with strong peroxidase reactivity. There areseYeraI peroxidase negative tfYlhroid precursors ifl the centre.
the blasts is demonstrated by MPO or S8B (3% or more of blasts) posi tivity and/or Auer rod s. ICD-O oode
9873/3
Epidem iology Acu te myeloid leukaemia without maturation comprises 5- 10% of cases of AML. It may occu r at any age but the majority of patients are ad ults; the median age is approximately 46 years. Clinical features The patients usually present with evidence of 8M failure with anaemia, thrombocytopenia and neutropenia, There may be a leukocytosis with marke dly increased blasts. Morphology and cytochemistry Some cases of AML without maturation are characterized by obv cos mveicorasts. some of which have azurophilic granulation and/or unequivocal Auer rods. In other cases, the blasts resemble Iymphob lasts and lack azurophilic granules: MPO and SBB positi vity are present in a varia ble number of bl asts , but always in at least 3% . The 8M biopsy sections are usually markedly nvperceuutar although rormocellular or nvooceuuiar cases may occur. Immunophenotype Acute myeloid leukaemia without maturation usually presents with a popu lation of blasts expressing MPO and one Of more of myel oid -associated antigens suc h as C0 13, C033 and C0 117. C0 34 and HLAOR are positive in approximately 70% of
cases.
r,~q'6' , ~ ~%'l '~\~' ,';\7 ex~ kine rec ep tor expression {18Sf, in vitro functional assays {18S, 3961. gene e xpression profiling 15781. as well as on the tumour-derived cell line CAL-l 11361 1all point toward a derivation from the precursors of a special subset of dendritic cells, !he plasma cytoid dendrit ic cells 1356, 857,20591 . These c ells are distinguished by their p rod uction of high amounts of u Interferon in humans 1357l; in the pas t. !hey have been defined with many different terms. such as lymphoblast, t-essocrated plasma cell , plasmacyt oid T-ce U and plasmacytoid monocyte {6541 . The i'nmunophenotypic heterogeneity with regards 10 TdT and the assoc iation with myeloid disorders suqqests a multihneage po tential lor some cases 01 BPOC.
Prognosis and pred ictive factors The c linical co urse is aggressive . with a median survi val of 12-1 4 months . irrespective of the initial pa ttern of disease . Most cases (80 - 90%) show an initial response 10 mulliagent chemotherapy, but relapses with subsequent resistanc e to drugs are regularly observed . Long-lasting remissions have been documented in spor adic c ases, usua lly occurring In young p atients who have been treated with acute leukaemia-type induction therapy, followed by allogeneic stem cell transplantation in first complete remission
192.920, 17351·
Blastic plasmacytoid cencntc cell neoplasm
147
CHAPTER 7 Acute Leukaemias of Ambiguous Lineage
Acute leukaemias of ambiguous lineage
Ac ute leukaemias of ambigUOlls line age encompass those leukaemias that show no clear evidenc e of differentiation a long a singl e lineage. They include Ieukaemias with no lineage-specific antigens (acute und ifferentiated leukaemia. AUL) and those w ith b lasts that express antigens of more tha n one line age to such a degree that it is not possi ble to assign the \eukaefT'Wa to any o-e lineage with certainty (mi xed phenotype acute ieukaermas . MPAL). The latter can eithe r contain d isIinc t b last populations. each of a different line ag e. or one population with multi ple an tigen s 01di fferen t line ages on the same cell s. or a com bin ation. Historically, there has been confusion both in the term ino log y and d efinitio n of MPAL. The term ac ute b ilinea l (o r b ilineag e) leukaem ia ha s been ap plied to leukaemias con taining separate po p cta.nons of b lasts of mo re than one lineage, and the ter m b iphenotyp ic leukaemi a to thos e co nta ining a sing le populat io n of b lasts c oexpressing antigens of mo re thanone lineage I885, l267, 1427 , 21 19}, although some times the ratter term also encom passed blnneaueu kaemta. Here the term mixed p henot yp e acute leukaem ia applies to this g roup of lesions in general, and , as d efined b elow, the mo re spec ific terms B/my e lo id (B/MY) and T/mye lo id (T/MY) leukaemia to refer to reu keemra s c onta ining the two linea ges specified, irres pec tive of whether one or mo re than one po pulation of bl asts is seen . Some well-d ef ined mye lo id leukaem ic en tities may have irnrnunoonenorvplc features that might suggest that they be classified as Bimye loid (BlMY ) Of Tlmyeloid (T/MY) leukaemras. However, MPAL, as de fined here, exc ludes c ases that c an be cl assified in another category, eithe r b y genetic or clinical features. These speci fic ally inc lud e c ases with the rec urrent acu te myeloi d leukaemia (AML)·associetec uansiocenons 1(8;2 1), t( 15;17 ) or inv( 16); the first of these especiall y freq uently exp resses muniple Bceu markers /22361. In addition, cas es of leu kaemi a with FGFR I mutations are not con side red TIMY leuk aemias Cas es of c hronic
150
mye logenous leukaemi a (C ML) in b last c risis, MDS-re lated AMl and therapyrelated AMl shou ld be cl assified pnma rily as suc h , even if they have a mixed phe notype, with a secon dary notation that they have a mixed phenoty pe . The d iag nos is of amb ig uou s lineage leukaem ias rests on irnmunophenotyping . Flow cytometry is the preferr ed method for establishing the d iagnosis, especially when a d iagnosis of MPAl is de pen dent upon demonstrating coexo ressoo of 1ymphoid and myeloid d ifferentiation antigens on the same cell. Cases in which the d iag nosis rests on demonstration of two distinct leukaemic populations with a d ifferent p henotype may also be established by immunohistochemistry in tissue sections, or with cytochemic al stains for myeloperoxid ase on smears c oupled with flow cvtomet ry to detec t a leukaemic B or T lymphoid population. The myel oid component of an MPAL c an be rec ogn ized in one of three ways: 1) When ther e are two or more d istinct pop ulations of leukaemic c ells, one of whic h wo uld meet immu no pheno typic c riteria for ac ute mye loid leukaem ia {with the exception that this po p ulation need not c omprise 20% of all nuc leated cel ls} 2} When there is a sing le population of b lasts that by itself wou ld meet c riteria for B acute lymphoblastic leukaemia (B-ALL) or T acute lymphob lastic leukaemia (T-ALl) and the blasts also expressmyeloperoxidase,
M ,J Borowitz M ,-e , Bene Nt.. Harris A. Porwit E. Mat ures
most freq uently show n by flow cvtomeuc positivi ty, on b last c ells coexp ressing 1ymp hoid mar kers. The myeloid lineage anngens CD 13, CD33 and CD l 17 are no! specific enough to allow identification cA a mixed phenotype leukaemia. 3) When there is a single population ot cells that by itself would meet criteria forB Of T-All in which the blasts also show tXIequivocal evidence of monoblastic differen tiation: either d iffuse positivity !t;) non-specific esterase or expression cA more than one monocytic marker such as CD 11c, CD 14, CD36, CD64 Of lysozyme The first of these three ins tances wooId previously have be en consid ered -bilineage leukaemia" while alternatives 2 and 3 represent wha t wou ld have been termed "bi phenotypic leukaemia". The t-een component of an MPAl is recognized by strong express ion of cvtop lasmic CD3, either on the ent ire blast population, or on a sepa rate suo oc ouanon of leukaemic c ells. Surface CD3, thOugh rare, also ind icat es T-cell lineage, Expres sio n of cC D3 is bes t determined by flow c ytometry using relatively brighl fluo roph ores such as phyc oerythrin or er lophyc oc yanin , and should be as bright o r nea rly as br ight as that of norma l residual T ce lls p resent in the samp le. T-cell linea ge can also be demonstrated by CD3 expression on b lasts by immunohistoc hem istry on bone marrow biop sies, thou gh it should be noted that polyvalent
Table 7.01 RllQuiremefils for assigrlingmore than onelineage toa Single ~asl populaton.
Myeloid lineage ~xidas.e (fbw cylomeIfy,
immunohislOChemistry or cytoChemistry)
"
Mi:Inocy1icdifterentiaticl'l (al least2 of lhe kllIowrng: NSE. CDlle , C014, CD64 ,~) Tlineage
Cytoplasmic COO (!kM' cytomeIry wi1l'l antibodies 10COO epsilon etIatn: irnn~nolliStoehemistry USIIIg polydonaI <W1b-C03 <W1tbody maydeled CD3zeta chain, wt\id'I is not T95% and in adults 60-85%. Approximately 80% of children with B·ALL appear to be cured, while this fig ure is less than 50% for adults Mo re intensive therapy makes a d ifference in c ure rates , and
r~
9.05 B IympIw)I:lIask leukaerria. L~ rnje. The
neoplastiC eels infiIlrate cMlusely sparW1g IUmallaides
there is some evidence tor youngeradlAls at least , that therapy with more intensive "paediatric-type" regimens is associated with better outcome 1233, 8721. Inlancy. increasing age (> 10 years), higher white blood cell count, slow response to initial therapy as assessed by morphologic ex· emmanon 01P8 and/or 8M , and the presence 01 minimal residual disease after the rapy are all associated with adverse prognosis 1488, 679, 19 76 , 2023 , 2093. 22951. The presence of eNS disease at diagnosis is associated with adverse out· come, and requi res specific therapy 14461. The prognosis of B-LBL is also considered relatively favourable. and as with BALL appears better in ch ildren than accns
113671.
B lymphoblastic leukaemiallymphoma with recurrent genetic abnormalities
This group of d iseases is c harac terized by recurrent genetic ab normalities, in-
clud ing balanced translocations and abnormalities involving ch romosomes, Many ch romosomal abnormalities that are non-rand omly associated w ith B acu te tymphoblastic leukaemia (B·ALL) are not inCluded as separate ent ities in this sectal. While inclusion or exclusion 01 a genetic -entity- is somewhat arbitrary, those lesions that are specifically mentioned are chosen because they are associated with distinctive clin ical or phenotypic p ropertes. have important proqnosnc implie arcos.demonstrate omerevidence that they ale biologicall y di stinct an d are generally mutually exc lusive w ith other ent ities.
BLymphoblastic leukaemiallymphoma with ~9;22)(q34;q 11 2); BCR·ABLt
Oefrlition Aneoplasm of Iyrnphoblasts corrmitted to lhe e -cen lineage in whic h the blasts harbour a trans location be tween the BCR gene on ch romosome 22 and the ABL 1 oncogene on ch romosome 9
ICD-O code The provis ional co de prop osed for the fourth ed ition of ICO-O is 98 12/3. Epidemiology and cl inical features Presenting features are generally similar to those of other pat ient s w ith B-All. BCR-ABL 1 associated ("Ph . -) All is relatively more common in adults than Children, accounting for about 25% of adult All but only 2-4% of childhood All. Most chil dren with Ph. B-All woul d be consid ered "hig h risk " b y sta nd ard age and white b lood ce ll (WBC) feat ures, but there are otherwise no cha racteristic docalf indings Though patients with t(9;22) B·Al l may have organ invo lvement. lymphomatous presentations are rare
_
and cytochemistry
There are no un ique mor phologic or
MoJ. Borowitz J.K.C. Chan
cytochemic al feat ures that d istingui sh this from other type s of ALl. Immunophenotype B-Al l wit h t(9;22 ) is typicall y C 01O . C0 19. and TdT • . There is more frequ ent expression of myeloid -assoc iated anngens C0 13 and C033 19851: COl17 is typically not expressed . C025 is highly associated with t(9.22) B-All, at least in adu lts 116791. Rare ca ses of t(9 :22) All have a T precursor phenotype. Genetic s The t(9 :22) results from fusion of BCR at 22q l 1.2 and the cy to plas mic tyrosine kinase gene ABL 1 at 9q3 4. w ith produ c tion ot a BCR-AB lfusion protein, In most chi ld hood cases of Al l w ith the t(9 ;22), a p1 90 kd BCR-ABU fusion p rotein is produced. In ad ults, ab out o ne half of cases of ALL w ith the t(9 .22) prod uc e the p2 10 kd fus ion protein that is present in chronic myelogenous leukaemia (C ML) . and the rema inder prcouce the p190. No de finite cl inical differences have been attribu ted to these two different gene produc ts. The t(9 ;22) may be associated with other ge netic abnorm alities, inc lud ing rare cas es that mig ht othe rwise c ause a cas e to be plac ed in one 01 the other categories below, It is ge nerally conside red that cl inica l features in suc h c ases are governed by the p resenc e of the t(9:22) .
Fig. 9.06 Ttis bone marrow from ., iICkJIl WIth 119"22) posIbve &-ALl is ~leIy replaced by tyrnp1ctlIasb. Mitolic figl.l'eS areI'lUI'IlefOUS.
ad d ition to hig h-dose c hemotherapy has been reported to imp rove early event-free survival {19751.
B Lymphoblastic
leukaemiallymphoma with t(v;11q23); MLL reafT8t1ged Definition A neoplasm ol lymphoblasts ccmm ined to the B lineage that harbours a transl oca tion between the MLL g ene at band t 1q23 and anyone 01 a large number of differe nt fus ion pa rtne rs. Patien ts with leukaemias that have dele tions of 11q23 w ithout MLL rear rangemen ts are not incl ud ed in trns group ,
Postulated normal counterpart There is some suggestion that the c elt 01 origin of t(9 :22) ALL is more immature than that of othe r B-All cases 14521.
ICD-O code The p rovis iona l code proposed for the fourt h ed ition is 981313
Prognosis and pred ictive factors In both c hild ren and adults , t(9 ;22 ) All has the worst prognosis among pat ients with All. Its hig her frequency in adu lt All expl ains in pa rt but not completely the relativ ely poorer outcome of ad ults w ith All. In ch ild ren . the prese nce of favourab le c linical features inc lud ing age. white count and response to thera py, is associated with somewhat better outcome 1771. althoug h prognosis is still cons idered relatively poor . Treatment with imatinib in
Etiology Wh ile the specific et iology of leukaemia with MLL transJocations is unknown . this translocation may occur in utero. with a sho rt latency between the transloca tion and dev elopment of d isease , Evidence for this inc lud es the fact that these leu kaemias are frequ ent in very young infants, as well as the fact that this translocation has been identified in neonatal b lood spots of patients who subsequently develop leukaemia {7451.
oucn-o
B lymphoblastic leukaemia/lymphoma With recu rrent genetic abnormalities
171
proteo-qryca n neural-glial antigen 2 (NG2) is also characteristically expressed and is relatively, thoug h not absolutely, spec ific.
Genetics
Fig, 9.07 B tymphoblasbc le ukaemia~ym phom a with MLL reerrarqement FISHstudy usingan MLL breekapa rt probe. The normal MU gene"MLL(11q23)"appears as ajuxtaposed red and green, Of sometirnas yellow signal, The trensJocatioo is demonstrated by separation of theredandgreen probes r MLLsp") (Cocrtesy of Or AJ carroll)
The MLL gene on chromosome 11Q23 has many fusion partners. The most cammon partner gene is AF4 on cnrorosore 4q 21. Othe r commo n partner genes incl ude ENL on chromosome 19p13and AF9 on chromosome 9p22. MLL·ENL fusions are also co mmon in T·ALL and fusions between MLL and AF9 are more typ ica lly associated with myel()d leukaemia. Leukaemias with MLL nanslocations are frequently associated with overexpresston of FLT-3 l 801. Cases with deletions of 11q23 are not included in this group of leukaemias as they appear not to share the same clinical, phenotypic or prognostic features.
Prognosis and predictive factors Leokaerreas with the MLL·AF4 translocation have a poor prognosis. There is some cont roversy as to whether reukeenee with translocations other than the MLL-AF4 rearrangement have as poor a prcqross as trcse that do , Infants with ML1. translocations, particularly those 100 OClO/J-J-L. There is also a high freq uency of eNS involvement at diagnosis. While organ involvement may be seen , pure lymphomatous presentations are not typical. Morphology and cytochemistry There are no uniq ue morpholo gic or 172
Precursor lymphoid neoplasms
cytochemical features that distinguish this from other types of ALL. In some cases of leukaemtas with MLL rearrangements it may be poss ible to recog nize distinc t lymphoblastic and monoblastic popul ations , which can be confirmed by immunoph enotyping; such cases should be consid ered Blmyeloid leukaemias . Irrrnu nophenotype ALL with ML L transiocanons. and most especially t(4;1 1) ALL typically have a CD 19+, Cu tn-neqenve. CD24-neg ative pro-B immunophenotype, also positive for CD15l985, 169 11. The Chondroitin sulfate
Definition A neoplasm of Iymphoblasts committed to the B lineage with a translocation between the TEL (ETV6) gene on chromosome 12 with the A ML 1 (RUNX 1)gene on ctecrcsome 12. ICD-O code The provisional code proposed for the fourth edition ol lCD-O is 98 14/3. Epidemiology and clinical features This leukaemia is common in chiklren accounting lor abou t 25% of cases ~ B-ALL It is not seen in infants and decreases in frequency in older children to the point that it is rare in adulthood. Presenting features are generally similar to those of other patients with ALL
Morphology-and cytochemi stry
•
There are no unique morphologic or cytochemica l features that diSlinguish this from ot her types of ALL.
.'
,
..
Imrru1ophenoIyp Basts have a C019+ , C010+ phenotype and are most often CD34+; other phenotypic features. includ ing near or complete absence of COO, C020 and CD66c 1245, 533,9851. are relatively but not absolutely specific. Myeloid-associated an tigens. especially CD13, are frequently expressed, but this does not indicate mixed phenotype acute leukaemia 11551. Genetics The t(12;21)(p13;q22): ETV6-RUNX1 translocation results in the p rodu c tio n of a fusion prote in that likely ac ts in a dominant negative fashion to interfere with normal func tion of the transcri ption factor RUNX1. This leukaemia appears to possess a unique gene expression signature 12469 1. The E1Y6-RUNX1 translOCahon is co nsid ered to be an ea rly lesion in leukaemog enesis, as evidenced by studies of neonatal blood spots that have shown the presence of the translocation Il'l child ren who develop leukaemia many years later 124001. There is evioeoce that the translocation is necessary but not suHicient for the development of leukaemia 12400 1. Postulated normal counterpart This leukaemia appears to d erive from a Been progeni tor rather than from a naematoooetrc stem cell 13441 Prognosis and predictive factors B-Al l with the TEL·AML 1 transloc ation hasa V8fY favourab le prog nosis with c ures seen in >90% of c hildren, espec ially if they have other favo ura ble risk factors. Relapses often occur muc h late r than those at other types of ALL. Beca use this translocation appears to occur as an early event, it has been sug gested that some laterelapses in fact de rive from pe rsistent "preleukaemic· clones that ha rbour the lI'ansIocalion and unde rgo ad ditional genetic events afte r the first leukaemic cICIIe has been eliminated 17191 Ch ildren "MIh this leukaem ia who also harbour adverse prognostic factors . such as ag e ewer 10 years or high white count d o not have as good a prognosis, b ut may still lare better as a g roup than other patients with these same adverse fac tors .
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"
,
Fig. U9 Hyperdiploid ALL. G banded karyotwe stlowlng 55d'll'omosomes. indudlng trisomies of 4. 10 and 17and kltrasomy 2t. Thefe are nostruc:llnl abnor'malitJes. (Courtesy of Dr. AJ carrol).
B Lymphoblastic leukaemia! lymphoma with hyperdiploidy Defi nition A neoplasm of Iymphoblasts comm itted to the B lineage whose b last s c ontain >50 and usually 90% of children. especially if their risk p rofi le is favourab le Presence of adverse tee te rs. such as ad vanced age or high white count may ad versely affect the prognosis, but patients may not fare as badly as otbers without this favourable abnormality.
B Lymphoblastic leukaemiallymphoma with hypodiploidy (HypodiploidALL) Definition A neop lasm of Iymp hob lasts committed to the B lineag e whose blasts co ntain 85%) of cases of HCl demonstrate VHgenes with somatic hypermutation indic ative of a post germinal centre stage of maturation 183. 348, 22351. A unique feature of HCl is the comm on c oexpression of multiple cronauv related 19isotypes. sug gesting arrest at some point during lsotype switching (22351. Cytogenetic abnormalities No c ytogenetic abnormal ity is specific for HCl: numerical abnormalities of chromosomes 5 and 7 hav e been de scribed, but transl ocations are distinctly uncommon
13481
Fig.10.17 Hairy cel leukae!l"ia, iml'T'l.J~ features. A,B,C Bone malfOWbiopsy. AD8A44 positivityothai'y
Postulated normal cou nterpart late, activat ed memo ry B-cell .
eels accef1luat nghairy projedlons. B com ~tYity ot hairy cells C Hairy cees express Annexin 11'ttli1e eryttwoid prew-scn arenegaUve. 0 Uver. Sinusoidal inFiltration byAn!lexinA1-pClSjbve leukaemichairycells.
Prognosis and predictive factors HCl is uniquely sensitive to either a -interferon or nucreosices (purine analog s) such as pentostatin and ctaonbme. Patients receiving pu rine an alogs often achieve com plete and durabl e remissions {2235 1. Prolonged remission may also result Irom splenectomy, but this is uncommon 17981. The overall t n-year surviv al rate exceeds 90% {642, 7981. Rituximab
offers therapeu tic effica cy in combination with pu rine analogs in patients with renact orwreiaosed HCL: experimental therapeutic ag ent s incl ude anli-C022 ant ibody therapy or anti-C0 25 immunotoxin therapy 118501. l ong term HCL survivors have an inc rease d risk of second cancers com pared to the general population with a cumulative probab ility of 30% for secon d neoplasms by 25 years after
190
Mature B-cell neoplasms
HCl diagnosis 1940 1- Hodgkin and nonHod gkin lymphomas as well as thyroid cancer pr edominate in these long term survivors 19401.
Splenic B-cell lymphoma/leukaemia, unclassifiable
M . Piris K. Fouca r M . Mollejo E. Campo B . Falini
There are a number 01 variably well-
Synonyms Splenic ma rginal zone lymphoma (SMZL)diffuse variant {1496 1, lym phocytiC lymphoma simulatin g hairy cell leukaemia 116811, splenic B-c eil lymphoma with villous lymphocytes (also used for SMZl and HCl-vatiant), splenic red pulp lymphoma With numerous basophilic villous lymphocytes 122621-
defined entities that represent small Be en Clonal lymphoprolil erations involving the
spleen, but which do not fall into any of the other type s of B-cell lymphoid neoplasms recognized in the WHO classifteaton. This chapter reviews the two best oeteeo of these relatively rare provisional entities. splenic diffuse red pulp small B-cel lymphama and hairy cell leukaemia variant. The relationship of splenic diffuse red pulp small Been lymphoma to hairy cell leukaemia variant and omer p rimary splenic B-celllymphomas remains uncertain, the ir precise diagnostic criteria are not fully established and the most appropnale terrTWdogy is wserned. Other splenic small B-cell lymp homas not fUlfilli ng Ihe criteria lor either otmese provisional enti ties or for other tetter established B-eall lymphomas should be diagnosed as splenic Been Iymp homall eu kaemia. uoclassifiable until more is known . Splenic diffuse red pulp small B-<elllymphoma Definition Splenic diffuse red p ulp sma ll B-c eillymphoma is an uncommon lymphoma w ith a diftuse pattern of invo lve ment ot the splenic red pu lp by small monomorphous B lymphocytes. The neopl asm also involves bone marrow (8 M) sinu solo s and peripheral blood (P8 ), co mmonly w ith a villous cytology, This is a provisional entity that needs add itional molecu lar studies tor defining its main features and
d iag nostic markers. This diagnosis should be restricted to ch arac teristic cases, fulfillin g the majo r fea tures d escr ibe d here and not applied to any lymphoma grow· ing diffusely in the spleen. Chronic 1ymphocytic leukaemia (CU). hairy cell leukaemia (HeL), _ " " " " Y l C IynVooma (Lf'L) and prolympI-ocybC ieLllogy LPL occurs in adults with a median age in the 60s and a slight male predominance 1581,23371. Etiology A familial predispo sition may exist in up to 20% of pa tients with WM {29, 2267f. These pa tients are diagnosed at a younger age and with greater 8M involvement .
194
Mature B-cell neoplasms
_..
-.
fl9- 10.22 lym~ ~ A Bone marrow biopsy shows a ~ infiltrate """ a PASpo5Itrve Ouk::her body (8fTOW). B The ~smaq1ic I1fi1lrale is alsoseen in ee asptalesme¥. Hepatitis C virus (HCY) is associated with type II c ryoglobulinemia and with LPL in some but not all series, perhaps related to geog rap hic d ifferenc es 1534 . 1271, 1450A, 1597 , 1680 , 1791 . 1932,21661 . Some of the HCV-associated Iymphoplasmacytic proliferations even if monotypic, are non-progressive and others may be more like chronic lymphocytic leukaemia (Cll) 11506. 23261. Treatment 01 these patients with anti -viral agents may lead to regression 01 the Iymphoplasmacync proliferations {1434 . 2 1661. Apart from the role 01 HCY, mast cells may help drive the proliferation in LPL 122591. Sites of invol vemen t Most c ases involv e the BM and so me, lymph nod es and other extranodal sites. About 15- 30% of patien ts with WM also have splenomegaly, hepa tomegaly and/or adenopathy {5811· Per ipheral blood (PB) may also be involved.
Cli nica l features Most patients present with weakness and fatig ue , usua lly related to anaemia. The majority of pa tients have an IgM serum parap rotein although othe rs may have a different paraprotein or no paraprotein at all. A minority have both 19M and IgG or other paraororens. Hyperviscosity occurs in up to 30% 0 1 patients, The paraprote in may also have autoantibody or cryog lobulin activity, resu lting in autoimmune phenomena or cryoglobulinemia (seen 10 up to -20% 01 patients with WM). Neuropathies occur in a minority 01 patients and may result from reactivity of the IgM parap rotein with myelin sheath antigens, cryoglo b ulinemia or pa raprotein deposition, Depos its of Ig M may occur in the skin or the ga strointestinal trac t, where they may cause diarrhoea Coagulopathies may be caused by Ig M binding to clotting factors. platelets and fibrin . Ig M paraproteins are not diagnostic 01 either LPL or WM as they can occur in patients with other lymphoid
neoplasms or without an oven neoplasm. A minority of pa tients inJ\ially present with an IgM -related disorder such as cryo-
globulinemiaor IgM-monoclona1gamrT"l()o pathy of undetermined significance and only later develop an overt lPl 1370. 1230. 15241.
-
Bone manowand peripheral blood Bone marrow involveme nt is c ha rac terized by a nodular. dlftuse and/or interstitial infiltrate usually composed predominantly of small lymphocytes admixed with variable rwroes of plasma cells and plasmacytoid tymphocytes 11672.16731 · Paratrabecular aggregates may also be p resent. Increased mast cells are often present. Similar cells may be present in the PB . but the white blood count is typ ica lly low er than in ClL.
Lymph nodesand other tissues In the most class ic cases that are usually associated with WM , lymph nod es show retention of normal architec tural fea tures with dilated sinuses with PAS+ material and sometimes small port ion s of residual germinal centres. There is a relatively mo nolonoos proliferation of sma ll lymphocytes. plasma cells an d plasmacyto id lymp hocytes with relatively few transformed cells. Dutcher bod ies (PAS+ intranuclear pseudoinclusions), increased mast cells and haemosiderin are othe r typical features . Other cases show greater arch itectural destruction, may have a vaguely follicular grcmlh pattern . more prom inent residual germinal centres, epithelioid histiocyte clusters and sometimes a much g reater proportIOn of plasma cells or a more poIynn-phic appearance with more numerous transformed cell slimmu no b lasts 11934AI. Protilerahon centres. as seen in CWsmal1 ~ic lymphoma (Sl l ) must be abo seN: and the presence of paler-appearing
margina l zone type cntterennatoo shou td suggest the diagnosis of one of the MZL There may be associated amyloid. other immunoglobulin deposition or crystal storing histiocytes. Spleens demonstrate a IymphopIasmacytc infiltrate tha t may form small nodules in the red pulp or grcrw more d iffusely.
invotving the CCND1, MALTt , BeL 10 or BCL2genes with the possible rare exception of the tarter. WM is reported to have a homogeneous gene expression profile. independent of 6q deletion, that is more sendar to CLl and normal Bcens than to myeloma 14291. This study also suggested the importance of upregulated Il6 and its downstream MAPK signaling pathway
",.",unophenoIype Most cells express surface Ig and the ptasmacvnc cells express cytoplasmic Ig . usually IgM. sometimes IgG and rarely IgA . They are typ ically IgD- , express a-conassociated an tigens (CD 19. CD2O, C022 , CD79a) and are COS-. CD1o-. CD 1Q3-and CD23- with frequent but not invariable CD25 and CD38 expression. Some studies report more varia tion especially in CD22 and CD23 expression . The p lasm a cells are CD 138 positive . lack of CD5 in most bu t not all cases an d the presenc e of strong cytop lasm ic Ig are useful in the d istinct ion from ClU SLl. Genetics Antigen receptor genes IG genes are rear ranged usually with V regions that show somatic hyp ermutation but lac k ongoing mutations (2349). The re ma y be biased VHusag e 11026 , 1193 ).
Cytogenetic abnormalities and oncogenes No speci fic c hromosomal or oncogene abnormalities are recognized in lPl. The previou sly reported IGH@!PAX5t(9;14)is rarely. if ever, found in lPlI463, 774, 13791. Deletion 6q is reported in up to somewhat over haN of BM-based cases but it is not a specific finding and appears at best to be infrequent in tissue based LPlI464 . 1379, 16 17, 19721. Trisom y 3 and 18 are infrequent . Trisany 4 has been reported in about 20% of WM 121831. lPl do not demonstrate any of the other B-eell Iymphomaassociated transocetoos such as those
Postulated normal COlSlIe rpart Probable post-follicular B-eel1lhat d ifterentiates to plasma cells.
Prognosis and predictive factors The clinical course is typically indolent , WIth median survivals 015- 10 years 1581. 23371Advanced age. PB cvtcoemas especially anaemia. oertomance status and high f}-2 microglobulin levels have been repor ted to be associated with a worse prognosis 158 1. 2337f. Cases w ith incr eased transformed ce lls/imm uno blasts may als o be associated with an adverse prognosis; however, a va lida ted g rad ing system doe s not exist 143, 1941. Cases with del(6q) have been associated with feature s 01 adver se prognosis 116171 . Transformation to d iffuse targe B-eeillymphoma occurs in a small propo rtion of the cases an d is assoc iated with poor survival 113111. Patients who have developed Hodgkin lym phoma are also reported 118631. Variant: gamma heavy chain disease Gamma hea vy chain dis ease results trom secretion of a trunca ted gamma chain, whic h lac ks uqnt-cnam bin ding sites. It is usually associated with a lymphoma that fulfills the cri teria lor LPl involving lymph nodes. 8M. liver. spleen and PB but some cases resemble plasma cell myeloma. The clinical course is vari able , but probably more aggressive than that of typical IgMproducing lPl.
l ymphOplasmacytic lymphoma
195
Heavy chain diseases
Definition The hea vy chain d isea ses (HCD) comprise
3 rare Be en neoplasms that produce monoclonal heavy chains and typically no light chai ns. The monoclonal immunoglobulin component is composed of either IgG (gamma HeD ). Ig A (alpha HCD) or 19M (mu HCD ), The heavy chain is usual ly inc om plete and thu s incap able of lull assembly. Variab ly sized p rotein s are produced , thai may not pr odu c e a c ha rac teristic se rum prot ein elec trophore-
sis peak. and require immunoelectrophoresis or immunofixation to detect.
Nt.. Harris P G . Isaacson 1 M. Grogan E.S. Jaffe
tight chain binding sites and does not bind to light chains to form a complete immunoglob ulin molecule. Synonym Franklin d isease .
Epidemiology Thi s is a rare d isea se of adults wi th a med ian age of 60 ; approximately 130 cases hav e been described 1687 , 23521. There
is no partic ular geo graphic d istribution , and a slight male predominance in most but not all series 123521.
Alpha HCD is conside red to be a varian t
of extranccar marginal zone lymphoma of rrccose-essoceteo tyrrVOO tissue(MAln. Ga'mla HeO is characterized by a ~ plasmacytiC population resembling Iymprcctasmacync lymphoma and Mu HeO typically resem bles eLL: however bolh are sufficiently distinctive to be considered separate enti ties .
ICD-O code
976213
, Gamma heavy chain disease Definition
Gamma heavy chain disease (gamma HCDj is a neoplasm of lymphocytes, plasmacytoid lymphocytes and plasma ce lls that p rod uce s a trun ca ted gamma immunog lobulin heavy ch ain, whi ch lacks
Sites of involvement The tumour may involve the lymph nodes, Waldeyer ring . gastrointestinal tract and other extranodal sites, bone marrow (8M), liver, spleen and peripheral blood (PB).
Clinical features Most patients have systemic symptoms such as anorexia. wea kness. lever. weight loss or recurrent bacterial infec tio ns. Au toimm une manifes tations are found in about 25% 01 the cases. mostlreq uently rheumatoid arthritis, but also autoimmune haemolytic anae mia or thrombocytopenia or both, va sc ul itis, SjOgren synd rome, systemic or cu taneous lupu s erythem atosus, myasthenia g ravis or thyroidit is 168 7, 997 . 235 2 ) Autoimmu ne d isease ma y pre ce d e t he di agn osis of lymphoma by seve ral yea rs Most pat ients have
~ .
~
..J!.
...,
Fig. 10.24 Gamma heavy lilain disease. A. This polymorptIous tymphoplasmacytic proIifefabon is coovised 01 admixed plasma cells, plasmacytoid ~es and IympIloid cells. B Immunollistochemistry shows monotypic staining lor gammaheavy chain,
196
Mature B-eell neoplasms
generalized disease, including lymphadenopathy, sp lenomegaly and hepatomegaly; involvement of Waldeyer ring, skin and subcutaneous tissues . thy. raid . salivary glands or gaslrointestinal trac t may occur, and PB eos inophilia may be present 16871. Circulating p lasma cells or lym phocytes may occasionally be p resent. The pa tients generally do not have lytic bone lesions or amy loid deposit ion, The 8M is invo lved in 30-60% of the cases 168 7, 997, 23521, Cl inica l and laboratory dis tinction from an infection or inflammatory process may be difficult in view of this co nstellation of symptoms and the some times broad band or near-nome serum protein electrophoresis. The diagnosis is made by demonstration 01 IgG without light chains by immunofixation in the PB, urine Of both.
-
L ymph nodes typically show a poIymor. phous proliferation with admixed lymphocytes. plasmacytoid lymphocytes, plasma cells. Wrm.JnobIasts. histiocytes and phi ls I 1540AI· The presence 01 eosinephils , beuocvtee and immunoblasts may ca use a resemblance to ang ioimmunoblastic T-eeill ymphoma (A ITl) Of Hodgkin lym phoma (HL); it is not cl ea r whether rare repo rted cases of gamma HCD assoc iated with AITl or HL rep resent a true association or a resem b lance of the infil· trate 01 ga mma HCD to HL 1565, 992J, In some cases plasma ce lls p redominate and may resemble plasmacytoma The PB may show lymphocytosis with or Wlthout plasmacytoid lymphocytes. reserrtJling chronic lymphocytic leukaemia (CLL) a Iymphoplasmacytic lymphoma. Transfor· mation to diffuse large B-eell lymphoma (DLBCl) is rare 16871 The 8M may stlOt¥ Iyrnphoplasmacytic aggregates or only a subtle increase in plasma cells with monotypic garrrna heavy chains WltholA light chains.
eosoc-
," ""'-
The cells contain monoclonal cytootasnc ga mma chain w itho ut lig ht chains, exp ress CD79a, CD20 on the lymp hocytic
Fig. 10.25 Gamma heavychain oseese. Bone marruw biopsy. ASmall ~les cx:mposed of plasma cells Md tympnoid eels arepreserK. C(ll'I'Ipl'iSing awroxma!ety 5%oflhe overaI marrow cellularity Some plasma cells appear malin. wtIile others are atypical WJ\h open etwomatin (B). C Immunohislochemital stain shows cytoplasmic IgG Images COU'leSy of Dr. AJiyah Rallemtula h {1~l
component, CDl38 on the plasma cell component. and are CDS and CD to negative (1S40Al. Genetics Immunoglob ulin genes are cronauv rearrang ed and conta in high levels of somatic hypermutation 16861. Deletions in the gamma heavy chain gene are present that result in expression of a defective heavychain protein that cannot b ind light cnem to form a complete irrvnunog lobulin molecule 121 . 658. 686 , 728 , 732. 1989, 235 11. These deletions involv e the VHregion and variab le amounts of the CHI region. and there may be insertions 01 large amounts of DNA of unknown origin 16861. Abnormal karyotypes have been present in about half of the reported cases. but no specific or recurring genetic abnormality hasbeen reported 123521. Postulated normal counterpart Post-germinal cen tre 8 cell with the ability to diHerentiate to a p lasma ce ll, with a defective gamma heavy cha in gene. Prognosis and predictive factors The clinical outcome is variable, ranging trom indolent to rapidly progressive; the
median survival has been reported to be 12 months (6861; but a recent study of 23 cas es rep orted a med ian of 7.4 yea rs, with over hall the deaths not related to the Iympnoprotiferative disorder 123521 Most patients with low-grade appearing Iymphoprasmacvtc infiltrates appear to respond to non-anthracycline-containing che motherapy, and respo nses 10 rituximab have been reported 123521.
Mu heavy chain disease Definition Mu heavy chain disease (mu HCD ) is a EkeII neoplasm resembling chronic I'ympt1ocvnc leukaemia (Cll). in which a defeclive mu heavy chain lacking a variable region is produced . The 8M contains an infiltra te of characteristic vacuolated plasma cells, admixed with small, round lymphocytes Epidemiology This is an ex treme ly ra re disease of adu lts. with between 30 and 40 c ases reported; a med ian age of 60 and an approximately equal frequency in males and females {6861. Sites of involvement Spleen. liver, 8M and PB are involved; peripheral lymphadenopathy is usually not present
Fig. 10.2! Mu heavy chain disease. Bone marrow asprIIe shows predomlnanlly plasma cells with prominenl C)t:ifJIasmic vacuolation.
Clinical features Most patients present with a slowly progressive disease resemb ling chronic 1ymonccvtlc leukaemia Mu HCD differs from most c ases of Cl l in the high frequency of hepatosplenomegaly and the absence of peripheral lymp had enop athy. Routine serum protein electrophoresis is frequently
normal. Immunoelectrophoresis reveals reactivity to ann-rno in polymers of diverse sizes. Although mu cha in is not found in the urine, Bence Jones light chains are commonly found (50%) in the urine, particularly kappa chains . The tatter. while stilt produced in mu HCD, are not assembled into a complete immunoglobulin protein because of heavy chain gene aberrancies leading to truncated forms 1136, 23501. Mo4 lime s mat of one with 3OgIL)
AND/OR
10% or more donal plasma ~I s in bone mai'TOW Norelated organ or bssoe impairment [end organ damage or bone IesionI(CRAB: hypercalcerria, nlIIaI inSufticjency, anaema. bone lesions))orrnyeIom&-it!lat s~ • No IeYeI 0( serum orume M-proIeIl is I1dlJl:led M-prolein in most cases II >3(91. 0( IgG or >25g.t 0( IDA or >19''24 Iv 0( unne Igtt d\ain I:d some pab8nts WIll! S)'frPIomabc III)"!lDma I'aYe ItveIs lower than htse.
• UonodcI'IaI plasma eels usuaIy exceed 10'% 01 nucleated eels i'llhe marT\1IfI' I:d no!1Onal1eWtl is designaled because abl:M: 5% 01 pabenls WIth s~tic; myeloma Ilave < 1O"fe manow plasma ceh. • The mo5l impcItantcrilerlalor symptomaoc myeloma aremaru1estalions 0( eod organ damage I1cIudIng 8naen'ia, hypercak::erma.1ytJC bone lesions, renal insu!lioeoty. hypefVlSCOSlfy. amy\Oidosts orl ecurrent i'llections. Modified from ,56).
could be followed by a mutagenic event initiating malignant transformation 18731. Most patients have no identifiable toxic exposure or known chronic ant igen ic sterwlation 113151. Sites of involvement Genera lized 8M involvement is typ ically present. lytic bone lesions and focal tumour al masses of plasma cells also occur . The most common sites are in 8M areas of most acti ve haemetopolesls . Extramedullary involvement is generally a manifestation of advanced disease. Clinica lleatures Symptoma tic plasma cell myeloma is defined by the presence 01 end-organ damage (CRAB: hypercalcemia. renal insuffic iency, anaemia , bone lesions) in a patient with an M component and clonal 8M plasma ce lls. In most patients there is a constellation of clini cal , laboratory, radiological and pathOlogical findings 113741. Radiog raphic sludies reveal lytic lesions. osteoporosis or fractures in 70% of cases of myeloma at d iagn osis, often assoc iated with bone pain and hypercalcemia 156, 1224, 18401 Renal failure is due to tubular da mage resulting from monodonal light chain proteinuria; recurrent intecuone may be partly a consequence of depressed normal immunoglobulin
produ ct ion; and anaemi a (67%) results from 8M replacement and renal damage with resultant loss of erythropoietin. An M-protein is found in the serum or urine in abou t 97% of patients 112261 (lgG 50%. IgA 20% , light chain 20% 1561, IgD. IgE. IgM and bicl onal < 10% ); - 3% of cases are non-secretory. The serum M-protelf"l is usually >3Og/l of IgG and >2Og/l of IgA. In 90% of patients there is a decrease in polyclonallg «50% of normal). Otherlaborat ory findings include hypercalcemia (20% ), elevated creatinine (20-30%) 112261. hyperuricemia (>50%) and hypoalbuminemia (- 15%) 1842, 12261. Clinical variants Asymptoma tic (smoldering) plasma cell myeloma In asymptomatic plasma cell myeloma. the diagnostic criteria lor myeloma are met but no related organ or tissue impairment (end-organ damage) is present 156, 12271. AsymptomatIC plasma cell myeIOrna is similar to MGUS in its lack of clinical manifestations. but is much more likely 10 progress to symptomatic myeloma 1582. 123 1, 12331, Patients with o ore -sanoo stage I disease are included in this category and in some series so are asymptomatic patient s with an apparent solitary plasmacytoma but with add itional bone abnormalities detected only by MRI 156,
582). About S% of patient s with myeloma areinitially asymptomatic 1123 11. The mao Jority have between 10 and 20% 8 M plasma cells and the med ian level of serum M-protein is nearly 3OgIL. Normal poIyclonal immunoglobulins are reduced in >90% of patients and -70% have mono-Clonal light chains in urine 11 226 1. Patients may have stable disease lor long periOds bulth e cumulative probability of progression to symptomatic myeloma or amyloidosis is 10% per year lor the first 5 years. 3% per year for the next 5 years and approximately 1% for the subsequent 10 years (1231}. Non-secretory myeloma
In approximately3% 01 plasma c elt mye1omas !hefe is absence of an M-protein on rTmXIOIixalion electrophoresis 156, 12261. Cytoplasmic M-protein is present in the reopiasnc plasma c elts in about 85% 01 these when eva luated b y immunohistochemistry. consi stent with impaired secretion ollg 1561 . In about 15% 01 these patients. no cytopl asmic Ig synthesis is detected (non-prOduc er myeloma). Acquired mutations of the Ig light chain variable genes or alteration in the light cha in constant region have been implicated in the pathogenesis of the non-secretory state 1477. 6221. In up to two-thirds of cases. however, elevated serum free light chains and/or an ab normal free light chain ratio are detectable , suggesting that manyare atreast minimally secretory 16101. The clinical features of non-secretory myeloma are similar to other plasma ce ll myelomasexcept tor a lower incide nce of renal insufficie ncy and hyperc alc emia and less depression of normal Ig (56,
20371
Ftg.10.32 Plasma cel myeloma. A PernnaIirMi¥emenl (e~ pIasmacyDna ). ~ assay pefWenal pIasmacyloma B Section of kidney shoMlg renallIbAr lanMI ~ sitionWIth casts refteclt,g renallI.Witr Sera JMes ~ reabsorpIloo (1rmu1opero ~. ~ ighI chain). ~1s lambda IighI~
characteristic s of the leuka emic pla sma cells span much of the morphologfc spectrum found in other myelomas but often. many of the plasma c ells are small with relative ly unte cytop lasm and may resemble plasmacytoid lymphocytes 1288 1. Typic ally, the immunophenotype of PCl differs from that of most other myeloma s by the lack of aberrant CD56 expression {17191. An abn orma l karyotype is more frequently found and there is a higher inc idence of unfavourable c ytoge netics
Macroscopy In plasma cell myeloma. the bone defects on gross examination are filled With a soft gelatinous. fish-flesh. haernorrhagic nssce.
Urilr~
SeN M
~- I
I
I .
•e
~
~ •
••
1 ~
Plasma cell leukaemia (peL) In PeL. the number of clonal plasma cells in the PB exceeds 2x1Q9A..or is 20% of the leukocyte differential count {56}. In addi100 to PBand 8 M, the neop lastic plasma cells may be found in extramedulla ry tissues. such as spleen and liver and in pleural effusions, ascites and ce rebrospinal fluid. pel may be present at the tsre of diagnosiS(primary PCl) or evolve as a lale feature in the course 01 plasma cell myeloma (secondary PCl) 17571. Primary Pel is found in 2-5% of cases of myeloma 1112. 583. 7571 . Compared to IgG Of IgA myeloma. a higher proportion of ~g ht chain only. IgD . or IgE myeloma present as PCl 1757. 916 1. The c ytologic
11121. Most clin ical signs of myeloma are observed in PCl. aJthough osteo ivtc lesions and bone pain are less frequent and lymphadenopathy. organomegaty and renallailure are more often present!75n PCl is an aggressive disease with short survival 1112. 583, 7571 .
.\-...!'"75 chromosomes). The rema ining tumou rs, which only infrequently have one of the five recurrent
[email protected] hyperdiploid. usually with gains in the odd numbered ch romosomes. 3, 5 , 7. 9. 11,
«48
Plasma cell neoplasms
205
Table10.06 Group
Tra n~tion
and Cyclin 0 groops in plasma oeI myelomas.
Primal)'
"""
O-Cytlin
Ploidy
F~qu&IlCy
Progno.i.
transJoc.tion
"'1
6021
CCNDJ
03
HH
3%
eeee
l1q1J
11Q1J
CCNOI
01
O.NH
16%
Go«
01
"'"
H
3"
Go«
"'" "'"
"'" "'" "'" ....
01 0 1+02
H
....
H,NH
11%
? "" ?
HH
'"
01+02
D2
D2
"'"
"'" "p16
FGFR3IIIMSET
02
NH>H
"'"
16q23
""'"
02
NH
D2
NH
4016
21lq11
",,/8
..
,.
15\
'"
1>, diploid: H.~: NH. ~. UocifIed from (2OOJ
? Go«
""
"" ""
,
ce.
Fig. 10.39 IlI1eIpIIase FISH 31'1illyses of reoJrrent abnormalities in plasma myeloma A FU$IOI1 signals for U:".1")(p16:Q32)./gHprobes-geen; MMSETIFGFRJ probes-fed. Two fusion sigIaIsinlicated by ye/kM' ~ mosl likely idefrtIlyderl"j and derl1") but txlUIlI represert two ccees oIllerj"). B Em copiesollhreedlromosomes 11 3 tly_ penjipIoId \l.fTllu. TIvee copies 01 chtol nOSOn. 5 (lSI D5S231D5S721"9f1!e11) alll cmmosome9 (CEP ~ [drded] and bs copies 01 cMlmosome 15 (CEP 15-ted). CTwo copies 01 etrom:lsome 17 and doIefi:)n 01 one copy 01 TP5J. TP53--fed, CEP 1111ll8fl. 0 Loss 01 one mpyolctrorrosome13/13Q. LSI13(CXI'lIiIining RB1}green. Dl3S319-fed. In all flu p;wleIs. 11'18 C)'tIplasm is tu ck.Ie m irmuloslair'Wlg 0I 1gobppa Of ~ ex.pressed by lhe U'noI.rplasma eels, and tie ptObe$ we mn Vysis. C»1asy 01 Or SColt \laJ'I We and Or Ra1aeI Fonseca
206
Mature B-cell neoplasms
15, 19 and 2 1 1430,431, 718,20991. Both IGH@ uanstocations and hyperdip loidy, appear to be early events in the genesis of plasma cell neoplasms, unified by associated upregulation of one of the eye/in 0 genes (0 1, 02, 03) 1199, 201, 405 , 20991. Gene expression profiling can determine the expression levels of eye/in D " 02 and 03 and identify myeloma that overexpress oncogenes dysregulated by the five recurrent IGH@ translocations. Using patterns of nensocations (T) and cycnn (C) D expression (TC groups) plasma cell myelomas can be classified into 8 groups that are based mostly on initialing ()( early pathogenic events 12001· Some or all of these groups may represent distinct disease enunes that require different therapeutic approaches I2CXlI. Anothe r molecular classification is based on unsupervised clustering of tumours by gene expression profiles 124951. This identifies seven rrolecurar groups that are similar although not identical to the TC groups, Withone at the seven molecular groups being defined by progression events that lead to increased proliferation . Monosomy or partial deletion of ctrcrosome 13 ( 13q14), which is found in nearty half of tumours by FISH, is another early event in pathogenesis, although the precise timing of these various early events is poorly understood 111t , 7181. Activating mutations of K-or NRAS are presentin about 30-40% of tumours. and are thoug ht to represent an early event in prog ression, perhap s mediating the MGUS to myeloma transition in some patients (718, 182 11. Some other recurrent genetic chan ges associat ed with di sease progression in bo th non-hype rd ip loid and hyperd iploid tumour s inc iude the following : secon dary IGH@ or IGL translocanons. deletion and/or mutation of TP53 (17p13), traosrocenons involving MYCor less often N·MYC, gains of chromosome 1Q and loss of t p , mutations of genes that result in activation of the NF-kappa B pathway, mutations of FGFR3 in tumours with 1(4:14), and inactivation of p lIr"""or RB 1145, 111, 200, 571, 880 , 1131, 1201, 2017,20991 . Epigenetic cha nges manifested by DNA memyianon also are associated with tumour proqression. Although genetic events appear to play the key role in initiation and progreso son of plasma cell myeloma. the 8M microenvironment is also important in pathogenesis and progressioo 114891.
Extracellular. matrix proteins, secrete d cytokines and growth fac tors, and/or the functional consequences of di rect interaction of the 8M stromal cells with neoplastic plasma cells are major constituents that influence the pathophysiology of myeloma 11 489/. Postulated normaJ cou nterpart Post-germinal centre long-lived plasma cells in which the immunog lobulin genes have undergone class switch and somatic hypermutatiOn.
Prognosis and pred ictive factors Plasma cell myeloma is usually incurable, with a median survival of 3-4 years. but the range varies from 10 years 18421, The Durie and Salmon (OS) staging system applies commonly avaaable clinical parameters to predict myeloma cell turTlOUr burden - low, intermedia te and high tumour cell burden 1160, 6331 (Table 10.07). There is a significant dlHerence in survival between each of three tumour mass stages; normal renal function versus renal insufficiency further defines lower versus higher risk patients in each stage 1633, 842. 18081. Additional indicators of higher risk patients include elevated serum 11-2· microglobulin (R2M), low serum albumin , elevated lactate dehydrogenase, high O reacnve protein, increased plasma cell proliferative activity , high degree of 8M replacement, plasmabl astic morphology and genetics PS9 , 160,84 1. 18081. An international stagi ng system (ISS) for plasma cell myeloma provides highly significant prognostic correlations, using acornbination of serum r..2M and albumin level to define 3 stages (8421 (Tabl e 10.08), Patients with abno rmal ities by conventional (metaphase) cytogenetics have a significantly shorter median survival than those without 1111, 4 16, 428, 787, 842, 880, 912, 1132, 1181, 2000, 20991. The most important independent negative prognostic indicato rs include: high risk ~4; 1 4) and the MAFtransJocations t( 14;16) and t(14;2O), deletion of 17p/TP53 se· qcences and increased serum B2M. A high-riSk molecular signature based on the expression 01either 70 or 17 genes provides perhaps the most robust , independent prognoslic indic ator 12001/.
F.g.10.40 5pectrakaryotypic(SKY)a'WysIsd~n1~l*smaoelrnyebna . ....C ~ spreads "lispIaycolcn. B,OQassdicalion dchOlllOlOl 'oes;A, B Hypenipklid Lm:u'Mlh 53 c:hOl 'iUSOIfIeS, n::t.d-
ing bs rearrnnged chDmDSQllleS IlYoIWlg two or fI'IOl'edtrerenl chOlllOSOllleS , trisOlnIesdchOlllOSOltleS 3, 9, u . 19 and letr'ascrT1es d c:MJmornes 15and 21. From f ISH MlaIyses (not$hDwrl), \here 1$no lGHor JGL ba lSkX:abol., tu ltYC is i'lSerIed 0l'I d'nomosome 6p23. C,O ~ bnlU WlfJ 46dlOllllSOl1eS,1lckDrlqalleast hee ~ ctrcrnosomes invoMng two orfI'ICII'e dillerenl d1n:Jrros70g1l, IgA :> 5Og/L: Urine lightchain :>12g124hr - Acvanceo, multiple lytic bone lesions - Haemoglobin 12mg1dL. Subclassification: Based on renallunclion A" serum creatinine 5 5 mg1l
"There are two calegorie$ Jar stage II: serun ~ 90% of patients with primary amyloidosis and with a combination of immunofixation and serum free light cha in ratio analysis in 99% 157. 1123 . 12251. Thelighl chain is lambda in 70% of patients 112251. Palhophyskllogy AL amyloid is composed of intact immunoglobulin light cha ins or rarely, heavy cha ins that are secreted by m0nocl onal plasma celts and then ingested. processed and discharged by macrophages into the extracellular matrix . The accumulated amyloid includes both intact light chain and fragments of the variable (V) NH2-terminus region . All tight chain V region fragmen ts are potentially amylodoqenic. and all plasma cell neoplasms that produce VAVI have AL 11225 . 1994), Macrosc opy On gross inspec tion amyloi d has a dense "porce lain-like" or waxy appearance,
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~ pIasmacybma 0( Ih8 skr1 wrlhabundard. Russel body tormabon (A B) wtidll3l prockIce ~ stanng by irmlullOhiSb:tletfislry. MonodonaIity is dem:nstraled by IlllIHadioacDve i'I situ hybridaabon ~ absence of kappa (e) and presence of Ian'bda mRNA ~ (O).
f ig. 10."
210
Mature B-cell neoplasms
Morph ology Biopsy section s of 8M vary from no pathologi c findings to extens ive replacement with amyloid, overt myel oma, or rarely. lymp hopl asmac ytic lymph oma. The most com mon findi ng is a mild inc rease in pla sma c ells that may appear norm al or exhibi l any of the changes foun d in pl asma cell myeloma 11 2251, Amyloid is p resent in many other tissues and organs. In H&E stained sectio ns, it is a p ink. amorphous. waxy-appearing substance , With a ch aracteristic cracking artifac t. Typically, it is found foc ally In thic kened blood vess el wans. on basement membranes , and in the mtersmnm 01 tissues such as tat or BM 124331. Macrop hages and foreign-body giant celts may be found around deposits Organ parenchyma may be massively replaced by amyloid (amyloidoma). Plasma
.
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'(;,,40% 01 individuals with amyloidosis but on ly 15-20% of those with a d iag nosis of nonIgM MGUS or myeloma 1718. 9121.
Parame ters that ha ve been associated wit h poor pr ognosis include elev ated serum c reatinine , hep atomegaly, major we ig ht loss, excretio n of lambda lig ht c ha ins in the urine (vs kappa light chains or no M-protein), elevated 112 mic rog lobulin levels an d a large whole bod y am yloi d load {57. 784 , 1228/. The single most frequent c ause of death is amyloid rela ted cardiac disease ( -40%) {122BI .
_ l i ght and heavy chain deposition dis8ases Definition Monoclonal light and heavy c hain deposition diseases are plasma cell or rare ly Iym phoplasmacytic neoplasms that sec rete an abnormal light or, less otten. heavy c hain or both, which deposit in tissues causing orga n dysfunc tion but do not form amy loid B-p leated sheets, b ind Congo red or con tain amyloid P-component [ 106,304, 580,934 , 1085, 1779 , 18 141. These d isorders include lig ht chain deposit ion di sease (lC DD) (304.1 776, 1779, 18 141. heavy c ha in d eposition disease (HC DD ) {106 . 934 ,1 08 51 and ligh t and heavy c hain deposition disease (LH CDD)
1304.5801
Synonym Randall d isease {18141. Epid emiolog y These are rare d iseases of adults (med ian age 56 years. range 33 -79) which occur in association with either myeloma (65% 01 cases) or MG US 1304, 1085 , 1776, 1779 1. There is no evidence of an ethnicity effect and the rnale.ternale incidence is nearly equal{304. 1085. 1779/.
Sites of lnvotvement lCDD and HCDD may involve many organs . IT'OSl <Xm'T'IOl'lIy the kiOOeys 117761. The liver. heart. nerves. blood vessels and occasionally JOints may be involved 1106, :»4,934, 1005,1779,181 4,2433I .Thereis prom inent deposition of the aberrant 19 on basement membranes, elastic and cotIagen fibres . Pulmooary involvement, eitherdiffuse or nodular. has been reported {214. 18751 Clinical feat ures Patient s present w ith symptoms 01 organ dysfun c tion as a result of di ffuse, systemi c imm unoglobul in deposits, usually manifested by nephrotic syndrome and/or ren al failure 1564 . 1776 1, Symptomatic extrarenal d eposition in lCDD is unco mmon and involves the heart (21%). liver (19%)
Progoosi. The median survival for patients with primary amyloidosis is approximately 2 years trom diagnosis 112281. Patients with amyloidosis and plasma cell mye lom a have a shorter survi va l than tho se wit h amyloidosis or myeloma alone 11225 1. Plasma ce ll neoplasms
211
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and peripheral nervous system (8%) 1304, 1462. 1776 1. HCDO of IgG3 ex IgGl .sotypes result in nypocomoiemen terea since the IgG3 and IgG 1 subclasses most read ily fix complement 19341, There is an M-prot ein in 85% of cases.
Pathophysiology
•
The M-p rotein in non-amyloid MIDD has unde rgone structural change due to deletion a! and mutational events 1304 , 580 , 1085, 17791. In LCDD the primary d efect involves mul tiple mutationS 01the Ig ligh t ch ain va ria ble reg ion wi th ka ppa lig ht c hain of V"IV typ e nota bly over represented 1304. 580, 17791. In HCDD the cntlear eve nt is de letion of the CH 1 constant doma in which ca uses failure to associate with heavy c hain b indi ng protein, resulting in p remature sec retion 1106. 934. 1085 , 17791. In HC DD the variable regi ons also contain amino ac id subs titutions that ca use an inc reased propensity for tissue dep osit ion and for bind ing blood element s 1106, 304,10851, Morphology There are prom inent tissue d epo sits of a non -amyloid , nonnbrtnarv amorphous eosinophil ic ma teria l, which d o not stain with Co ngo red. They are often see n as
refrac tile eos inophilic material in the glomerular and tubular basement membranes . bu t may also be seen in BM and other tissues. LCOD is usually diagnosed by renal biopsy using fluorescent antilight chain antibodies and electron microscopy 11 776 1. Kappa chains a re observed by immunoflourescence in the renal glomerular and tubular baseme nt mem brane. The hallmark 01the disease is the p rom inent, smoo th, ribbon-like linear per itubular deposits of monotypic irrrnunoglobulin alon g the oute r ed ge 01the tubular ba sement memb rane. These depo sits by electron mic rosco py are typically discr ete. den se pu nct ate , granular, nonfib rillary deposits, with an absence of the a-oreateo sheet structure by X-ray di ffrac tion. Althoug h in some ca ses plasma ce lls are found in the vic inity of deposits, it is more c ommon to find 19 deposition in visceral organs with few, jf any, plasma ce lls, Bone marrow p lasmacyt osis is prese nt in most cases; rarely, a Iymphoplasmacyt ic or marg inal zone lymphoma has b een repo rted 1214, 305, 23911. Immunophenotype In contrast with pr imary amyl oid o sis, which has a predominance of lam b da lig ht chain with overreoreser uaton of the
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V1IV1 variable reg ion , LCDD has a prevalence 01 kappa light chains (80%) with overepreseotatco of the VICIV variable region 13041· Irrmunohistochemistry on 8M sections may reveal an abe rrant kappa! lambda ratio 124331.
Prognosis The med ian ove rall survival lor patients with LCDD is approximately 4 years. Prognosis is correla ted with age. the presence of plasma cell myeloma and emarenat lig ht chain depos ition 11462 , 17761.
Osteosclerotic myeloma (POEMS syndrome) Definition Osteosc lerotic myeloma is a p lasma cell neoplasm c ha racterized by fib rosis and osteosclerotic chan ges in bon e trabeculae, and often with lymph node changes resem bl ing the plasma ce ll va riant of Castleman disease, This disorder is often a co mponent of a rare synd rome that inc ludes polyneu ropathy, organomega ly, endoc rinopathy, monoc lonal gammopathy. and skin c hang es (POEMS) 11483). The relations hip of thi s d isease to typical pla sma cell myeloma is not known .
Synonym Crow- Fukase synd rome. Epidemiology This is a rare disease. occurring predominantly in adu lts, and estimated to c0mprise 1- 2% of plasm a celt dvscrasas 114831. Many cases have been reported from Ja pan. Men are affec ted slightly more often than women (M.F ratio 1.41) and the median age is about 50 years F~ 10,48 lighI chain depoSlbon disease in kOIeyshowring (A) pale anorphous palttIes IIo'Iltlin gIorroenAi (nodulaf gIomenJosdetosi) and (81 ~ stain stlowing renalllMar andel1rabbJlar c\epOSlbOn ~ Il.ippa IicJ1l chain in a smooIh inearpallem.
2 12
Mature B-eeU neoplasms
15901.
Etiology An imbalance of p ro-inflammator y c ytokines is common in POEMS syndrome. Vascular endothelial growth factor (VEGF) produced by the tumour cells may be responsible for some of the symp toms of the disease 1634. 23631 . Some cases of POEMS syndrome . especially those associated with Cas tleman disease, have been reported to be associated with hl¥l'laflherpesvirus 8 (HHV8) 1175. 14831· Q inica! teensee Most patents do not present With all of the manifestations of POEMS syndrome and not all are requi red for diagnosis. The map clinical feature is a chronic pr ogressive polyneuropathy 15901. O rganamegaly is present in at least 50% of patients and enoocnocoamv and skin changes each in two-thirds 15901. In 75-85% of patients ther e is a serum M-protein that is either IgG lambda or IgA
lambda; the quantity is typic ally low (median 1.1 g/d l ) 15901. An M-p rotein is found in urine in 15 centrobtas tsmpt . Gra de 3 is further subdivi d ed accordi ng to the propor tion of
centrocytes. In gr ade 3A, centroc vtes are still present, wh ile g rade 3B follicl es are co m po sed entirely of large blastic ce lls (centroblasts or immunobl asts), If dist inct areas of g rad e 3 FL are present in a b iopsy of an ot herw ise g rad e 1-2 Fl, a separate d iagn osis of g rade 3 FL should also be made, and the approx imate am oun t of each g rade rep orted Since bot h pa ttern and c ytology vary among foll ic les, lymp h nod es mu st be adeq uately samp led . Any area of d iffuse large B-ceillymphoma (Ol BCl) in a FL shou ld be repo rted as the primary d iag nosis , with an estimate of the proportion of OlBCl and Fl, p resent. Thus , in grade 3 follicu lar lymphoma, the presence of a diffuse c omponent warrants a separate d iag nosis of d iffuse large Bcell lym phoma. In other words , it is never correct to make a di agnosis of "follic ular lymphoma, g rad e 3 (A or B) with d iffuse areas": the di agnosis is: "1. Diffuse large B-c eil lymphoma C%) 2. Fo llic ular lymphcma, g rade 3 (A 01 B) L %). To d istinguish large , co nfl uent fo llicl es or inte rfollicular invotvement from areas of DLBCL staining
Immunopheootype The tumour cells are usually Slg+ (lgM+/IgD, IgG Of rarely IgA). express B-cell associated antigens (C019, C020, C022, C079a) and are BCL2+ . BCL6+, CDlO+ , CDS- and CD43-. Some cases, especially grade 3B , may lack CO lO, but retain BCL6 expression 1248, 346, 1111. 1239, 1668, 17601. COlO ex pression is often stronger in the follicles than in interfollicutar neoplastic cells . and may be absent in the mtertoucotar component, as well as in areas of marginal zone d ifferentiation, PB and BM 1599. 8991. BCl6 is frequently downregulated in the jntertonlcutar areas . IRF4/M UM 1 is typically abse nt in FL. Rare c ases of predominantly Grade 3B, C01~ FL have been described that express IRF4/M UM 1 and lac ked BCL2 rearrange· men t; 59% were associated with OLBCL 111111, Meshwork s of FOC are present in fo llic ular areas 12508 ); thes e may be spa rser than in normal foll icl es, and may variab ly express C 0 21 and C023. so that ant ibo dies to both ant igens may be needed to de tect FOC meshwork s. BCL2 p rotein is expressed by a variable pro por tion of the neo plastic ce lls in 85-90% of cas es of g rade 1 and g rade 2 FL , but only 50% of gra de 3 FL using standard antibodies 112381. In a proportion of the cases, abse nce of BCL2 p rotein is d ue to mutations in the BCL2 ge ne that eliminate the epi tope s rec og nized by the most commonly used antibody, and BCL2 ca n be de tect ed using antibodies to other BCL2 epitopes 119731. BCL2 protein can be useful in diSlinguishi ng neoplastic from reac tive follicles, although ab sence of BCL2 protein does not exclu de the diagnosis. It is essential for the d iagnosis of "in sltil' Fl; in these cases and in partially involv ed follicles, the expression of BCl2 is etten much stronger than in more typical neoplastic follic les. BCL2 protein is FollICular lymphOma
223
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Fig.10.61 Survival Q.fVM lor pabents .... loIic:ljar ~. gr.Ided according to !he WHO cnteria {237.cj. A 0veraISIIViYaI d pabents lreatedWJlh regimens nollX:l'llaiWlg am. (pdiative Ihefapy):!here is no cllfterenc:e in ~ lor patients with!J'ilOe 1 'IS grade 2 toIicuIar lymphoma (o- SO and 51·150 centl'ObIastsl10 hpf). those Mlh!Jade 3 (>150cenIrtJblas3I1 0 ~ hada sigMicamIy worse oYefaI survival. B 0ieraI $UI"o'FvaI of patientstrealed WIlh adriamycin-alnI regmeos (ar.tIMl intoot): Ihe 3 StniYaI a.nes areidentical. irdcaIlrlg lhallhent is 110 Slnival benelk lor pabents WI1Il grade 1 and !1acIe 2 FLIrealed .... ~ 1M Ihat!he adYefse PfO!1lOSis of pde 3 Fl is elirTwWd by 8WessiYe therapy. C Faln-lree Sln'ivaI of pabenls trealed with adriaJTl)Ul: lhere isa suggestion d. plaleau in Ihe cuvelor pde 3 Fl (>150 ~10~. SUlpSlng Ih8 ~ 01 an lor some d It'lese pabeflls; in lXlIlIrasl, palierlls WIth !7ade 1 rod grade 2 Fl conlInue toexperience re6apse$.
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not useful in d istingu ishing fol licular from other types of k:lw-grade B-cell lymphoma, mos t of which also express BCL2 protein. The interpretation of BCL2 immunostainiog in germinal centre c elts req uires caution as r-ceus. primary follicles and mantle zones normally expres s this protein, Occasional cases of grade 3 follicular lymphoma are C D43 +. In ad dition 10 FOC, neop lastic follicles contain numerous other non-neoplastic cells normally found in germinal centres. incl ud ing follicular t-eens (CD3+ , CD4+ . CD57+ . PD 1+ , CXC L13+ ) and varying numbers of t asnocvtes. The pro life ration ind ex in FL generally co rrelates with histologic grade; most g rade 1-2 c ases have a proliferation frac tion 20%, altho ug h there is co nsi de rab le variation among stud ies, prob ably du e to tec hnical di fferenc es in immun ostaining 11 183, 1400 , 1668, 2358 BI. A subg roup of morp holog ica lly low -gr ad e FL with a hig h T~ bIe
10.12 Genetic aboofmalities in fdliaJlar 1ympOoma.
Cytoge netic abnormalities ~1 4:18)(Q32;q21) 80%
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224
Mature B-ceU neoplasms
proliferative index ha s been described 11183. 23588 1. which behaved more aggressively than those with a low proliferative index. and similarly to grade 3 Fl 123588 1. Thus , Ki67 staining should be considered as an adjunct to histologiC grading and its use is c linic ally jrsnned. although not formally requ ired at this time. Genetics
Antigen receptor genes Immunog lo b ulin heavy and light c hains are rea rrang ed ; variable reg ion genes show extensive and ongoing somatic hypermutation {448, 16701. As a result of these mutations in the CD R-regio ns, PCR prime r annealing may be hampered and de pend ing on the primers used. immunoglobulin-PCR may not yield monoclonal pro d ucts in a pr opo rt ion of FL cases (10 - 40%) . Mu ltip lex PCR reactions using B IOMED-2 expa nded pr imer sets d etect cl ose r to 90 % of IGH(V-D-J) g ene rearrang ements, and clonantv det ection approximates 100% when p rimers detectin g IGH(D-J) and light c hain g ene rearrang ements are inclu ded [652 1.
Cytogenetic abnormalities and oncogenes FL is genetically characterized by the translocation t( 14:18)(q32 :q2 1) and BCL2 gene rearrangements. Alternative BCL2 translocations to imm unogl o bulin ligh t chain ge nes have been re po rted . The t(1 4; 18) is pr esent in up to 90% of the gr ad e 1-2 FL 19 79, 18851but the proportion depends on the technique used 118. 93 . 1508 . 22801_ FISH see ms 10 be tre most sensitive and specific method 122801 . BCL2 rearrangements are much less freq uent in grade 3B Fl 116681 Geographic variation in the detection of
BCL2 tran slocatioos in FL between Western and Asian populations has been reported 121 51. The BCL2/IGHO rearrangemen t is found in the P8 of 25-75% 01 hea lthy donors . and also in reac tive rooes. particutarty if using sensitive nested or RT-PeR assays 11876. 1967, 21211. A rece nt study suggests tha t rather than be ing naive B-cells, these BCL2-rearranged ce lls are memory Beene 118771. Abnorma lities of 3q27 and /or BCL6 rearrangement are found in 5-15% of FL. most co mmon ly in gr ade 38 cases 11119, 16681. FL grade 3B associated with DLBCl have been reported 10have a frequency of BCL6 rearrangemen ts similar to that seen in DlBCL 1248, 249 , 1119, 16681. In addi tion to the t(14 :18) , other genetic a ltera tions are found in 90% of FL and most co mmon ly inc lude loss of to. 6q, tcq an d 17p and ga ins of chromosomes 1, 6p , 7, 8, 12q , X and 18q/dup [954, 1621, 22 39 ), The numbe r of ad dit iona l alterations inc reases with histo logi cal grade and transformation 11930}. Rare cases of FL ca rry the t(8:14) or variants tog ether with the t(14;18) [ 102, 23431. Gene expression prof ile stud ies have show n the im po rtanc e of the mic roenvironment in the pat hogenesis. evolution and prog nosis of FL 1510. 8041 . Transformation to DLBCL may totlOlN oneeragenetic pathways including inactivaticn of TP53. p 1~, and activation of MYC 1513,637, 1338,1756. 19301. Postulated oormaJ counterpart Germinal c entre B-cei L Prognos is and p redictive factors Prognosis is c losely related to the extera 01 tbe d isease at diagnosis. The International
Prognostic Index (IPI) and especially the International Prognostic Index for FL (FlIPI) are strong predictors of outcome 149. 5 1,
20481 Histologicalgrade correlates with prognosis in follicular lymphoma, with grade 1-2 cases being indolen t and not usually CU"able, except for the infrequent localized cases /40, 806. 1070 , 1335 1. The majority of published studies show a signi fic antly more aggressive clinical course for ular lymphomas cl assified as large ce ll or Grade3/40. 153. 1400. 14431; but the use of regimens containing ad riamyc in and/or rrtuximab may obviate these d ifferenc es and requires further stud y 138, 153 ,752 , 807,863 , 1102, 1860 , 2374, 23841. Many stud ies have ind ic ated /47 , 1273 , 1820, 23601 that the p resence of even very large diffuse areas in fo llicul ar lymphoma classi fied as grade 1-2 ("small cleaved" or "mixed sma ll and larg e ce ll") doesnot significantly alter the p rognosis . In most repoted studi es. cases 01g rade 3 Fl with diffuse areas >25% (no w rec ognized as areas of DLBCL) have a worse prognosis than purely follicular cases 138, 153,752.807,883. 1860.2346.23841. The presence 01 more !han 6 ctromosomal breaks and a compl ex ka ryoty pe ha s been shown to be assoc iated with a poor outcome: in addition, de l 6q~26 , de l 17p and mutations in TP53 as we ll as - 1p. + 12. +18p. - xp cooter a wor se prognosis and a shorter lime to tran sformation /1284. 22391. Rare c ases w ith both «14;18) and t(8;14) have a poor prognosis [102.23431. Recent gene expression data have suggested a role of the microenvironment, includi ng T-cells and accesso ry cells including FOG and macrophages in determining the clin ical behaviour of FL 1510. 804, 893J Currently, no spec ific markers are available other than histo logicgrade and proliferation traction that can be used in cli nica l prac tic e to predi ct
tome-
outcome or direct therapy. In 25 -35% of pa tients w ith FL, tra nsformat io n or ' p rog ression' to a hig h grade lymphoma oc c urs , usually DLBCL. bu t occasio nally resembling Burkin lymp homa Of with features intermediate between DL BCL an d Burkitt lymphoma 128A. 748. 964A. l803A 1· This occurrence is usually associated with a rapidly progressive cl inical cou rse and death from tumour thai is refract ory to treatment {88 B, 748 1. Rare pa tient s develo p acute B-ee ll lym p hobl astic leukaemia. whi c h in most cases appears to repr esent blast transformation of the orig inal B c ell tumour [5 18A. 764A. 1197A ). Transformation typically involves additional genetic abnorma lities , partic ularly MYC tranetccatrons: the combination of a BCL2 and a M YC rearrangement is associated with a partic ularly aggressive course {702A. 1266A. 2468 AI· Rec ently. the occurrence of histioc ytic/d endr itic cell sa rcomas has been described in patients with FL, in which the sarcomas shared both IGHtI and BCL2 rearrang ements With the FL. This ph enomenon may represent de-differentiation of a B cell due to loss 01PAX5 activity /675A I.
Variants Paediatric follicular lymphoma This va riant often involves cervic al lymph nodes. other periphera l lymph nodes or Waldeyer ring ; however. other extrarooat involveme nt also oc cur s, with FL of the testis well des cribed 1707 . 1337. 1754, 2132 1. Ch ild ren with FL typ ically have early-staqe d isease 1707, 1337, 1754 , 21321 Paed iatric follicular lymp homas have many features ind istinguis hab le from those seen in adults, but demonstrate an inc reased proportion that are loc a lized. lac k BCl2 protein expressio n and 1(14:18) and are grade 3 11337.21321. They also
tend to have larg e expansite follic les . Rare cases of florid tomcutar hyperplasia. particu larly in you ng ma les . may have clonal populations of CD1O+ Beene detected by flow cytometry and molecular analysis. A d iagnosis of lymphoma should not be made in the absence of morphologic features of malignancy 11 21 11- The prog nosis of paediatric patients ap pears to be good, with the majority of reported cases d isease free at the l ime 01 last follow -up 1707. 133 7, 17541. Expression of BCl2 protein in paediatric FL was associated in one report w ith hig her stage at diagnosis and a worse out com e than BCL 2 negative cases I 1337f. Prim ary intestinal follicular lymphoma The majority of cases of primary follicular lymphoma in the Gt trac t occur in the small intestine , and involvement of the d uodenum is a freque nt feature 11486. 1939. 2005 , 24721. Duodenal follic ular lymphoma is p red ominantly found in the second portion of the duodenum, p resen ting as multiple small polyps. often as an incidental findin g on endoscopy pe rformed for other reasons. The morpholOgy, immunophenotype and ge net ic feat ures are similar to those of nodal follicular 1ymphomas . Most pa tients have localized disease (Slage IE or liE). and survival appe ars to be excellent even without treatment. Other extranodal fol licu lar lymphomas Follicu lar lymphoma s c an occur in almost any extrenodel site (6971 . In many of these site s. the morphology. immunophenotype and genetic features appear to be similar to those 01 nodal FL, although da ta are spa rse. Despite this, patients usually have localized ex tra nodal d isease, and systemic relap ses are uncommon . Testicula r follicu lar lymphomas are reported with inc rease d freq uency in ch ildren but also are reported in ad ults 11191.
F"'II. lD.69 PalKMtric follicular lymphoma. A Follicles of varying size and shape. many WJlh preserved mantle zones. extending beyond 1tle ~ rooe capsuie. ~ of centroblasts (Grade 3). C The folliCleS are negative Jar Bell.
Follicular lymphoma
225
.. '."'"~'
l
A large nodules 01 lymphoid eels are present in lhe rru::tl5a The lolIides are I.IiformIy posItIveb BCL.2 (8) a'ldposiIiye lor C010 (e).
Intrafollicular neoplasiann
situ- follicular
lymphoma Cases occur in whiCh architecturally normal-appearing lymph nodes and other ~ tissues haveone or more follicles that demonstrate BCL2-overexpressing centrocytes and cennootasts. with or without a monomorphic cytologic ap-
pearance suggestive of follicular 1ymphoma 14621. Some of these patients are found to have follicular lymphoma elsewhere, either before or simultaneously,
some develop overt Fl later, and others have remained without evidence of Fl. In patients with overt Fl elsewhere , this phenanenon likely represents colonization at pre-existing follicles by neoplastic follicle centre cells. In patients without known Fl, the significance of this phenomenon is difficult to ascertain. It may represent the tissue counterpart of circulating clonal Bcells with BCL2 rearrangement -lhal is. a clone of cells that have the translocation but not the other genetic abnormalities to
resu lt in overt progressive malignancy, Of in some cases it may represent the earliest evidence of a true follicular lymphoma that will progress 10 overt Iymphc:ma . This phenomenon cannot be recogniZed withoul BCl2 staining , The pathology report shou ld indicate that the significance of the finding is unknown, and that c linical evaluation for evidence of overt H elsewhere is suggested .
'.
•
226
Mafure
Been neoplasms
Primary cutaneous follicle centre lymphoma
DefiMion Prinary cutaneous follicle centre lymphoma (PCFCL) is a tl.rnour of neoplastic follicle centre cells, including centrocvtes and variable numbers of cemrootasts. w ith a follicular, follicular and d iffuse or d iffuse gro.vth pattern, thai generally pr esen ts on the headOf trunk 124071. Lymphoma s with a diffuse growth pattern and a monotonous proliferation of centrobasts and immunoblasts are. irrespective of site , cl assified
as primary cutaneousdiffuse large B-cell Ijmphoma (PCLBCL). leg type 124071
ro.ocode The provisional COde proposed lor the fourth edhon oi ICD-Q is 959713. Synonym Peucuotnsnocvtoma or me dorsum Ic rostrs disease) 12061.
_ohlgy Prinary cutaneous follicle centre lymphoma is the most common type of pri mary c uta-
neous B-cell lymphoma, acc ounting for approximately60% 01 all cases, It mainly atJects adultswith a median age of onset of 51 years and a male:fema le ratio of approximately 1,5:111993, 2502).
Siles of involvement Primary cutaneous follicle cent re lymphoma characteristically presen t with solitary or localized skin lesion s o n th e sc alp , the forehead or on the trunk. Approximately 5% present with skin lesions on the teg s. and 15% with muttltocat skin lesions (1170. 1993. 25021 Clinical features The clinical presentation consists of firm erythematous to violaceous plaq ues, nodlAesa nmocrsof variable size. Particu larly on thetrunk. tumours may be surrounded by erythematous papules and slightly infiltrated . sometimes figu rate plaq ues. which may precede the de velo pment of 1I.m:lurous lesions by mon ths o r yea rs 1200, 1933. 2409/. In the past PCFCL with such a typical p resenta tion 00 the ba ck 'Nel"e referred to as "reticulohistiOCytoma
R, Willemze SH . Swerdlo w N.L. Harris B. Vergier
of the dorSlfll" or "Crosus tymphcrna" 1200/. The skin surface is smoot h and ulceration is rarely ob served . Presentation with multifoca l skin lesions is observed in a small minority of patients, but is not associated with a more unfavourab le prognosis 1824. 1993/· II left untreated, the skin lesions graduaUy incr ease in size over years, but d issem ination to extrecutereoue sites is lXiCOIlil 0 I (-10% of patients) 11993, 25021. Recur rences tend to be proximate to the initial site of cutaneous presentation
Fig. 10.72 PrYnary eutaneolIs lctide t'efWe~. Characlerisbc clinical presentabon with bcailed $lli1 lesionson !he scalp.
Mo6 months) increase in the number 01 per ipheral b lood (PB) large granular lymphocytes (LGl), usually between 2-20x 1()8i\... without a clearly iden tified cause.
ICD-O cod e
as lymphocyte reconstitution occurs 1732A, 14 14AI . Clona l populations of T-l Gl are also otten seen in association with low grade Bccell malignancies, inclu ding hairy cell leukaemia and chronic lym phocytic leukaemia. These are usually stabl e and d o not p rogress to clinically signilicant disease. They appear to represent a type of host respon se 182, 14031.
9831/3
Sites of invotvement Ep;demiology T·l GL leukaemia rep resents 2-3% of cases of mature lymphocytic leukaemias. There is an approxima tely equal ma le:lemale ratio with no clearly de fined age peak . The disease is rare «3%) before 25 years and the majority of cases (73%) occur in the 45-75 years ag e group _
Etiology The und erlying palho p hysiologic mechanisms for T-LGL leukaemi a are not well und erstood. This disorder is fairly unique in that the cl onal T-LGL cells retain many phenotypi c and functi ona l pr op ertie s of normal cytotoxic effector r-ceus 12201, One theory po stulates that T-LGL leukaemia arises in a selt ing of sustained immune stimulation. The frequent assoc iation of T-LGL leukaem ia with autoimmune disord ers sup ports this hypothesis 1220, 2428 1. Absenc e of homeostat ic apo plos is is also a feature of the T-LGL , as these cel ls exp ress high levels of FAS and FASL , lead ing investiga tors to pr opose ac tivation of pr o-survival pa thway s in T-LGL whic h p revent s FAS signaling [648, 1954 1. FASL levels are ele vated in sera of many patien ts, which may be impo rtant in the pathogenesis of neutropen ia 113231. Clonal expa nsions of T-LGl can be observed following allogeneic bo ne ma rrow (BM ) transplantation, usually reflec ting a restricted t-een reper toire. However, rare cases of T-l Gl leukaemia have also been observed as a torm 01 post-transplant Iymphoproliferative disorder 1103, 15731. A pitfall in diagnosis is the frequent d evelopmen t of oligoclonal T-cell populations following anooeneic BM transplantation 272
Mature T- and NK-cell neoplasms
T-lGl leukaemia involves the PB, BM, liver and spleen. lymphadenopathy is very rare . Clinical features Most cases have an indolent clinical cou rse 1390, 563, 1247, 16831. Severe neu tropenia with or withou t anaemia is frequent while thrombocytopenia is not; lymphoc ytosis is usu ally between 2-20x 1Q91l. Severe anaemia due to red cell aplasia has be en repo rted in assoc iation with T-l Glleukaemia 112471. Mod erate splenomegaly is the main physical finding, Rheumatoid arthritis, the presence
D. Catovskv
" "_
The predominant lymphocytes in PB and 8M films are lGL with moderate to abundant cytoplasm and fine or coarse azcrophi lic granules 1278, 390, 14411. The granules In the LGL often exhibit a characteristic ultras tructu ral ap pearance described as parallel tubul ar arrays 11441 1 an d contain a number of proteins that p laya role in cytolysis such as pertorin and granzyme B. There is no agreement on the level of lymphocytosis required tCJ" dia gnosis of T-LGL leukaemia 119921, but a l Gl count of >2x 1Q91l is frequently associated with a clon al proliferation. However, cases with l Gl lower than 2x10"n.
F"IQ.tt.G4 The various na phologic 'IlWla"IIs of LGl. in !he perVoeraI bk:lod (Wriltlfs slain).
-• . f.. l1,D5 Bone marrow lindn;Js in H.Gl.Ieukaerria. A ~ceIs ridlr.rte mrslibaly. as dernalstTaIed by 5lai1b TlA1. B,C ReadiYe ~ iJW'e9iItes.l~ lDUesin... bone marrow irnrIuIostainec wrth iII'l..cD2O (S) Md ri-C03 ie). !k:eIs in ltle nodule /If1I8O'Ined wrth C03 poS/lro'e T<eIs lNl predominate iIllhe~.
but which mee t all other appropriate crtene. are consistent with this dia gnosis. Despite the cvtopenlas. the 8M is norrrocellular or twoocenurar in about 50% of cases; in the remainder, the 8 M is typically slightly hypercellular 1152 1, 1662} . The granulocytic ser ies often show left s meo matu ration and mild to moderate -etccnn fibrosis is present 13901. The extent 01 8 M invo lvem ent is va riable and LGL usually comprise less than 50% of j-e cellula r e leme nts w ith inte rstitial/intrasinusoi da l infiltra tes which are d ifficu lt toidentify by mo rpho logic review 11 52 1). Non-neoplasl ic nod ular lymphoid agg regates containing many surrounded bya rim of CD4 + T-cells are also freq uently present 11662 1. Sp lenic invo lvement is characterize d b y inf iltration and exp ansco of the red pulp cords and sinuso ids by T-LGL with spari ng of the often hyperplastic white p ulp 116631.
express C08, the remainde r are C04/ COB-negative 11303. 1926, 19921. Abnormally d iminished or lost expression 01 COS and/or C07 is common in T·lGl leukaemia 11348, 15201_Co57 an d C0 16 are expressed in over 80% of the cases 11247 , 1520 1. Expression of the C0941 NKG2 and KIA families of NK-assoc iated MHC-class I recepto rs can be d etec ted in 50% or more of T-lGlleukaemias. KIA positive cas es usua lly sho w uniform expression of a sing le rsotorm and thi s finding can serve as a surroga te indicator of cronanty 11 348, 15201, The r-t.e t, express the cytotoxic effecto r proteins TIA 1, gr anzyme Band g ranzym e M. Bone marrow co re b iop sy immunohistoch emi stry using ant ibodies to th ese antig en s a nd COB can be used for c onfirmation of the diagnosis by revea ling the mainly interstitial o r intrasinusoida l T-l G l infiltrates 11519, 1521,16621.
Cytochemistry The granules are aci d phosphatase and ~ ~idase positive. However, enzyme cytochemic al stains are rarely used for rc:utine diagnosis.
Genetic s Antigen receptor genes Cases classified as T-lGlleukaemia are, as a rule, clonal. as documented by TCR gene rearrangement studies 11247f. The TRG@gene is rearrang ed in all cases regardless of the type of receptors expressed. The TRG@gene is rearranged in cas es expressing the TCfbP receptor, but the TRB@ gene may be in ge rmhne connquranon in cases expressing the TCR')'l5 receptor 123361.
a-ceus
~ RGL leukaemia is typically a disorder of mature CD3, COB and t-een receptor (TeA) o il-positive cytotoxic t-eens 1390. 16831. Uncommon va riants include C04 TCfbIl-positive cases and TCfTr,S-positive cases; approximately 60% 01 the ratter
Cytogenetic abnormalities Thefe is no unique karyotypic abnormality, but nume ric and structural chromosomal abnormalities have been described in a small number of cases 112471 _ Postu late d normal counterpart COB-positive t-een subset for the common type and a subset and T lymphocytes lor the rare typ e expressing the
'" TCA Prog nosis and predi ctive factor s The tvmobopronterauon is typ ically indolent and non- prog ressive and some investig ators feel that it is bett er regarded as a c lonal d isord er of uncerta in sig nificance rather than a leukaemia. Morbid ity is associated with the c ytopenias especially neutropenia, but mortality due to this cause is uncommon. In a series of 68 pat ients, median survival was about 13 years 15631 . Rare cas es with an agg ressive course have been described 1773, 22491. Patients who require treatment may benefit from cvcrosponne A, cyclophosphamide and corticosteroids, low dose methotrexate or pen lostalin 11247,
16641.
t-een large granular lymphocytic leukaemia
273
Chronic Iymphoproliferative disorders of NK cells
N Villamor W G . Moric e W C . Chan K. Fouc ar
Defin ition Chronic Iymphoprolileralive disorders of NK cells are rare and heterogeneous. They are characterize d by a per sistent (> 6 months) inc rease in peri pheral blood (PS) NK cells (usually ~2x 109/l ) w ithout a clearly identi fied ca use. It is d ifficult 10 d istinguish between reacti ve and neoplastic conditions. without hig hly specialized tecnoques. Chronic NK-ceU Iymphoproliterative disorder (ClP().NK) represents a proliferat ion of NK cells associated with a chronic c linic al course , and is co nsidered a provisiona l entity.
ICD-O code
9831 13
Synonyms Ch ronic NK-cell lymphocytosis , chronic NK-Iarge g ranular lymphocyte (LGL) tyroobopronterauve disorder. Nk -ceuuneaoe granular lymphocyte prolifera tive disord er, Nk-ceu LGL lymp hoc ytos is. indolen t larg e g ran ular NK-eeil lympho prol iferative dis orde r. Ep;dem;ology CLPO-NK occurs predominantly in adu lts with a median ag e of 60 yea rs without sex p redominance 11248, 1304. 1799 1. Unlike Epstein-Barr vi rus (EBV)-associated agg ressiv e Nc-ceu leukaem ia . there is no rac ial or ge netic pred isposition .
Etiology A transient increase in circul ating NK cells may be encountered in many conditions such as autoimmune d isorders Of viral infections 11248, 17991. NK-eell activation d ue to an unknow n stimulus, presumably v iral, is postulated to pla ya role in the early pathogenesis of chronic IymphoproIilerative d isorders of NK cells by selecting NK-eell clones, althoug h no evidence of direct NK-eell infection has bee n observed 113)4 .1340.1799.24831 , Agenetic susceptibility may be linked to haplotypes containing higher numbers of activating kille r immunoglobulin-like rec ep tor (KfR) genes (649, 1982, 2482),
274
Mature T- and NK-eeHneoplasms
Fig. 11.06 ChroniC tymphoproIifetative disorders of NKcells. Penpheral blood ftlms show the lymphocy1e 'Mth coarse azlJfOPhilic granulation(A), ~mphocyle withnumerous ftne granuiations (8), lymphocyte withscarce granlriaoon ;,,\IlI limit of~isi bility (e). 0 Intrasinusoidal marrow infiltrationby granzyme B positive cells, Note the bland nuclearcytology of the antigen ~ti l'El cees.
Sites of involvement Predominantly PB and bone marrow- (BM) . Cl inic al features The majority of patients are asymptomatic , but som e may present with systemi c sym p toms and/or cytopenia(s) (mai nly neutropenia and anaemia ). Lymphadenopathy, hepa tomegaly, splenomegaly and cutaneous lesions are infrequent 11304. 1661, 1799 /. Chronic Iymphoproli le rative disorders of NK cells may occur in associanoo with other med ical conditions such as solid and haemato log ic tumours, vasc ulitis, splen ec tomy, neuropat hy and autoimmune d isorde rs 11304, 166 1, 1695, 1799 1.
-
The ci rculating NK cells are typically intermeot ate in size with round nuclei with con d ensed ch romatin and moderate amounts of slig htly basop hilic cytoplasm co ntaining fine or coarse azurop hilic gr anules. The BM biop sy is ch arac terized
by intrasinusoid al and interstitial infiltration by ce lls with small. minimally irreg~ nuclei and modest amounts of pale cytoplasm , These infiltrates are difficult to de tect w ithou t the aid of imm unohistoc hemistry. Immunophenotype Surface C03 is negative. while cytoplasmic C03t: is often positive. CD16 is positive , while weak C056 expression is frequently observed 11304, 1519 , 1520. 1695. 236 11, Cytotoxic markers including TIA 1, gra nzyme B and granzyme M are positive , There may be d iminished or lost expression of C02, C07 and C057; also seen are aber rant cce xpression of CDS and abnormal uniform expression of CDS 11517. 15201, Expression of the KIA family of NK-eell receptors (NKA) is aboorrrl80% of all leukocytes); anaemia. neut ropen ia and throm bocytopenia are c ommon , Serum lact ate de hydrogenase leve l is ofte n marked ly elevated Hepatospl enomegaly is commo n, sometimes acco mpa nied by lymphadenopathy, but skin lesions are uncommon. The d isease may be complicated by coagulopathy, haem ophagocytic syndrome or multiorgan failure {386 , 1004 . 1223 , 1515 , 1639 ,2052, 2128/. Rare cases may evolve from extra nodal NKIT-ceillymphoma or c hronic Iymphoproli lerative d isorders 01 NK cell s 1911 ,1628,1661 , 2049 1. While it has been sug geste d that ag gressive NK-ceil leukaemia may merely repr esent the leukaemic manifest ation of extranodar NKIT-cell lym phoma , the following fea tures are d istin ctive for the former: younger median age by more than a decade ; high frequency of hepatos plenic and 8M involveme nt; low freq uenc y of c utaneou s involvement : di sseminated
dis ease with uniformly fatal outcome irrespective of treatme nt; and freq uent ex· pression of CD 16 11582, 2128 1. Morpholog y Ci rcula t ing leukaemic cel ls can show a range of appearances from cells indistinguishable tram normal large granu lar lymphocytes to cel ls with atypical nuclei featuring enlargement, irregular fold ings. open c hromatin or distinct nucleoli. There is an ample amount of pale or lighlly besophilic c yto plasm con taining fine (X co arse azu rophilic granules , The 8M show s mass ive, focal or subtle infiltratioo by the neoplastic cells and there can be intermi ng led react ive tuenocvtes wilh nae rroonac ocvtoeis. In tissue sections the leukaemic c ells show d iffuse or pat chy destruct ive infiltrates. They often appear monotonou s, with round or irregular nuclei, c ondensed c hromatin and small nucleoli , but the y can sometimes show sig nificant nucl ear pieororphem There are freq uentty ad mixed apoptobc
More than 90% of cases harbour EBV, wh ich occ urs in a c lonal epi soma l form
1386.903. 11261.
A Ft.l1.oaAgpssMI NK<el IetAaema. A Giemsa-stained I'I\¥TOW asprate. The neoplasllccels show pleolnoqnc ~ b*l ru:IIi. prorrinenI ru:illoli lWId cytopla:stric 3lIftlPhIc granJes in ltle basoIt*~ , Bl~ IIlde. The neopIastJc eels appear mOlloD lOUS. and poss.e$$ l'OI.I'ld nudei. There are many inl~
--
bodies Necrosis is co mmon, and there
mayormay not be ang ioinvasion .
IrrmLllOphenotype The neoplastic ce lls are CD2 +, surf ace C03-. COOt: +, CD56+ and positive for ~ molecules. Thus . the irrmunopheoo-type is identical to that of exnenodet
cvto-
neg ative 1381. 1659 ). The neoplastic cells express FAS ligand . and high levels of FAS ligand ca n be found in the serum of affect ed pat ient s 11117, 1369. 2 156 1.
Genetics
NKIT-ceil lymphoma, except that C0 16 is
j-ceu receptor ( TeR) genes are in germline configuration . Clonalily therefore has to be esta bl ished by other methods, such as
frequently positive (75%) 121281. CD 11 b may be expressed. while CDS7 is usually
cytogenetic stu dies and patt ern 01X c hromosome inaclivation in female pa tients.
A variety of clonal cytog enetic abnormalities have been reported , such as d el{6){q 2 1q25) and 11q deletion 119021. An array -based com pa rative genomic hybr idizat io n study has shown signi ficant d ifferenc es in genetic ch anges between aggressive Nx -cenre ukaemta and extranodal NK/T-celilymphoma: 7p-, 17p. and 1q ... are frequent in the for mer but not the latter, while 6q- is comnon in the tatter but rare in the former 115671. Postulated normal counterpart NK ce lls. Prognosis and predict ive factors Most cases pur sue a fulminant cli nical course frequently complicated by mult iorgan failure . coag ulopathy and haemophagcx;ytic syndrome . The median survival is less than 2 months 1381, 1902,2052, 2 1281. Response to chemotherapy is usually poor, and relap se is almost lhe rule in patients ach ieving remission with or withou t BM transp lantation 12 128 1.
, , , j
s
,. Agg ressive NK-ceil leukaemia
277
EBV-positive T-cell Iymphoproliferative disorders of childhood
L. Ouintanilla-Martmez H. Kimura E.S. Jaffe
Two maiO' types of Epstein-Barr (EBV)-
extensive lymphadenopathy. and careytoc enta has been described in Japan {11 49. 1150. 21271. These patients have higher viral copy numbers in peripheral blood (PB) , and inste ad of or natura l killer (NK )-cells are EBVinfected. These cases frequen tly manifest monoclonal t -een populat io ns and prog ression to ove rt malig nant T-cell maliqnan cy is the rule. CAEBY with monoc lonal EBY+ r-eef proliferati on rep resents partct the spectrum of systemic EBY+ T-cell LPD of childhood 117971. and to avoid confusion should nOI be referred as to CAEBV.
associated T-cetllymphoprolilerative disorders have been reported in the paediatric age group . Both occur wi th
IC().() code The provisional code proposed for the fou rth edi tion of ICO-Q is 972413.
increased frequency in Asians. and in
Synonyms and historica l annotation
Native Americans from Cen tral and South America and Mexico . Hydroa vaceiniformelike lymphoma is a c utaneous ma lign ancy with an indolent c linic al cou rse, but it usu-
Historica lly this p roc ess has been d escri bed und er a variety of terms inclu di ng: fulminant EBY+ t-een LPO of chil d hoo d , sporad ic fatal infec tious mononuc leosi s (FIM); fulm inant haemophag ocytic syn d rom e in c hild ren in Taiwan 121151: fatal EBV-associ ated baemopn aqocvttc syn drome in Japan 11 144 1: an d severe CAE BV {1149, 1636,21271. The term fulminant or fatal haemoph agocytic syndrome has been used to describ e a systemic d isease secondary to acute primary EBV infection affecting previously healthy children . It has been shown to be a monoclonal COB+ EBVassociated Iymphoproliferative disorder. and therefore is now considered equivalent to systemic E8V+ T-celllPD of childhood
ally progresses over time Systemic EBV+ f-cemvmoro oronterauvedisease (LPD) of childhood t ies a very fulm inant clinical cou rse. It may be associated with ch ronic ac tive EBV·intec tion (CAEBV ). and in these patients is p reced ed by a p rodromal phase 01 ootycronat or oligoclonal expansion of EBV-infected T-cells .
Systemic EBV-positive T~II IymphoprolifBrativB disease of childhood
Be ene.t-eens
Epidemiology Systemic EBV + LPO of childhood is most prevalent in Asia . primarily in Japan and Taiwan 111 44 , 1149 .2115.21271 , It has been reported in Mexico and rarely in Western countries 117971. It occurs mosl often in children and yCM.mg adults. There is no sex predilection .
t-een
l179n Definition
t-een
Systemic EBV+ LPD of childhood is a hfe-threatening illness of children and you ng adults c haract erized by a c lonal proliferation of EBV-infec ted with an activated cy toto xic ph enoty pe , It c an occur shor tly after primary ac ute EBY infec tion or in the sell ing of chronic ac tive EBV infe ction (CA EBV), It has a rap id progre ssion with mul tiple organ fa ilure , sepsis and death, usua lly from days to weeks. This entity shows some overlapping clinico pathologic features w ith ag gr essive NK-cellieukae mia.
t-eens
278
Mature T- and NK -cel l neo plasms
The term CAE8V was coined to describe an infectious monooucleosis-like syndrome persisting for at least 6 months, and associated w ith hig h liter s of antibodies to EBY-cap sid antigen (VCA.lgG) and early antigen (EA -lg G) wit hout assoc iati on to malignancy, autoimmune d iseases or immunodefic ienc y 121071. These cases are mostly seen in West ern popu lations ; pr og ression to EBV-po sitive T-ce ll LPO ha s been rep or ted rarely in suc h patients 11069, 109 4, 17971. A more severe form of CAEBY ch aracterized by high feve r, hepatospl enomegaly.
Etiology Alt hough the etiology is unknown, its association with primary EBV infection, and the racial predisposition, strongly suggests a genetic defect in the host immune response 10 EBV 11 144, 1149, 1797, 21 15, 2127) , Sites of Invo lvement It is a systemic di seas e. The mos t commonly involved sites are liver and spleen followed by lym ph nodes, bone marrow (BM) , skin and lung {1 144, 1149 , 1797 2115,21271 ·
"_.1Ii
_ G .. .
Fig. 11.12 Systen"ic EBV. T<el lPO of childhood A The liver shows a subde sinUSOIdal lymphoid infiltrate Iac:U'lg cytOlogIc atypia EIyIhrqlhaglxyts is pronWIenl. BThe rlliIlrabng Iyl'npI'locyfes are C08-positive. C Nearlyall ~ in the S1llUsoids are EBER-posb'te.
CDcaI features
Mmphoklgy
Previously healthy patients present with
The infiltrating t-eens are usually small
acute onset of fever and general malaise S:.Jggestive of an acute viral respira tory illness. Within a period of weeks to months. patients develop hepa tospleno megaly and liver failure. sometimes
and lack signif icant cytologic atypia 117971. However, cases with pleomorphic med ium-sized to large lymphoid cells, irregular nuclei and frequent mitoses have been descri bed 121271. The liver and sp leen show mild to marked sinusoidal infiltration with striking baerroobaoocvtosts. The spl enic white pulp is dep leted , The liver has prominent porta l and sinusoida l infiltration. cr orestasrs. steatosis and nec rosis, The lymph nodes usually show preserved architecture with open sinuses. A variable deg ree of sinus histiocyt osis with erythrophagocytosis is presen t, Bone marrow biops ies show histioc ytic
I
eccoroaned by lymphadenopathy. tate-
t
rat(l(Y tests show panc ytopenia, abnormal Iver uncton tests and often an abno rmal EBV serology with low or absent anti-yeA 19M antibodies. The d isease is usua lly complicated by haemophag ocyl ic syndrome, coagulopathy, mulli organ failure ant! sepsis (1 7971. Some cases occu r in patients with a we ll-d oc umented his tory cfCAEBV infection 11 069. 10941.
hyperplasia with prominent erythrophagocytosis, Immunophenotype The most typical phenotype of the neoplastic ce lls is CD2+ CD3+ CD56- and TIA 1+ Most cases secon dary to acute prima ry EBV infection are CD8+ 11113, 1797, 21151, whereas cases in the setting of seve re CAEBV are CD4+ 11069, 1094, 1797). Rare c ases show both CD4+ and CD8 + EBV·i nfected T-ce lls 117971. EBVencoded RNA (EBERl is positive, Genetic s The cells have monociooauv rearranged t-een receptor ( f eR) genes. All cases
72 bp ·
TeRr ~ 11.13
lPO fA etill:tlOOd A The spleen sIJ:Ms depIebon fA tIM! ~e!up and prorninenl inMrales. The nodules are composed predomil'Iaolly DI CQ4.poWte eels I EBER inSCU ~ shcM t'lal 1tle C04-positiye eels are also positivelor EBV RNA. SysIerNc EBV.
-ada! d products. The c umulative inc idence of ATlL is est imated to be 2 ,5% among HTLV-1 carriers in Japan 121441. Sporadic cases are described, but the affected paIients often derive from an endemic region of the wor ld. ATLL occurs only in adults and the age at onset ranges from the 20s to the 80s , with an average of 58 year s. The male to fema le ratio is 1.5; 1 12462 1_
K. Ohshima E.S, Ja ffe M . Kikuchi
Fig. 1U 7 Adull T<elIleu kaemiahymphoma. A r3lio-
lrc'Ph shcIws extensive ¥ic bone lesions.
Etiology HTLV-1 is causally linked 10 ATLL, but HTLV-1 infection alone is not sufficient to resull in neoplastic transformation of infected cells. The p40 tall: vital protein leads to tra nscri ptional ac tivation of many genes in HTLV-1 infected lymphoc ytes 1726}. In add ition. the HTLV-1 basic leuc ine zi pper fac to r (H8Z) is thought to be impo rtan t for T-cell proliferation and oncogenesis 119401. f-iowever, add itional genetic alternations acquired ove r time may result in th e dev elopment of a ma lig nanc y, HTLV-1 also ca n indi rectly cause other d iseases, suc h as HTLV-1 associate d myelopathy /tropical spas tic parap a resis {21481.
Gastroilleslinal lraC!
'-
Ulcersfu!1
T"m. ..
"" .... """""
Portal orSinus inliltfation
IJ*traIion "Mill or Wllhout fibrosls
~ dilO rden
""""""
HTlV-l-woaa1ed myelopathy (HAM) HTlV·l-1UOCill!ed lIVefbI HTlV·1-associa1ecl tyrnpnadenrtlS
-
.......
HTllJ.l..as:sociB\ed ~(HAB) HltV-l~ 8l'thnlpIthy (liMP) IfTtV·l-a&SOCia1ed ,.eptwopaltly
Sites of involvement Most ATLL patients present wit h wid espread lym ph node involvement as well as involvement of PB , The number of cirdoes not correculating neopl astic late with the degree of bone marrow (8M) involvement, sug ges ting that ci rculating cells are recru ited from other org ans suc h as the ski n. In fact , the skin is the mos t common ext ralymphatic site of involvemen t (>50%). The distribution of the d isease is usually syste mic, involving the spleen and extranodal sites including skin. lung , liver. gastrointestoatnact and central nervous system 1298 1. Epidemiologica l differences occur in patterns of presentation. For example.
cens
Mao.........,...
fC.p.11.11 MAT-5% ci rculating neoplastic cells , ATll cells are generall y small w ith a normal appearance. Patients frequently 282
Mature T- and NK-cell neoplasms
,- _
Table 11.G2 lXaglW)Slic mlefia fordiniCal subt)1les 0( Ad~ Tl an) (stage 11B~
St.iJge III
Skin ~ witherytIVtlderma. no oreerty (N1-#Q) Ifnlih node IIWCWemenl am absenl: ex IcM blood Unc:u"bun:len «100G\d CI'OJlalI'lg seza,y eels)
Stage rI
!'to;;! t:bld UTn.r tud8tt (:>1000lt1 ~ SUary oeis l ard'or eXlerlsi'o'e ~ node ifflCIwment (NJ)orvisalrallll'Mllver'nel1 (Ml ).
of sma ll to medium-sized T lymphocytes
with cereontor m nuclei . The term MF should be used only lor the class ical cases characterized by Ihe evolution of patches , plaques and tumours, or for variants showing a similar clinical course ,
lCD-Ocode
970013
Epidemiology
TOIbIe 11.06
MF is the most corrmoo type of CTCL and accounts lor almost 50% of all primary c utaneous lymphomas 1240n Most patients are adults/elderly, bullhe disease can be observed in children and ado lescents. The mare.temaie ratio is 2: 1 124071.
~
Sites of involv ement The disease is. as a rule, limited to the skin,
staging lor dinicaIyabnormaIlyn1tJ nodes (:>1 .5 an)., mycosis!lJ1goides and 5ezary s.,..,.nme
ISCLreORTC (1642)
.,
DutchIystem (195aA)
NO clusifitation {lJ4(lA}
Categ«y 1, DL, no atypical CM(;
l NO. no atypicaIlymphocy1es LN l : oa:asionaI, isolated atypK:aIlyn1JIlocyIes lN2: ~ (3-6 oe1s ) d at)'piCal ~
Categ«y 2 Dl withearly lIIVOIvemen! with sc.anered atypical cue
.3
trac ted pe riod, Extraculaneous dissemi-
Category 3: parllal effacement 01 architeclll'e withmanyCMC
nation may occur in advanced stages. mainly to lymph nodes, liver, spleen ,
Calegory 4 wnpleteeflacemen1 of architecture
with widespread distribution. lor a pro-
lung s an d blood 12407). Involvement of the bone marrow (8 M) is rare 12407J Clinical features MF has an indo lent clinica l co urse with slow p rogression ove r years o r some times dec ad es, from patc hes to more infi ltrated p laques and eve ntua lly tumours. Patie nts with tumo ur stage M F c haracteristically show a combination of patch es. plaq ues and tumou rs, which often show ulceration
lN3 iIggI'llQates ofalypicaIlyrnphocyIes, bul
""''''''''-
l~ parllal ex complete eflacemenl 01 a~ lecture with manyatypical lymphocytes
Ol, dermatopathic lymphadenopathy; CMC, cerebriform mononlJdear cells with nllClei :>7.s...m ' N2 is divided into2 categories, N2a withoot donal!)'rearranged T-eellsand N2b with donaUy rearranged T-rels.
124071. Uncommonly. pa tients present with or develop an erythrcxiem1ic stage of disease that lack the haem atolog ic criteria of Sezary syndrome !23421.ln some patients, lymph node and visceral org ans ma y become involved in the later stages of the disease.
Fig.11.41 Myoosis blgoides A Early sageW!Ih palches. B DissenWlated plaQlJe stage.
Morpholog y The histolog y of the skin lesions varies with the stage of the disease. Early patch lesions show superficial band-like or lichenoid infiltrates. ma inly consisting of lymp hoc yte s and rnstocvtes. Atypical
Fig.1u a Eany MF W11h in6Itrates of CItypiCaI.1\aIoell ~ II the basal layer of epicIem'Is
296
Mature T· and NK-cell neoplasms
lmmunophenotype • The typ ical phenotype is CD2+ . CD3+ . TCRfl+. CDS+, C04 +. Coa- I1809I. Rare c ases ma y be positive for CDa 118091. Suc h c ases have the same clinical be-haviour and p rog nosis as CD4+ cases, and should not be consi dered a separate entity {24071. ACD8+ phenotype has been re port ed more commonly in paediatric MF. A lac k of C07 is freq uent in all stages of the d isea se 118091. Other alterations in antigens may be the expression of seen , but mainly occur in the advanced (tumour) stages 118091. Cutaneous lymphocyte anti gen (CLA) associated With lymphocyte homing to the skin is expressed in most cases. Cytotoxic granuteassociated proteins are only rarely expressed in the early patch/plaque lesions, but may be positive in a fraction of the neoplastic cells in the more advanced lesions 123331_
t-een
cells with small to medium-sized, highly irdented (cerebriform) nuclei are few, and rrostty conlined to the epi de rmis wh ere tt"ey characteristically colonize the basal layer 01 the epi dermis often as haloed cells, eithersingly or in a linear distribution 11411J . In typical p laq ues , epi de rmotropism is more prono unced. The p resence of intraepi de rmal collectio ns of atypical cells (Pautner mic roabscesses) s a highly c harac te ristic featur e. but is observed in only a mino rity 01 c ases 114111. With progression to tumour stage, the dermal infiltrates become more d iffuse and epidermotrop ism may be lost. The tumour cells increase in number and size, showing variable p rop orti on s of small , medium-sized to larg e c erebriform cells , blast cells with prominent nu clei and Intermediate forms 12407f. Histologic transformation. d efined by pr esen ce of >25% large lymphoid ce lls in the d erma! infiltrates may occur. ma inly in the tumou r stages 1361. 567. 23301. These large cells may be CD30-negative or C D30-positiye. Entarged lymph nodes from patients with MF frequently show dermatop athic lymphadenopathy w ith oaracor t'car ex pansion due to the presence of large number Ii renocvtes and interdigitating cells with abundant. pale cytoplasm. The ISCL-EORTC staging system lor cunlCally abnormal lym ph nodes (> 1.S cm) in tEm Sezarysyndrome 116421integrates se previous NCI and Dutch lymph node staging systems I 1940A. 1958AI . There ow-e 3 categories . essentially reflec ting no
involvement. early involvement (With no architectural effacement). and overt involvement (with partial or complete arct»tectural effacement). Recognition of the ea rly infiltrates can be d iffic ult and can be aided by T-ce ll rec eptor analysis 11642 1. N3 lymph nodes may simulate peri pheral lymphoma. NOS Hodgkin Iym.
f-ceu
pr oma.
or
Genetics T<ell rec eptor genes are clonally rearranged in a variable proportion 01 cases , possibly depending upon the number 01 tumour cells and the detection technique employed 11765. 23981. Complex karyotypes are p resent in many patients , in par tic ular in the advanced stages 11 381 . 2 1901. A vast number of
Fig. 11.50 MF!um()IJf stage (AJ wiltl histological translotmation toa large cellymphoma (8).
Mycosis fungoides
?37
12297f. Due to the deep localization 01 the neoplastic infiltrate. the d isease is less accessible to skin-targeted therapies, The disease-specific 5-ye ar-survival is approximately 70-80%, w hic h is significanny worse than that of p atients with classical plaque stage MF 1797. 22971 .
Fig. 11.$3 Mycosis l.npdes. A FoIo.*Jtropic myoosis foogoides Wlt!l atypic:al ~ irlfiltrabng a _bide B Hole O8lebllforrn nudIi , C The alypicaleels areCOJ.potsi\i'we. 0 The irM:llYed loIde shows IIlI.ICinOuS ~lion WIlh ~ of AIc:ian bkJe-positive matel'ial.
different structural and numerical alterations have been desc ribed . Constitutive activation of STAT3 and macuvauon of CDKN2A1p ltr" ... and PTEN have been identified and may be associated with d isease progression 11583. 1951,1952, 205 1, 24241. Ge ne ex p ress ion p rofi ling studies have srown tumour necrosis tactoe (TNF) antr-acootonc pathway activ ation in the tumouri ge nesis of MF 1226 11.
in patients with skin tumours andJor extracutaneous d issemination 12298}. Age above 60 years and eleva ted lactic dehyd rog enase are othe r adverse prognostic parameters 15681. Histologic transformation wilh increase in blast cells (>25%) is also an adverse parameter 13611.
Postu lated nor mal counterpart Mature skin-homing CD 4+ t-een.
Ponloulctroplc MF Fo lliculotro pic MF is c haracte rized by the presence of follicular infi ltrates of atypical (cerebri form) CD4+ T lymphocyt es etten with spari ng of the ep ide rmis 1797f. Most c ases sho w muc inous de ge neratio n of the hair fo llic les (fol licu lar mucinosis) bu t similar c ases with out fo llicular mucinosis have bee n reported {2297}. The lesions p referentially involve the head an d neck area and often present w ith g rouped follic ular papules associated with alopecia
Prog nosis and predictive factors The sing le most important prognostic fac tor in MF is the extent of c utaneous and extracu taneous d isease as reflect ed in the clinical stage. Patients with limited d isease ge nerally have an excellent prognosis with a simi lar survival as the general population 122981. In the more advanced stag es. the prog nosis is poor, in pa rticular
298
Mature T- and NK-ceU neoplasms
Variants
Pagetoid reticulosis Pag etoid reticulosis is characterized by the presence of patches or plaques with an intraepidermal proliferation of neoplastic t-eens 1870}. The term should only be used for the localized type (WoringerKoIopp type) and not for the disseminated type (Ketron-Goodman type) as cases corresponding to the latter category woUd currently most likely be classified as aggressive epidermotropic C08-positive CTCl or cutaneous y&-positive T-cell tyrophoma 124071. The atypical cells have medium-sized or large. sometimes hyperchromatic and cerebriform nuclei, and either have a CD4+, C08- or a CD4- . CD8+ phenotype. CD30 is often expressed. In contrast to classical MF. extracutaneous dissemination or disease-related deaths have never been reported 124071Granuloma tous slack skin Granulomatous slack skin (GSS) is an extremely rare subtype of CTCl characterized by the slow developme nt of folds 01 lax skin in the major skin fol ds (axillae. groin) and histologically by a g ranuloma· tous infilt rate with clonal CD4+ T cells. abundant macrop hages and multinucleated g iant cells 123001, In approximately one third of the repo rted patients. an assoc iation w ith C HL has be en observed, An association with c lassical MF has also been reported (2300 ). Mos t patients have an indolent clinical c ourse [12611.
I
Sezary syndrome
Definition 5ezary syndrome (SS) is defined by the reo ct erythroderma. generalized tym~lhy and the presence of CIOnaJIy related neoplastic with cerebriform ru::lei (5eZ8ry cells) in skin , lymph nodes and peripheral blood (PB). In addition. nc. moreof the foiloNing criteria are reIpfed: an absolute 5ezary cell count of aeasr 10CXJcelis per mm3,an expanded CD4+ t-een population resulting in a C04ICD8 ratio 01 more than 10 and/or
t-eens
'oss ol one 01 more t-een antigens.
-
9701/3
KDOcode
ThIs is a fare disease, which accounts for less than 5% of all cutaneous t-een Iym-
E. Ralfkiaer R. Willemze SJ . Whill aker
immunoperesrs associated with loss 01 normal circulating CD4 cells 19891. MOrpho logy The histological features in 55 may be similar to those in mycosis fungoides (MF). However, the cellular inliltrates in SS are more often monotonous, and epidermotropism may sometimes be absent. In up to one third of biopsies from patients with otherwise cl assical SS the histologic picture may be non-specific 122701. Involved lymph nodes cnaractenencanv show a dense, monotonous infiltrate 01 Sezarv cells with eff acement 01 the roemal lymph node archi tectu re 119591 _Bone marrow may be involved, but the infiltrates are oft en sparse and mainly interstitial 12018}.
eeree 124071_ II occurs in adults , char-
eiensncanv presents over the age 0160.
Fig. 11.54 sez.y S)'!Doole. Geoeralzed skin eseee lIIiltlerylhrOOenna.
M-Auorescence in ssu hybridization (FISH ) and comparative genomic hybridization (CGH ) tech niq ues have shown a high rate 01 unbalanced nansiccanons and associated deletions often involving chromosomes 1p, 6q , 1Oq, 17p and 19. suggesting a high rate of genomic msrability 113821. Inactivation of TP53 and p I(J"I' 75%) of the tumour c ells (2407 1. Patient s with C-ALCL should not have cl inical evid ence Of history of myco sis fung oid es (MF ); in this selling the diagnosis should be considered trans fo rmation of MF to tumour stage. whic h may be CD30-positive or negative 124071. The d isease must also be d istinguished from systemic ALC L with cutaneous involvement, which is a separate disease wi th different cytogenetics. clinical fea tures and outcome 16131. ICD-O code
97 1813
Epidemiology C-ALCl is the second most common type 01 CTCl 11721. The median age is 60 300
Mature T- and NK-cell neoplasms
E. Ralfk iaer
R. Willemze M. Paulli M.E. Kadin
Cli nical featu res Most patients present with solitary or localized nodules or tumou rs. and soretimes pap ules , and otten show ulceration 1172,2407). Mullifoc al lesions are seen in about 20% of the patients. The skin les ions may show partial or com ptete spontaneous regression as in lyP. These lymphomas freq uently relapse in the skin . Extracu taneous disseminat ion occurs in -10% of the pat ients , and mainly involves the regional lymph nodes 1172, 2407 1. Morphology Histology shows diff use , usually noneot cermotropic infiltrates with cohesive sheets of large CD30-positive tumour cells. In most cases the tumour cells have the characteristic morphology of anaplastic celf s , showin g round, ova l or irreg ula rlyshaped nuc lei, prom inent eosinophilic nuc leoli and abundant cy to p lasm 124071Less commonly (2Q-.-.25% ), they have a non-a nap lastic (p leomorphic or immuneb lastic) appearance (172 , 17 111. Reac tive lymphoc ytes are often present at the per ip hery of the lesion s. Ulcerati ng les ions may show a l y P-like histology with an abundant inflammatory infiltrate of reactive T-cells , hlstto c vtes. eosi no phils, neutrophils and relatively few Co30-posilive cells. In suc h c ases ep iderma l hyp e rp lasia may be prom inent . The inflammatory background is espec ially p romin ent in the rare neutrophil-rich (pyogenic) vari ant 12991. Immunophenoty pe The neo pl astic cells sho w an activated C04 + t-een phenotype with variable loss ot C02, C05 and/or C03 and freq uent exp ression of cytotoxic p roteins (granzyme B . TlA1 , pe rtonn ) {255 , 1204 . 24071 _ Some cases «5%) have a CD8 + phenotype_C03J is by defll'\ilionexpressed
t-oea
FIg.11.5a C-ALCl with conAuent sheets 01 large cell with anaplas tic ~.
by a majority (>7 5%) of the neoplastic cells 12407 1_Unlike systemic ALCl, most C-AlCl exp ress the c utaneous lymphocy te antigen (CLA ), but d o not express EMA or AlK (anaplast ic lymphoma kinase) (5 16 , 537 , 21821. Unl ike Hodgkin ano Reed-Sternberg cells. staining for CD15 is g ene rally negative, Coexp ression of C056 is observed in fare c ases, but does not appear 10 be assoc iated with a~ unfavoura ble prognosis (15811. Genetic s Most cases show c lonal rearrangement ci the t-een rec eptor (feR) genes 124071 However. TCR p roteins are often not expresse d 12381. Stud ies usi ng comparative genomic hyb ridi zation have revea led c hromosomal imbalances with gains of several puteee oncogenes 113831. However, specmc and consistent cytogenetic abnormalities have as yet not been identified. Unlike svstere AlCl, C-AlCl does not carry transccetions involving the ALK gene at chromosome 21537. 613 . 2182 1.
Postulated I'lQI"mal couterpart Transformed/activated skin-homing T IyrnphJcyte. Prognosis and predictive factors The prognosis is usually favou rable, with a l(}.year disease-related survival of approximately 90% 1'72, 13221. Patients :resenting with mounocarskin lesions and patents with involvement of regional tyrrch nodes have a similar prognosis to patients with only skin lesions 11721. No dlfl!fence in clinical oresentanon. clinical oehaviour or prognosis is found between cases with an anaplastic morphology and cases WIth a non-anaplastic (pletllTl()(phic CJ i'Tvnunoblastic) morphology 1172. 1322.17111.
Lymphomatoid papulosis Defr'lilion
l'lfTlPhomatoid papulo5is (LyP) is a ctvcoc. recurrent, self-healing skin disease comPlSEld 01 largeatypical anaplastic. irTTnJnoblaslic or Hodgkin-like cells in a marked lIf4arrmatory background. In some cases Ole pattern of cu taneous involvement may resemble MF (type B).
(;[}{) cod.
97 18/1
Epidomdogy lyP most often occurs in adults (med ian
age, 45 years). but children may also be affected. The male 10 female ratio is 2-3: 1 1172, 1322, 1996, 2303). Sites of involvement lyP isa skin-limited disease that most freq'Jently affects trunk and extremities 11721. Rarely, oral muc osal lesions may te present. tln ical leatures
lyP is characterized by the presence of papular. papulonecrotic and/or nodular skin lesions at di fferent stages of oeveropment[1721 . Individual skin lesions disappear within3-12 weeks, and may leave tlehind superficial scars. The duration of fie disease may vary Irom several months klrrore than 40 years. In up to 20% of pa\Ief'I1S. lyP may be preceded by. associaled with. or followed by another type of malignantlyrnphoma, generally MF, cutaIIlnJS anaplastic large ce ll lymphoma or ttxigkin lymphoma 1172,10791 .
Fig. 11.59 lYfl'lhomaDd papIbas, l p A..lDlSISling d atypicaIlyrnphoid eels adrriJced \MGl many nftarrmaDyeels (A). The alypical eels havea cerebriIorm or Hodglc.n-like ~y (B) and are strongty posrtiye forC030(el ·
-ogy
The histologic picture oflyP is extremely variable. and in part cor relates with the age of the biopsied skin lesion. Three histologic subtypes ollyP (types A, B and C) have been described, which represent a spectrum with overlapping features 1172. 2407j, In l yP type A lesions. scattered or small clusters of large, sometimes multinucleated or Reed-Sternberg-like. CD3Q. positive cells are intermingled with numerous inflammatory ce lls, such as histrocvtes. smal l lymphocy tes. neutrophi ls and/or eosinophile. LyP. typ e C lesions demonstrate a monotonou s popul ation or large clus ters of larg e CD30- posi tive T-c ells with relatively few admixed inflammatory c ells. l yP. typ e B is uncommon « 10%) and is c haracterized by an eprdermotropic infiltrate of small atypical cells with ce rebriform nuclei similar to that observed in MF.
Genetics Clonally rearranged T-een receptor genes have been detected in approximately 60% of lyP lesions 110791. Identical rearrangements have been demonstrated in LyP lesions and associated lymphomas 110791. No consistent abnormalities have been described The (2;5)(p 23;q35) translocation is not detected in l yP 1613. 614).
Postulated normal c ou1erpart Activated skin-homing T lymphocyte, Prognosis and predi ctive factors LyP has an exc ellent prognosis, In a study 01 11BlyP patients, only 2 patients (2%) died of systemic disease after a median follow-up duration of 77 months 11721, However, since risk factors for the deve lopment of a systemic lymphoma are unknown, long-term follow-up is advised.
lmmunophenotype The large atyp ic al cells in the l yP type A and type C lesions have the same phenotype as the tumou r cells in C-AlCL The atypical cells with ce rebriform nuclei in the l yP. type B lesions have a CD3+. CD4+ . COB· phenotype and do not express CD30 124071. Rare cases of LyP with COB and NK-cell phenotype have been reported 1709. 13661. Primary cutaneous CDJO.-posillVe T-eelllymphoproliferative disorders
301
Primary cutaneous peripheral T-cell lymphomas, rare subtypes
P. Gaulard E. Berti A Willemze E.S. Jaffe
Perip he ral T-cell lymp hom as (PTeLl not uncommon ly involve the skin, either as primary or secon dary manifestation of the disease. Within this group, three rare provisional entities were delineated in the
WHo-EORle classification lor cutaneous lymphomas. inc lud ing primary cutaneous -,fJ t-een lymphoma , primary cutaneous aggressive epidermotropic COO-positive cytotoxic r-ceu lymphoma and primary cutaneous CD4-positive smalVmediuffisized p1OOlTlOfphic t-een lymphoma The tarter two entnies are sntt c on sidered provtsicoar. It should be emphasized that a diagnosis of mycosis lungoides (MF) must be ruled out by complete c linical ex-
arrmanon and an accurate clinical history.
Primary cutaneous gammadelta T-calllymphoma
Fig. 11.60 Primary ~s -yI) T-c:el IympIloma. l esions are dinicaIy diYefse. alld consist 01 plaques. with or.... out lkeration (A,B), ortulTOUrs (C). The lesion may consisl 01 an indlrclled plaque. with subl::ul<wleous i'IMtrcIIicn(DI.
Definition Primary cutaneous rt'i t-een lymphoma (PCGD-Tel) is a lymphoma composed of a clonal proliferation of mature, activated yS T-eells with a cytoto xic phenot ype . This group includes c ases p reviousl y know n as subc utaneous panniculitis-like t-een lymphoma (SPTCl) with a y() ph enotyp e. A possibly related co ndition may pres ent primarily in mucosal sites. Whether cutaneou s and mucosal y(i TCl are all part of a single disease, i.e. m uco-cutaneous yO TCl , is not yet clear 11 040 , 24321. ICD-O code The provisional code p roposed for the fourth edition of ICD-O is 9726/3 Epidemiology PCGD-TCL are rare, representing approximately 1% of all cutaneous T-cell lymp homas 12254. 2407 , 24081. Most cases occur in adults. Thereis no sex predilection.
Fig. 11 .61 Primarycetaoecos -yI) epidermis is neaotic.
T~ llymphoma .
The
Impaired immune function associated with chro nic antig en stimulation may predispose to the developm ent of PCGD -TCL
[81,24321 .
Etiology
Sites of involve ment PCGD-TCl often p resent with generalized skin lesions. p referentially affecting the extremities 12254, 24081.
The d istribution of d isea se reflects the localization of normal ylJ t-eens. which are believed 10 p laya role in hos t mucosal and ep ithelial immune responses 12291.
C linical features The clinical presentation 01 patients with PCGD-TCl is variable. The disease may
302
Mature T- and NK-eell neoplasms
Fig. 11 .62 Primary cnaoeccs yO T-cell lymphoma In ltlis case the iI1filtrate is primarily dermal.
be predominantly eotoermotrootc and present with oatcnesroraques. Some patients may present with deep dermal a subcutaneous tumours. with or without epidermal necrosis and ulceration lS1 207, 1068,2254,2408,24321. The leeces are most often p resent on the extremes. but other sites may be affected as wei 11410.2254.24081. Dissemination tOrTlr cosar and other extranccar sites is frequently ob served, but involvement d lymph nodes, spleen or BM is uncorrm:n. A haemophagocytic syndrome may 0CCl1
Postulated normal counterpart Functionally matu re and act ivated cytotoxic yO T-cells of the innate ITrru'le system. Prognosis and predic tive factors
PCGD-TCl are resistant to mulliagent cll emotherapy and/or radiation and have a poor prognosis with a median survival of app roximately 15 months 12254, 2408]. Patients with subcutaneous tat involvement tend to have a more unfavourable prognosis as c ompared with patients with epidermal or dermal disease only 122541.
Primary cutaneous CD8-positive agg ressive epidermotropic cytotoxic T~1I1ymphoma
Fig. 11.63 Pnmary cutaneous yO TCD8, arltigen loss frequent (C07, C05, CD4IC08. CD52). C03(h1+. C056-/+,COlD-, CLCX1J.. POI-
~fTII1unob1a stic lymphoma
CD4+ or mi ~ed CD4I8. C010+/-, BCl6+1•. CXCl13+.P01+, hyperplasia 01 EBV+ C020+8 blasts
AdlAI T-cea IeukaemiaJlymphoma
CD4+, C02So , C07·, C03O-l+, COl5-l+, FQxP3+/.
Anaplasticlarge eel lymphoma
C030+. ALK+/·. EUA+. CO25+-. cytOtoxic glilnules+, CD4+/-, C03-l+. CD43+
acre..
roc.
I.¥ga C020+ bIasls m background of Coo+reactive T- type, early stage d isea se, parti al lymph node involvement, lac k of enlarged follic· ctar dendritic celt meshworks and lack cJ prominent high endothelial veocies distngu ish it from typical angioimrnunoblasllC T-eelllymphoma. Recently. a 1(5;9) Iranslocation has been reported in a subset cJ cases with these featu res 121121. Other terms have been used for this variant, n. cluding per ifollicu lar. intrafollicular, paracortical nodular and expanded mantle zone 11002, 13581.
T-zone The T-zone vari ant is characterized by a pe rifollic ular growth patte rn throughout the lymph node 11894 , 23591. The ne0p lastic cells are p redominantly small wlll1 minimal cytological aty pi a, and the process ma y be mista ken for benign pa rac orttca t hyperp lasia. The cells express CD3 , CD4, and may show loss 01 CD5 or CD7, Some studi es have sug· ges te d that this variant may be associated with a more indo lent cou rse than other PTCL, NOS 11894, 2359 1. but data are limite d. Many PTCL can show focal residu al tomcures: this histologic al feature alone does not constitute evidence for the 'l-eone va riant.
Angioimmunoblastic T-cell lymphoma
A. Dog an P. Gaulard E.S. Jaffe E. Halfkiae r H .K, MuJler,Hermel ink
Definition Angloimmunoblastic t-een lymphoma (AITL) is a penpheral t -een lymphoma
Characterized by systemic d isease. a poIyrnorphouS inlil trate involving lymph nodes. with a prom inent pr oliferat ion of high endothelial venules and follicular deool'llic cells.
970513 ~ and historical annotation
AITl was previously tett to be an atypical reactive process . angioimrnunoblastic ~aclenopathy, with an inc reased risk fA progression to lymphoma . Cu rrently. tHerNhelming ev idence sug g ests that A1TL rises de novo as a peripheral t -een
""""""'" 15971. -kllogy "Ill occurs in the middle-aged and elderly, with an eq ual incidenc e in ma les and females 15971. It is one of the mo re com--
man soecmc subtypes of peripheral t-een ~,
acc ou nting lor approximat e ly
15- 20% of cases, or 1- 2% of a ll nonHodgkin lymphomas 11896).
a
E!K>kJgy The nearly constant association with EpsteinBarrvirus (EBV) has suggested a possible role for the virus in the etiology, possibly through antigen-d rive (6231. fbwever, the neoplast ic T cell s are EBV
regative.
Ft 11.74
-
Fig. 11.73 Angioimu'IobIasT-demJology Classical HL accounts for 95% of all Hodgkin lymphomas. with a bimodal age curve in resource-rich countries , showing a peak at 15-35 years of age and a second
CHl
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NlPHl. nodular IympilocyIe predominant Hodgkin lymphoma: TCRBCl, T~kid11arge 6-ee11 lymphoma:CHl, classical Hodgkin lymphoma: DlBCl, (li1l1JSe large B<eIlIymp!loma;ALCl, aflaplaslic large T-oeII lymphoma,
+an cases are posihve. +1· majOrity of cases positive, -1+ minoOty creases positive. - allcases arenegative, S strong elpression. ' Positive in rare cases, • PnJrninenI e~ III anaplaslic variant and variable expression in mediastmallargefk:8II subtype. s0lxaSl0I'IaI cases may show local positMIy. • Present in up1040% 01 ee cases but usuaIy expressed 01\ a rninonIyofturnourceis WIlh variable 111eoso1y, ~ Up 10 10'li.lT1lI1lt be negab...e ' The COfTVTJJIl posiIMlyb IgG and boIhIg IighI chalf1s reIIects upta ke oflhese proIeins by !he hJrnoIJ"ceIs rather ItIan S)flthe$i$ ' Slmng e.q)rMSion bJnd in - 10'J1, of tIWI cases. ' Rarecases (- 10'Ji,) may shaw scatIered 'lW8iI/I posIbvily. , any II minOrIty is negative II; W8ak e.qnssion may be seen in VnOur eels in 51. 01 !he cases. " Most ~ seen in DL.BCl wiII'I anapIask IfIOIllI'Dogy
peak in late hfe. Persons with a history d infectious mononucleosis have a higher inc idence of CHL 115351. Both familia l and geographical cl ustering have been desc ribed 115351. Etiology EBV has been postulated to p laya rote in the pathogenesis of C HL EBV is found in only a proportion of cases, pa rticula rly in MCCHl and lDCHL, but a sea rch for other viruses has been unsuccessful, loss of immune surveillance in mmu-cd efic iency states such as HIV infection m ay pr edispos e to the d ev elop ment 01 EBV-associated CHL. In tropical reg ions, up to 100% of CHl cases are EBV-positi~e !64 A, 1277A , 2369 , 2370 1. It is possible that EBV infection of a B cell replaces one of the gen eti c alterat ions ne cessary lor the d ev elopment of CHL. Sites of invo lvement Classical Hodg kin lym phom a most often involves lymph no d es of the cerv ical regio n (75% of c as es) followed b y the mediastinal, axillary and paraaotc regictls Non-axia l lym p h nod e groups such as mesenteric o r epitrochlear lym ph nodes are rarely involved Primary extranooet involvemen t is rar e . More than 60% ci patient s have localize d d isea se (stage I and II). Approx im ately 60% of patients. Ihe m ajority of them with NSCHl, have mediastinal involvement. Sp len ic involvem ent is not uncommon (20 % ) and IS associated with an inc reased risk 01 extranodal d issemination. Bone marrow (8M) involvement is much less corrmon (5'\)
~
.
_~·r.
12.09 Classical Hodgkfl ~ A Mononuclear Hodgkrl eels (awws) and a rnbu:I8ated Reed-S1etlWg eel (lW1CI'tI!lead) areseee in a c:etiiIr ~ and tor\IaIIWIg hiStiocyIe$ and some eosirophis. B Onerrumified Hodgkil OlIIlamJw) rod w VItal Hodgkn eels can be seen.
As !tie 8M lacks lymphatics. 8M infiltration ooc ates vascular dissemination of the disease (stage IV). The anatomic distei:Moo varies among the histological sub~s of HL
120091.
Clir¥caI features Patients usually present with pe ripheral ~thy, localized to 1 or 2 lymph ~e-bearing
areas. Med iastinal involve-
ment is most freq ue ntly seen in the nodular sclerosis subtype, while abdominal and splenic involvement are more common in mxedcell ularity. B symptoms co nsistin g c tever. drenc hing night sweats, and signkant body weight loss are present in up1040% of patients.
Macroscopy Lymph nod es are enla rged , encapsulated
and on cut section show a fish flesh tumour, In NSCH L there is p rom inent l'JOdularily, d ense f ibroti c bands and a thickened ca ps ule. Splenic invo lvement usually shows scatte red nodules within tile wt1i te pulp . Sometimes ve ry larg e Masses are seen, these can demonstrate
fibrous bands in the nodular sclerosis subtype. Classical HL in the thymus can be associated with cystic degeneration and epithelial hyperplasia 113131. Aare cases can be confined to the thymus.
-logy The lymph node architecture is eHaced by variable numbers of HRS cells admixed with a rich in"arrvnalory background. Classical diagnostic Reed-Sternberg (AS) cells are large. have abundant slightly basophilic cytoplasm and have at least two nuclear lobes or nuclei . The nuclei are large and often rounded in contour with a prom inent, often irregular nuclear membrane, pale c hromatin and usua lly one prom inent eosinophilic nucleolus , w ith perinucle ar clearing (halo), resemb ling a viral inclusion. Diagnostic AS ce lls must have at least two nuc leoli in two sep arate nuc lear lobes. Mononucl ear variants are termed Hodgkin ce lls. Some HA S cells may have conde nsed cyto plasm and pyknotic red dish nuclei. These variants are known as mummifie d cells. Many of the neop lastic cel ls are no t proto typic HRS cells. The lacunar
~
rid! n
AS variant is characteristic 01 nodular sclerosisHL. The reccasrc cells typically represent only a minority of the cellular infiltrate With a frequency ranging from 0.1- 10%. The c0mposition of the reactive cellular infiltrate varies according to the histok:lgical subtype. Involvement of secondary sites (8M and liver) is based on the identification of atypical mononuclear (CD3J-pos;live Hodgkin cells with or without CD15 expression in the appropriate inflam matory bac kground ); thus diag nostic multinuclear AS cells are not required in a patient with classical HL diagnosed at anothe r site 11 8 19AI. Irrvnunophenotype H AS cells are positive for CD30 in nea rly a ll cases 11 97BA, 2088, 209 1/, and for CD 15 1987, 209 1, 2092] in the ma jor ity (75-85%) of cas es and are usually neg ative fo r CD 45 and co nsistently negative fo r J c hain, CD 75 and macroph age spec ific ma rkers suc h as the PG-M 1-epi lop e of the COB8 molec ule 1427. 662A ) (Table 12.02). Both CD3Q and C01 5 are typ ic ally present in a mem brane pattern with
Classical Hodgkin lymphoma. introductlOl1
327
accentuation in me GoIgi area 011he cytoplasm; C0 15may be expressed by only a minority 01 the neoplastic cells and may be restricted only 10 the Golg i area. In 30- 40% of cases. C020 may be detectable but is usually of varied intensity and usually present only on a minonty of the neoplastic cells 11964. 25071 . The 8 -cell-associated antigen C079a is less often expressed. The B-cell nature of HAS cells is further demonstrable in approximately 95% of cases by their expression of the s-een specific activ ator protein PAX5!BSAP 17231 - The immunostaining of HRS cells for PAX5 is usually weaker than thai of reactive B cells . a feature that makes the PAX5-positive HAS cells easily identifiable. The plasma cell specific transcription factor IAF4/MUM1 is consrstenny positive in HAS cells, usually at high intensity, In one study, BLiMP1, the key regulator of plasma ce ll differentiatio n, was expressed in on ly a small proportion of HRS cells in 25% of CHl 12941 . The plasma -cell -assoc iated adhesion molecule CD 138 is consistently absent 12941, EBV-infected HRS ce lls exp ress lMP1 and EBNA-1 without EBNA-2, a patt ern characteri stic of latency typ e II EBV
328
HodgkIn lymphoma
infection 15521. EBV-encoded LMPl pos sesses strong transforming and annapootonc potential. Expression (usually weak membranous or sometimes globular cytoplasmic) 01 one or more t-een antigens by a minority of HRS cells may be encountered in some cases 1504 /. This is, however. often difficult to assess because of the T cells that usually surround the HRS cells . Most of the T-cell antigen-po sitive classical HL cases have IG gene rearrangement in the HAS cells instead of t-een receptor gene rearrangement. so that the expression of t-een antigens is either aberra nt or artfactual \19871. Expression of epithelial memb rane antigen (EMA) is rare and usually weak if present. A further characteristic finding is the absen ce of the transcription factor OCT-2 in - 90% of cases and absen ce of its coactivator BOB,1 in the same frequency. Cases in which both OCT-2 and BOB.l are ccexpressed are rare 113281, The transcr iption factor PU,1 is consis tently absent from HRS ce lls 11328, 2250A). Most HRS cells express the proliferation-associated nuclear antigen Ki67 1775Cl. CHl cases rich in neoplastic cells may
resemble anaplastic large cell lymphoma (ALCL), a T-cell neoplasm. Their identJlication as classical HL is facilitated by demonstrating positivity for PAX5 and absence 01 EMA and ALK protein 1723, 20871. The detection 0 1 EBV-encodea RNA (EBER) or LMPl is indicative of classical HL 1992AI_The most difficult dillerenter diagnosis is with large B-cel lymphoma displaying anaplastic morphology and expressing CD3O. There may be a true biologic overlap between such cases and CHL (See Chapter 10). Cytokines and chemokines CHL is associated with overexpresson and an abnormal pattern of cytokines and chemokines and/or their receptors in HAS cells 1919, 962A. 1080, 1081, 11 08. 2293). which likely explain the abundant admixture of inflammatory cells P067, 21861. fibrosis 110801. and the predominance at Th2 ce lls in the infiltrating t-een population 122931. Genetics Antigen receptor genes HRS cel ls contain clonal immunoglobulin (IG) gene rearrangeme nts in more than
98% of cases. and clonal r-ceu receptor gene rearrangements in rare cases 11105, 1388.1553. 1987,20861 The clonal rearrangements are usually detectable only in the DNA of isolated single HRS cells. and not in wh ole tissue DNA. The rearranged IG genes of the tumour cells harbour a high load of somatic hypereuatcos in the vanaore region of the fG teavy chain genes (IGHVtI), usually wuhC'JI signs of ongoing mu ta tions. These tr1dings. in conjunction wi th the study of CO"TllQSIte lymphomas c on sisting of etasseal Hl and loIli cular non -Hodgkin lym:tuna . support the view that HAS cells of B-cel lineage are derived from a germinal cenlre BceU 1261A. 1387AI.
AL:notmaI gens expression Oespte their derivation from germinal centre B cells. HAS c ells have lost much j eeB-eett speci fic expression program and have acquired B-cell inappropriate gene produc ts [636A . 1205A . 1388A. 14 1M. 1977A. 2090 . 1047AI. ln addition . oeregulated transcription fac tors in CH L P"OITIOte pro nteranon and abrogate apopese in the neoplas tic cells. The nanscnoton fac tor NF"B is constitutively activated in HRS cells. and there is el\ered activity of the NFKB targ et genes. which regulate proliferation and survival 1938A. 9388 . 962Al. the AP-1 complex 11416A. 1416B) and the Janus kina se/SIgnal transducers and activators 01 transcrption (JAK/STAD signaling pathway 12030Aj. Mutati ons of the JA K reg ulator SOC- l are assoc iated with nuclear STAT5 accumulation in HRS cells . indicati ng a bockage of the neg ativ e feed bac k loo p cHheJAK!STAT5 pathw ay 11 070A, 1459A .
fig. 12.13 0assicaI HodgkIn ~ A EBV infected HRSceIs suongIy eapress!tle EBv~ 1alenI~ proIein 1fLMP1). B EBV4lf8ded HRS cells consistently ihow a 5trr6lg e~ of EBER il \llei' ~ as revealed by l'lOIHadio rescence in situ hybridization (FISH) stud ies show aneuploidy and hypertetraploidy. consistent w ith the multinucleation 01 the neoplastic cells; however. these techniques fail to demonstrate recurrent and specific chromosomal changes in classical HL 11935,19601 . Comparalivegenomic hybridisation, however, reveals recu rrent gains of the chromosomal sub-regions on ch romosomal arms zp. so. and 12q and d istinct hig h-level amplifications on ch romosomal bands 4p1 6 . 4q23-q 24 and 9p23-p24 11071]. Thetranslocalions t(14;t 8) an d t(2;5 ) are abse nt from HRS cells 1831. 12441 but 1(14; 18) may occur in CHL arisi ng in follicular lymp hom a 11561AI. In a recent study using interphase cytogenetics breakpoints in the IGH@ loc us were
cesesttaatzq. Postulated normal counterpart In more than 98% of CH L. the neoplastic c ells are derived from mature B cells at the germinal c entre stage of differentiation { 1105. 13881. In rare cases. they are derived from peripheral (post-thymic ) T cells 1514.1553. 1987 1. Prognosis and predicti ve factors Modern rad iation and chemotherapy have made CH L curable in more than 85% of cases 1462A. 571AI · Staging determ ines the mode of therapy. and both clinical and laboratory pa rameters are relevant to prognosis 19041. The response after two courses of ABVD as seen on FOG -PET imaging is an important prognostic ind ica tor 1748A] Histo log ic subtype is less important as a p redictive fact or 125. 10761.
23881 Epstein-Barr virus infection -he prevalence of EBV in HRS ce lls var ies according to the his tological subtype and epidemiologic factors . The highest fre~iJency {.75 %) is found in MCCH L. and ee cwest incidenc e ( 10-40%) in NSCH L 1992AI. In resou rce-poor reg ions and in pa:ients infec ted with the human immune delIClency virus. EBV infection is more p-evaIenl approaching 100% 164A, 1277A, 2369.23701. The type of EBV strain also enes among geographical areas. In resarce-rich cou ntries strain 1 p revails , i'ld in resourc e-poor countries strain 2. ~ 0081 infection by both strains is more c:onmn in resource-poor countries 1280. 00.23701.
100 BEACOPP
80 COPP.ABVD
60 t - ---y-- ' < - - --
-
-
-
-
- - - -f I QQQ Q3)
onlyalkylating • (IQiS)
40 20
o
no treatment (1940)
o
1
2
3
4
5 years
Fig. 12.1 4 HoclgIoo tymp/loma. Progress oflhe natrnent of advarad Slages since 1940.
ClassiCal HodgkIn lymphoma. in troduction
329
Nodular sclerosis classical Hodgkin lymphoma
H . Stein A. von Wasiele wski S. Pop pema KA Mac l ennan
M. Guenova
Definition Nodular sclerosis classical Hod gkin lymphoma (NSCHL) is a subtype of CHL Characterized by collagen bands that surround at least one nodu le, and HOdgkin and Reed-Sternberg (HRS) cells with lacunar type morphology
ICD-Ocode
966313
Epidemkllogy NSCHL accounts for apprOl(imately 70% of CHL in EuroPe and USA ; rcwever. the rate varies greatty among other geographiCal reg ions: II is more common in resource-rich than in resccrce-occe areas . and the risk is highest amon g those with high socioeconomic status 14451. The incidence of NSCH L is similar in males an d females and peaks at ages 15-34 years 11 01 . 1525A I.
r'lJ. 12.15 Nol1JIa' sdetosis dassicaI Hodgkll ~ ACTscan shcM$ a Ia'ge90%) of PTLO in solid organ rec ip ients are of host origin and only a minori ty of donor origin . Donor origin PTLO appear to be most common in liver and lung allograft rec ipients. and frequently involve the allograft 178, 378 , 1255,2069, 23801. In contrast, the majority of PTLO in BM allograft reci pients are of donor origin, as would be expected. since successful engraftment results in an imm une system that is nearly exclusively of donor origin
t-een
t-een
125101.
Sites of involvement Involvement of lymph node, gastrointestinal tract. lungs and liver are common in all
Post-transplantlymphoproliterallve d soroers
343
allog raft types, whereas ce ntral nervous system (eNS) invo lvement is rare 1699, 1569, 1723, 23671. The e NS may be the only sile 01d isease or may be associa ted with multiorgan involvement 13431. In solid organ recipients, PTLO frequently involves the allograft and this may cause diagnostic con fusion since rejection and infection may result in a similar clinical picture. Allog raft involvement appears more common in earty-onset. EBV-positive disease 1133. 7911· The heart is the only organ in which allograft involvement is very rare. "Early lesions ' often present with tonsil and/Of adenoid involvement but may also occur at other sites. Overt BM involvement by polymorphiC aOO monomorphic PTLO is not comoon. and PB is rarely involved . Bone marrow auograft recipients tend to present with widespread disease involving nodal and extranccat sttes. including liver, spleen. ga strointestinal tract and lungs 11723. 1998. 2510 1.
Fig. 13.12 Intecbws rrDU'lUdeosis-ie(lM)Iesionfla D"ISiI ofan 11--year-"'~1'W "" 1fl
• :
" A
Fig. 14.20 Fojlicular dendriticcej l sarcoma This&lectron miCrograph shoo.Ys nOOlel'OUS cytoplasmic processes. do one weI-formed desmosome presenl lnee Cflfltre as well (3841, Less common morphologic features include: epi thelioid tumour cells with hyaline C')1OpIasn, clear cells. oncocytic cells. myxoid stroma, fluid-filled cystic spaces, prominent fib rov asc ular septa and admixed oeteoctastc giant cells 1384, 385, 1724 , 17251. In rare cases, the large neo plastic ce lls are scattered singly in a bac kg round of small lymphocytes, mimic king Hodg kin lymphoma. Rare cases may also show jig saw puzzle-like lob ulation and perivascu lar spac es , mimi c kin g thymoma or ca rcinoma show ing thymu slike element (CASTLE) 14341. The inllammatory pseudo-tumour-like variant of follicular dendritic ce ll sarcomas occurs exclusively as primary tumours in the liver or spleen 171. 409, 19911. The reoplastic spindled cells are dispersed within a prom inent lym phoplasma cyt ic infiltrate. Theruclei usually show vesicular chrornallO patten and disflnct nucleoli. Nuclear atypia is hig hly var iable: usually many cells are bland-looking. but sere cells with enlarged. irreg ularly-fo lded or hyperchromatic nuc lei are always found. Some tumour ce lls may even resembl e Reed -Sternberg c ells 1199 11. Necrosis and haemorrhage are often present. The b loo d ves sels frequently show fibr inoid deposits in the walls .
364
Ultrastructure The neoplastic cells have elongated nuclei . often with cytoplasmic invaginations. If-ere are characteristically numerous long, slender cytoplasmic proc esses , often con nected by scattered , mature desmosomes. Birbeck g ranules an d numerous Iysosome s are no t seen. Immuno phenoty pe Follic ular dendritic cell sarcoma is positive lor o ne o r mor e of the follic ular dendritic marke rs, suc h as C02 1, C D35, C023, KiM4p and CNA .42 1159 11. Clus terin is almost always strongly positive, while this marker is usually neg ativ e or only weakly positive in other dendritic cell tumours lB53. 8541. In addition, thel1.mour is usually positive for desmoplakin, vimenbn, tascn, epidermal growth factor rec e ptor and HLA -OR 1384, 21221. It is variably positive for epithelial membrane antige n, S l00 protein and C068. Exce ptionally. cytokeratin, CD 45 or C020 c an be expressed . Staining for C0 1a. lysozyme, myeloperoxid ase, C034, C03 , CD79a. C030 and HMB 45 are neg ative. Ki67 labeling range s from t to 25% (mean, 13%). The ad mixed small lymphocytes are pr edominantly B cells in some cases.
HisllOCytlC and dendritic cell neoplasms
predominantly T cells in some , and mixed Band T cells in others 1385,17451.
Genetics The immunoglobulin and
t-een receptor
genes are in a germline conligJ'ation 123751 Data on genetic changes are c urrently very limited 119271, Postulated normal cou nterpa rt Fo llic ular dend ritic cell of th e lymphoid follic le . Prog nosis and predictive factors The behaviour is usually indolent. much like a low or intermediate-grade soft tissue sarcoma 13851. Most patients are neater by complete surgical excision . with Of without adjuvant radiotherapy or therapy. Local recurrences occur in rTli7l! than 50% of cases, and metastases OCCU' in about 25% of pa tients: SLJCh occurrences may be delayed after many years 1384 1725 , 2054 , 23131. At least 10-20% 01 patient s ultimately d ie of the d isease. often after a long period of time Cases showing high -g rade features (significant cvtoccc atypia. ex tensive coa gulative necrosis and a high oroseranve inde x), large turro.I size (greater than 6 em) or intraabdooll'lal location can pursue a rap id ly fatal course 1365.17451 .
crerc-
Other rare dendritic cell tumours
L.M . Weiss J.K.C , Chan C.D.M. Fletche r
There are rare types of dend ritic cell tumour other than the better-delineated entities covered in the previous chapters. These may be derived either from myeloid-derived dendritic cells, such as ooetermmate dendritic cell tumour ; or from stroma-oenveo dendritic cells, such as fibroblastic retic ular cell tumour. Some dendritic c ell tumours may rema in unclessifiabledesp ite extensive work-up or show hybrid features, and such cases may be tentatively designated "dendritic cell tumur, not otherwise specified".
the alleged precursor cells of Langerhans cells . These neoplasms are extraordinarily rare 144, 203, 236. 391. 11n, 1859. 1865. 2019,2315.2325,2441 .24501 . There may be an association with low-grade a-cen lymphoma 12315 1. Patients typically present with one or, more commonly, multiple generalized papules, nodules or plaques, Systemic symptoms are usually not present. The lesions are usually based in the dermis, but may extend into the subcutaneous fat. The infiltrate is diffuse, comprising cells resembling Langerhans cells, with irregular nuc lear groove s and clefts. Cytopla sm is typica lly abundant and usually eosinophilic. Multinucleated giant cells may be present. In some cases, there may be spindling of the cells, The mitotic rate varies widely from case to case . An accompan ying eosinophilic infiltrate is usually not present. By defin ition, these cells lack Bsbeck granules on ultrast ructural examination . There can be complex interdig itating cell processes. but desmosomes are lacking. The proliferating cells consistently express atco protein and COla. Langerin has been negative in one studied case . They are negative for sp ecific B- and t-een markers. CD30 , the histiocytic marker C0 163, and the follic ular dendritic cell markers C02 1, C023 and CD35, They are varia bly positive for C045 , C068, lysozyme and CD4 . The Ki67 index is highly variable. One case has been shcM'n to be clona l by human androgen receptor gene assay The dinical coese has been tvgtVy variable , ranging from spontaneous regression to rapid progression. There are no known prognostic factors. One case has been associated with the deve lopment of acute myeloid leukaemia 12325},
RbrobIastic reticular cell tumour ICQ.{)
code
The tumour is histologically similar to follicular dendritic cell sarcoma or interdigitating dendritic cell sarcoma, but lacks the irrmunophenotypic profile of these tlXT1ClU'" types. There are often interspersed delicate collagen hbres . Ultrastructu rally, the spindle cells shaw delicate cytoplasmic extensions and featu res reminiscent of myofib roblasts (filaments with occasional fusiform densities, well-developed oesmosomal attachments, rough endoplasmic reticulu m and basal lamina-like material), The tumour cells show variable immunoreactivity lor smooth muscle actin, desmin, cvtoeeratm ( in a dendritic pattern) and CD68
975913
Indetermina te dendritic ce ll tumour Fibroblastic retic ular ce ll tumour is very rare, and the entity reported as 'cytokeratinpositive interstitial reticulum ce ll tumour" probably rep resent s the same entity 144, 3001. Thistumour can occur in lymph node, spleen or soft tissue {44, 380, 822 , 10651. The clinical outcome is variable, with some patients dying 01 the disease.
ICD-Ocode
9757/3
Indeterminate dend ritic ce ll tumour, also known as indeterminate cell histiocytosis, is a neoplastic prolifera tion of spindled to ovo id cells with phenotypic features similar 10 those of norma l indeterminate cells ,
Other fare dendritic ceutcmours
365
Disseminated juvenile xanthogranuloma
Def inition Disseminated juvenile xanthogranuloma (JXG) is characterized by a proliferation of histiocytes similar to those of the dermal JXG . commonly having a loamy (xemromatous) component with Touton-type giant cells. There is evidence 1Q( clonality
in some instances.
Synonyms Deep JXG (if soft tissue involvement). Benign cephalic histiocytosis. progressive nodular histiocytosis or generalized (nonlipidemic) eruptive histiocytosis (cutaneous disorders wi th multiple JXG but withou t systemic mvotverrenn . Xanthoma disseminaturn (if skin and mucosal lesions). Erdhesn-Chester disease (possible adult form with bone and lung involvement) 12488A.238 1AI.
Epidemiolog y Solitary dermal JXG is vastly more common than other forms and does not progr ess to more d isseminated forms 1538Al. The majority 01deep, viscera l an d d isseminated forms occ ur by age 10 years, ha lf within the first yea r of life, except for the adult Erobem-Cbester form 110458 1,
Etiology There is a know n association with neurofibr oma tosis typ e 1 (NF l); pa tient s with both are at slig htly high er risk of juvenile myelomo nocytic leu kaemia (J MML) 125 1OAI. Patient s with bot h Langerhans cell d isease (LCH ) and JXG are encountered. Sites of Involvemen t Skin an d soft tissues are most common, and, in disseminated terms. mucosal surfaces es pecially upper aerocnoesuve tract . The central nervous system, dura and p ituitary stalk can be affec ted as well as eye , liver, lung , lym ph node and bo ne marrow (8 M). Retroperitoneal and pe riaortic involveme nt is noted in ErdheimChester d isease 1538A, 733A . 104581.
366
A, Jaffe C.o.M . Fletcher W. Burgdorf
Cl inical features Skin lesions other than the common papular solitary fo rm are small (1-2 mm) and multiple. Soft tissue lesions can be large. and the lesions present as mass effect. Optic lesion s can cause g laucoma , CNS and pituitary lesions, like LCH. can c ause diabetes I1sipidus, seizures, hydrocephalus and mental status changes 1538A, 733A . 104S8 1. In contrast to LCH . liver involvemen t does not target the b iliary system Of lead to sclerosing cI1oIar'Qrtls 11042A1. There is some ca pacity lor lesions to slowly regress. While JXG appears to be benign, a concomitant macrophage activation syndrome can lead to cytocentas. liver damage and death in the system ic forms . Morphology The JXG cell is small and oval , sometimes slightly spin dled with a bland round -toov al nucleus without g rooves and pink cytopl asm. Touton cells are less common at no n-derm al sites. The cells become progressively lipid ized (xanthomatous) . A mixed inflam matory component is invariable, Varia nts include epithelioid cells with g lassy cy topla sm , The ultrastruct ural feat ures a re histiocytic without otstlngu ish ing features 124BBAI. lmmunophenotype ln co mmon with macrophages, ce lls express vimentin, surface C0 14, C0 6B (PG M 1) in a co ars e gr anu lar patt ern , C01 63 in surfac e and cytoplasmic pa ttern and Staoiun- t (MS- l antige n). Fac tor Xnta stain ing is common but not unive rsal. Fascin stai ns the cell cytoplasm and 8 100 is variab ly pos itive in less than 20% of the ca ses; however, none of these ma rkers is specific lor JXG. C0 1a and Langerin are negative 1392A, 118BA, 193 1A,24B8AI . Genetics No consistent cytogenetic or molecular genetic change has been identified. B and 't-een receptor gene rearrangement are qe rtruire. An association with NFl is known in some. There is evidence for clonality in some instances 11045AI.
HIShoc yhC and oenontc cell neoplasms
Fig.14.24 A Radiograph ofa case of Erdheim-ehesler disease showing a lytic and sclerotic lesion in the ~ femur and theproximal tibia, There is destrudioo ti the antttrior femoralcortex, with an impactedpatllolo:9c fracture through the lesion and an aote~ateral s.oII--tissue mass extending from the destroyed femur (arrow) Reprinted from {187lA}. Courtesy of Or SuS¥! ~ ram, B Abdomioal CT from a patient with ErcIlet1IChester disease showmg a soft tissue infflm! SUrroundll'lll lhe aortaand kidoeys (wtVte arrows), is a sclerotic lesion in the veteea (blaet. arrow), Reprinted from {1479A}. Courtesy 01 Dr. RGdbE!l1O Gl:JI.
n-
mo..
Fig. tUS Systeri: JXG inYoMng Mr. A The nfiltrate is portal in natJSe but spares ee bi& duct. FewToulon cells n p-esenl. 8 Faco Xilla There is d1ltuse stailing of the portal hJStJocy1eS.
Postulated normal counterpart The celt of origin is debated , In spite of macrophage prerotvoe. it has been sa id 10 be a defmaVinterstitial dendritic cell on eebasis of shared Factor Xllla and tascn immunostaining. but these have limi ted specificity 11 188A1.
Prognosis and predictive factors All clinical forms are benign. though multiple lesions in brain , dura. or pituitary c an cause local consequences and even death. Systemic teems tha t involve liver and 8 M have been treated with lCH-type therapy
Dtsserranated juvenile xanthogranuloma
367
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288 Bru!Yll-nll RD, McKema RW 119941 PlliIImll eel dji!lUMllOS afK! rl!l3led ~ In Alia ol TIIIllOI' PaIhabg, Nmed fl)l'OIlI Inlllllule ~ ~, eQ, WIlShIl'lglOl'l, DC..
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Epslein--8arr "'ill S gene llClI~ III I\II.Il T~KoOIIIlyrT\I)'IofNs and normlIl rIMlIl - . - : ~ (lit wus.... II InllIiqnn:y Int J Cancer 80: J56.:l64 ~1&. Chiea:IIo:J l PtoIlerue Rlt IbraM AM, C/llu'lg KL Roo:klud< C ~ GP e.t-as EO Pan.er T Nighlo'lgalt ... ~"-~KH,IWTiIatlCJ Crou He MIlf9In GJ. Rost fM ~l DIlIlionof
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d .... _13dM1dedby~t'JI) g.noliQ •• tnIICIIlJ't9'IOiliC !Icb' .. myebmaI.aAemla2ll161G-1617. 417. CNUIsu "I. KalIN H Suzulo:aod 1. $II A ~ T Ouooa H y
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"...." 411 ow- k."
'* R 2OO ... no~I"llII\'lII'Y~SqI ~ Br J 0ermeI0I "" 735-1,w 420. CMOII M DogIIor'j C MIg, hni A, "'l1W(II'I'II G, Kramperl M, ~ G, RIIheI D, Plldron S ElenedeI!j A, Scardor' M MIen E, l eslitl, M. Mentsrlt1a F, f'iuolo G, ~'P' A
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e.preUion III fIOIl-Hlldgloraltw Groop 0'ilI!View 0143 randomlzlll trials. J On Qnc:oj 21. 1798-1809 447. Ctm8z A Tlllma"" I,l l~defs H. !I'aml M. f'M-..~ R. Schellong G Oorllel
lBrge Bf .kn:lI G. ~isdI T 8ordon A De Week D. f •....n S (2OCl!l1 nW II ' " HIV Coro1 SI.dy- ~. _ 0'PmII'Il:l0ekierq, S'OlOlorlg. IRl ~ . . . _ _ waI ~ J NalI '11 425-'32 U1A. Caba/teoIa C 8uIIlongw Y 12008
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...
489. ~ B, La suna R, Nomii C 001 S Macle\.ca C, Rood S RgICO L GarIto P Boil A Mwtllli IE tdaryneo P. t.Iecua:I C 12(01) Poloi9uIIar t'f\ll9'.'l'I!Itf'O.
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(2003). ZAp·70 e.~ e M.il ~S8lt$ GtnIfII ~ Nfl J Suog PalNlI23 ,356~
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493.
W 8IsI M. Vosot JI,l M'nGge JO JM SmIlIolG Ea, KYlJIoy S Ide H F..... RLMIIlII'TP, ~ E. WisI:on WI1 B¥JI" lJlIO H Vq l PfIWII J Somorl R cr.. StaucllW (20C!61 .IIIc1lIcIU' _
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t.Ied 1 _ 314 131351• . DI~Itee CIIikl'll/l *'11I '~1CiDrI B-aIIl aau ~ .....,.,t..ft,a i'OI-I'IodgUll~ 8f J HIImlIkll125 41.1-4 15 m ell Wolle T 00Il! ~ mil! II T· QlI ~ lWkr;rrua wrth CAMPA m· 11-11lkxx1911.112I· \/26. 537. DeCoIIIlltl Jf Butmart JR l(inrwJ y Me l:SNnJ
_1flIl~"_
s..gPIIlOI V
531. (2000
51J-!lS3 0Inng!r lIN ~.... Iliem 101
The lIlOlIcut¥ tIooIogy 01 C/lfOllll: 1IMIlIcl...-ril 8Iood!l6 3343-3356 540. ~R.~Ht,l ~ MJ. TIIDIl: Id ueo.te KS. ffl!l'.m EJ (INn T h I ~ o I ~_ _ _ urad""" ~ d . . - ... chrOAC ~ _ ........ '-509 1739-1743 541. 011 Guhe:e I MaIll!!6 E. MorIa II, Mar... A, Owuto·A.-..omlIh K. RafIq F, A i1lIm
(1\191) A.-!iUbI',1Ia of IqlI !l-t:IlI
01 Delglldo J. IlaZertJ8SIlI Ull CIIMk~ 0 (2OOIf The dragnoIlic YlIIue QIC0123.. 8-aIlI dWI1IrI .... . . , or ...,. ~
0.:. 0 e.-.;,yO(2lll6' 19V"'gIIl8I"'" ... nl . . ., ZJi>-1O.., ro38 ~ pIOIOdI _
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. . HIM,......... IIld l~ T l~ lIP 2JO.235 ~ SH (1990\
IAflCPr.-
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PIIWIl21 699-703 551. Oef'ond W SiIIdNt T.... T 01 S Ij of T./arge 1130\11I ~ e;t... i T-eel ~1I1~ oIl,11lle1errnnad _ nofir.aooa7 Blood 84 1620-1621, 564. ~ MV Mar1irli G SoIi:no:Il A (19911, 1lloio:Igy.-.d ll'Iolrnpy aI ~ ~ - I1enwIII Oncol Cko
flow cyIQmIllrj ~aIu*ln t;J eryIhroId dysplI-
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N ............ ~5lIC5,.oomt L..o<emiI20: S49-555
561 DI Iltr.-.o G Cawdo A.. . . . "GIogtn A.. IWtobG ~ 1/119M .....,Cf*lO'C'-....:l ..... dol-. CIIIic:Il. t:eIDoglc. n ..... aI onI cae c.-. 63 \1)4.1 _ Do DonIlo C CnXI G. i.Imo ~ L Vqd II, !lull" T w.a:.; S ~ N:. 11!l16 0 WllI::** _ _. ~ d • "" . . ~ ... Ol JCloo 116: . .371 5111. ~E.~ ll
SSI.
OMoIG llSuliT
~KC.GnII
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Ua!lO" oY (1918
QI dlIIlIIIi
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PahlI1M) 241.2!tJ 553. OebaIG.l-w:L M:arwre8, PuIloRl 1(, Dasllq.le fl , 81t1ussel P, ~ F II SiiIlI T. CerTlIIt DP, t.lo:lfris ':NY, MMon OY
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HomII:lIJ51t!1·167 596. Cloeden K ~ 11 ~ E
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(2003) ~ T.CIfI ~ BrJ HeIIn'8klI121 681.aill 5ge . DogIn A BIAe JS GcMn Go SlIr.on f{tolf «I'" CXlI'\Jll'I'llI ~ s.nin lllIgn P-.ol" ~7 l3t. E........Jo7rIion 1(5 z.-.oscmo A u.- A. ~ L ~ OW RaIloIcI .. J* ES 0998) ~ g-.ur P'QIIin - - . . ~ - . . , 1)'Pe,~
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SSO , ~ L Orillo A, ViIImIboiI J. [Ul·A.gl/*Ie e:.-oC RICI5A. v...ooJl.. Co.dId J Nr4tro JL Sen "'9JII JF (19981 ~~of"""" tIone l1l/I,",* lIWIl cell A """ cyIDm8tnc
*'Y r:A llOlI'ftII ana ~ llQnrf ~ ~ AnalCtI PefO'6 151-159 651.
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Feedl8Ili F W Mason D CoIcnne I.l (2003) 1'ht plIiIrrlIc,Ud IIl(llll)cytaJ......... procM;ng 0lIl V\rctlowI Ardl
2562 IJIlIirIIIII . . 1It...ud........-.a i 9:t 666. F... B MiIcucoC T«:o E
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Y. RoIIrI R. PasoulIuc:o L La SIirZI DMm D CoIorI'CO E. SInluco A " " l Peori R Pu<x-n A. tiIo A. ~ U P, Mel.. N. Pe!InlIsl V SIgIioG, Lo-Coco F. PeIcci PG, ~ IlF C)'llJpIBami; lItJdeop/'l(lsf .. 8ClAll
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398 References
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T. . . , CP, 1/..--.1-,11112005) Oisllnd'nol primary em-ous llove &.g Ka!lOS"S ~ td hllfpel.'ftI$IOOmaIl hetpesYirus-8 Bk:lod 90'
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1186-1191
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1&4. fiomick Jl Jaffe ES, Filltd\er CO 12004\ E.ger1 &l ptflNion pafteml retlectiog qenotype r1f aculll ~I lll\Jl._ ' 6. 1233-
"50
Hso EO. Singtfflon TP &,v; nnen l, 0unpI1y CH, ~ S (2Ol'll1 Mueou ~ ttl ~ -*type lyrTV.omas 0CXlXfIIlg rl poW·b. . . . . . . Pfl*1ls Nn J Surg Pall1oI2~ liJO.lllll, !NI7. ~ Stol. JaIlI, E5 (lll6o'l tAu Ml .m jlM'lI/l *9II'ullrWl ........ '*'lJlI;IDl; 0IIil a/ Hodo;IkfI'l dIaaMI Aln J an PIltloI82 29-32
986.
!NI7A. Hu H (1967)
~POCiIJled
~ Iwo~MtdlI)l1171.172
. . tWng JZ SangII WG Grww TC 5lad LM ~ 00 Poemg Ol. lJ"dl JC. ~ .10. w.nq AA AIadIIl u.. IS. l.evy II: Cha'Iwe (2002) Tlw ~1. 18) deIlnlI$a ~ SI.ClIIl01clIlUe ~ B-<JIlI ~ ... a lIIftIWI'I ~ B-<JIlI
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...... a~oflolOS~_1I9O' IiiItd deIekIn 5Q tnd a pI!lWellma ~, and myeloid h)1lefPla· si&lmMgoank.qica 75 532·535 1008. Inw. 1d 01" , f>&I"ra MJ, Wililhe 0 , Jon&~ A, Oavin EG, IC.\etI1 NJ(2000) AbMnaI of platIoIe! CDAm. o:IerIIIlIK pabenl'l wrt!l ~. 19M synOrOll"4 CI.Jl E.,.. ImmuncM
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~ 0117 patients lIld rPvIeW o1lhe ill· erature, Mediooe jElalbrnorel 50' 139-159 1210. Ku.ssidc SJ. Fromm JR. ROO5OfN A L' y, Crli1nO A, Nt>I'WOOd TH. WC>:Jd Bl12005i FOOf· cob" I\ovI cylometry shows wong concordllnoe With bonll marrow ~~ ami cytrJg8""t· ice in the eva luattlll1 for nlyelodyspl~.ia, Am J Clio PatI1Ol 124: 170·1 81, 1211. Kuslid SJ, KaInosKi M, Brat", 1 RM, WOOO 8l(20041 Prominent donal !Hlell popII. laliornl identltiedby flow cytor»etry In hislOlo7cally I"IlildJve lymphoid proOferatJOtlS Am J Ctil
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~... 0 I'orIifIrIi G.Wwnf P, Fan:eI ... Arno:Ud L 11996) " -
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17)1. ....... T. 1.4e'fe'" CJ 0alIc S R Milynad.. Y. Mad\e( l e.-rov. 0 V~ B. T. . IdA (2004) TCL1 ....:l eLA ~ '" itgrenullr
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nauII kJIIr 0lIl !1i E Zonzano pt , PlccekJga PP, I'W1 A, Jr. GU1ti M. faMi 6. Solis Ga. StooIi (20021 1io:Id9kin'1 ~. lh~ P1~1 ..... ~ J ClI'II'aI'd 55 11;2· flti 17". Pfter, SA. GaldanoG bIzanoPl. F_ G.ullwd p. ZUox:a E PllII'I F I*ta E. SabIIn £ ~ $, Pll::ci:llIM JoI'tlton PW, Gi8niini R, Pe1carmone £ ~ D
e
F'IrX:a.'IJll!'P t.t..-"T,AklnkI"'CMIl~ (2003) """-'Y mecinW4I 8e e~.....,.. 01 PI'lf'>. . T oalI ~ lII'IspfICIIialI . . . . . . WlCt ~ and _ paIInIiIIIlw,,** •. oats J ClirIIn>tIel 111 123--8305 1740. ~pp ~C ~S Z - Pl.. ~ SA 1200'1 u;r- rJ
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~ E PUiotr:l Il ,JcrIea '" 1dltlIIt· tterrnMrIk ..:, f .,; B R.....- E P6Iri S PuztII F, Wdf-f'eeIers C MJet 0 S\IIi'l H
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lli&ua.~pliOb' ...... ~ >Ulu-
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1151. ~LE ,~JFl &..-JJ o.bomI Ilt.l. VeIllsquaz WS Iti.aqoifl P s-..F~"""'~fB.F.
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CIolO:lPi*dCyc an:I imnu'dllQlc ItUdy of &3 ~ Caro:er 67: 2311·2326 1U1, SInIul;Q Id. ~ "". ..... O. tN (20061. TCAjooil''''' ' iarge Il"lIl'JIif ~
~
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It)
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~
I( t ~ facIO! gene mRNA IUW'J'I$~ of adIA. T c..IlII/I;lWIU ceI5 Pnx f'C!Il Aca:l Sci
~ 'eapiell~
·Mltl ~ EJ)5lerl
Ba!l "t C 0angIIt A, Krober A. Kern W Ha/emd'l T (2lXl81 0Bteaim01 an LlPLW5 15 mulallC1l\ln a 1Ct~
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'* ...,
oftlllllnlure Vi'clIcMs N d> A PIhlI Anal HiIIopaIt>oi 412
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liS&-'. Sd'eIIer E, .... CJ, ~." V1o;Iten WA (1'l8O). Dermiklpatillt ~"""~Ih)' aro;l ~ oode ~ 'II my
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e-:.
AD,i1l L~ L"'. ..... (All) ..... ~ In-.I) ~ ~ WrII HIgh ~'P)' ChIld<er'-s 0nc0I0lw
eo.
~
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Sd>I.«l kR ~ OJ SaIw +fII. snu. JJ. 0avdII N. ~ Ir,lJ c.roI "-I, tWemJ NA. RJblI.l:.IE ltII'll4. R-.u EA.l'Moc):kJ
c--.
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Il"CJll'lO'k ....'" Iroon .... ~ (POGI II'Ill CIlilthn's e- Grtl4l ICCGl 6iood 1119 ".." 197U.. ~ A, ~ J ~ H. FaIN 8 P.lIn S. SMI H 11_1 BfR·H2, I . - anl-fG.l lCOJOl ~ .-body
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2710 19n A
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A, IUeon U. D.nI v. ~ "'L, DallI--F_1 R Ra;ewsly K. Ko.iPl*S A (2003) LOllI rJ III ~ ~ expttlllOl'l progo-am in filldgkin and RwclStetrCer9 cella rJ HocJ;jIo'" ~. Blood 1011505-1512 197& $ctowyz9f A. S/len'rIMn GG. C::ton RJ, ~
B. Tonguely
1,1.
POOII JE,Wilem P (1996) GranulDc:jot1c SIlO)-
rna in ~ ..-il!1 aeu1. m\'floblalbC lauI:&mia ~8:21). Meoj Pediatr Dnoli31 144·1.g 111111. SconI J. CurtIs C, Wwpom It Slakler 1,1, .Joll.,ancl 1,1, Gtancl FH, Cross "Ie 12(06) identifICAtIOn rJ a 1lO'I1!i imIllinib r~ KIF 5B-~DGFRA f-.ion 1I""'lI 1oIow0r'0g ~. 11'19 lor PD(lFRA olltrtllj>fflS1ion in pali&nts
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1980. Scott A.A. H&tel DR ,
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244-255. lMl , SooIl lJ,l Tong '1'1, Le\Wle RL, Soon MA, BeerPA, S/nlIIon MA. FutrMI PA Erber 'Mi, r.u.lA'I Mf , HamIon CN, W..- M GiIilnl 00 , lOiWl ~ Aft (2OOJl, JAK2IXOfl 12 ~ ... ~ "llI1i lJnd ~ erylhnxykIM to Eng! J Mecl
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l ......erro.a 19. 734-740 2124. SUVllfdllC N. MatlSllv1jlivic 0 Krag uljac N PanllC M, Djrdjevic 1/, Ja~~ovic G. CarTlllrik,c-ManillOvlC 1/. CoIO'I'ic M (2004) Acute penmyelosis WlIh myelo!i)rQ,;i!;: dtnical, ~typIC IIfld cytogenetIC study rJ ~C3S8S levk Lymnhom;l 45: 1873-1879 2'2 5, Suzuk.awa K, P~as E, Gajjar A, Abe T, T~S, TallIK. Asano5 Asoo It, KIITIada N. VO~(l/3 J, 1/ !I ,Yl94j 1denIilicabon of ~ bfeaIo+Klonl dIMer '''9(\11 3'of !he rtlopIlom I gene at ~1 a-2 ~ ~ 1 ilOOf P'O'1" rtOIIisllle:-d~~t,& p/>olnI h Je.ut 118 2182·21119 2141. T _ T. Luo WJ "-" IE ~ 101, IudlI I( ~ I( QOO3I E4iU ....
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s-dIootStl,V~Wllu~LR,
21C2. T Maul K
IrlMlUllflC'l' at EBY associaIion a'ld ~ __ lion'" !he lMP·l gar-.if1C056 ~al h >JWfIl" aenxJigl!$IM'I lrlIct Palhol 1m 54 \58-166 21"". TIjoNI It IiroImII Y (19911 ~ d HTlV-lIlI .. ./aI)in and l!le WOtIcl In· ~ on AdIJl 1-(AI ~ and Hnv~ ReseilIdI lGirro ~ OIl CIncef Res8¥ch1. TakilIUar'* !'tm. To/I)'O. pP 129-149 2145. TlIkiNslI E ~ K. "..... T Y~ 101. Ema T NaUmIn S i2OO5 lnn~ 19t9t' T-/IIIf CA.. A/lpebl0tId G, Ca-Wleth PA. W_i~ PH, Rowe JM 12004) "'wt a nlQrlOCytlC 1$oJi13 lA, Wibom R, Helistrom-Liodberg E (2005~, Ablrri!lt rrYIOCtlotIdrial ~oo d,sviDullOO I/lCl n'IIhI\IllI:In arrest dIaracleru:e \'J8/1)' err-
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21M. ThoIblImorII C. FIlma!I P. CItlIt· 8IuChJ E. T'_rw·Glehe!> A. SIIIes G IleIgIr F. COftIr B /2llll3). SpiInic II'lIJgII'IIo .... ~ • liIiIr>d. cb::II IIIIl peIlo1DQaI-*J I.MIoeI()ICd 4' 9S-1G3 21' 7, 1hIblIrnonI C. " - V, FIlIna'I P. ~ K, -ao S. ,*&m. E. LClIiocl B, ~ 5. GIulinl P, f9Q.IfI C. T _ CJIIlI!l A. L Betl.co F. e.orrt.mD, ~ F. MIIOWIi!III 5 ,1,- .....-, H. SIIII G. Coder B. Berger F ~ R l2OO4i· SII\IlI ~~, IftlI9lIIIl
e.wo
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422 References
III
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261-2t16 221M! n..J.K-.-..nt1M(2003lo.mc 1ItfiIlOp"""*,, diSl.lflltn ..... ~ cyIlIIriI' • ~ SIll1Y lit IlIO ~ syswns\PVSG. WHO) Ofl aJ6 pIWIl Am tWnIluI 82' 143-152 22111. ThJelI J. Kv,lSr.cu 11M (2003) ~ ~ lit -.bal blJlIbo.
'*'"
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..... dlrQric idoopi1lhic myeloIibroIiI by liIl:fMrl. ....1I1r11l'/1is of 00ne "'Wll7IfI' ltat.......... dIfI.
ocoplIthl:*:lgidIlgIind"lmcodloplhc ~. Orocxll J2 J80.~
s.rr..
2205. Thotle J. K.WId.a HM (2008) ao~ C1tetII b" difterInIIIa.,. _ rJ III _ _ fIl)'IIl> ~ ~
SetrIn TIltarrtt I1IIIIIlIl 32 21i-2Jll, 22Ol. 1lIotII J, K"4$ftd.I HM (2007) ...,....... . -W!W·s.. a 1l" " - $, ~ M F.;j Sot. I200lll Pos4-tr-. plInl II • priIInc renal PdK PttiaIr 8lo<xI Ca'lcer -47 218-:123 2161. TeGeIdlI .... Barate C, IolIrdil E ....".,. E (2007), ~_ Illood RIlV 21 1&3-200. 2167 . re!leli A (2000). Myelo/ibrOSIs .. ill'l ",ye\:)i(l rTIllliplKja. N Eogi J Mell 342: '25~
c.r--
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