HODGKIN’S AND NON-HODGKIN’S · HODGKIN’S AND NON-HODGKIN’S LYMPHOMA edited by JOHN P. LEONARD, MD ... pathology and imaging have provided a better understanding of the pathogenesis

HODGKIN’S AND NON-HODGKIN’S LYMPHOMA

edited by

JOHN P. LEONARD, MD Center for Lymphoma and Myeloma

Weill Medical College of Cornell University New York Presbyterian Hospital

New York, NY

MORTON COLEMAN, MD Center for Lymphoma and Myeloma

Weill Medical College of Cornell University New York Presbyterian Hospital

New York, NY

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John P. Leonard, MD Morton Coleman, MD Center for Lymphoma and Myeloma Center for Lymphoma and Myeloma Weill Medical College of Cornell University Weill Medical College of Cornell University The New York Presbyterian Hospital The New York Presbyterian Hospital New York, New York New York, New York

HODGKIN’S AND NON-HODGKIN’S LYMPHOMA

Library of Congress Control Number: 2005934592

ISBN-10: 0-387-29345-0 e-ISBN-10: 0-387-29346-9 ISBN-13: 978-0387-29345-5 e-ISBN-13: 978-0387-29346-2 Printed on acid-free paper.

© 2006 Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed in the United States of America.

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vi Hodgkin's and Non-Hodgkin's Lymphoma

8. Blood and Marrow Transplantation for Patients 251with Hodgkin's and Non-Hodgkin's LymphomaIan W. Flinn, MD, PhD and Jesus G. Berdeja

9. Vaccine Therapies for Non-Hodgkin's Lymphomas 283Sarah Montross, MD and John M. Timmerman, MD

10. Management of Early Stage Hodgkin's Lymphoma 317David J. Straus, MD

11. Management of Advanced Stage Hodgkin's 333LymphomaNancy L. Bartlett, MD and Avram J. Smukler, MD

12. Nodular Lymphocyte Predominant Hodgkin's 353DiseaseCarol S. Portlock, MD

13. Lymphoma Imaging: Nuclear Medicine 363Lale Kostakoglu, MD and Stanley J. Goldsmith, MD

14.Novel Small Molecules in the Treatment 413of LymphomasJohn Gerecitano, MD, PhD and Owen A. O'Connor, MD, PhD

INDEX 461

FOREWORD

The lymphomas are the most common malignancies where the toolsof the medical oncologist serve as the principal treatment modality and canfrequently result in cure of the patient. Over the past several decades, theuse of chemotherapy for lymphoma has rapidly evolved to allow forimprovements in efficacy as well as the reduction in some short and longterm toxicities. Targeted therapies, such as unlabeled and radiolabeledmonoclonal antibodies, have enhanced outcomes for patients with Band Tcell malignancies. In parallel, advances in molecular biology, pathology andimaging have provided a better understanding of the pathogenesis oflymphoma to define new therapeutic strategies and have allowed for moreaccurate determination of prognosis to better define therapy.

In this volume, we have asked a distinguished group of lymphomaresearchers to summarize the state of the art in some of the most importantaspects of the disease. The result is a current review of our knowledge of thelymphomas, standard diagnostic and therapeutic approaches, as well as ourviews on the most promising new directions. We hope that this informationprovides value to anyone working in the field, for both "lymphomanics" whofocus in these diseases and for those for whom dealing with lymphoma is aminor but important part of their activities.

We are grateful to many individual for their contributions to thiswork. Dan Muss spent many hours in formatting and editing texts, withoutwhich there would be no end result. Laura Walsh and Maureen Tobin fromSpringer very valiantly tried (unsuccessfully) to keep us on schedule. Weare grateful to them for their patience and for the opportunity to participatein this project. A book of this nature is only as good as its contributors. Weare extremely appreciative of our friends and colleagues made so manyefforts in putting together this review. Our authors have provided anoutstanding summary of current information, which clearly reflects anenormous effort particularly given all of their other ongoing projects andpriorities. As with any of our academic efforts, this project would have beenimpossible without the support of our families. They constantly accept themany diversions of time and attention toward scientific and clinical activitieswith understanding and grace. Most importantly, we appreciate thecontributions of our patients. We learn so much from them on a daily basis,as well as through their participation in research, without which there wouldbe no progress. It is our most sincere hope that in the near future we canreach a point where all lymphoma patients can be cured.

John P. Leonard, M.D.Morton Coleman, M.D.

CONTRIBUTING AUTHORS

Nancy L. Bartlett, MD, Associate Professor of Medicine, WashingtonUniversity, Siteman Cancer Center, Division of Medical Oncology,StLouis, MO

Jesus G. Berdeja, MD, Assistant Professor of Medicine, Schoolof Medicine, Lorna Linda University, Lorna Linda, CA

Ethel Cesarman, MD, PhD, Associate Professor of Pathology, Departmentof Pathology and Laboratory Medicine, Weill Medical College of CornellUniversity and The New York Presbyterian Hospital, New York, NY

Amy Chadburn, MD, Professor of Pathology and Laboratory Medicine,Department of Pathology and Laboratory Medicine,Weill Medical College of Cornell University, New York, NY Director,Immunopathology Laboratory, New York Presbyterian Hospital, NY

April Chiu, MD, Assistant Professor of Pathology, Departmentof Pathology and Laboratory Medicine, Weill Medical Collegeof Cornell University, New York, NY

Morton Coleman, MD, FACP, Clinical Professor of Medicine,Weill Medical College of Cornell University, New York, NY

Andrew M. Evens, DO, MS, Instructor in Medicine and Associate Director,Hematology/Oncology Training Program, Northwestern University FeinbergSchool of Medicine and the Robert H. Lurie Comprehensive Cancer Center,Chicago, IL

Richard I. Fisher, MD, Samuel E. Durand Professor of Medicine, Director,Hematology-Oncology Unit, Director of Cancer Services, Strong Health,Director, James P. Wilmot Cancer Center, University of Rochester MedicalCenter, Rochester, NY

Ian W. Flinn, MD, PhD, Associate Professor of Oncology, Director,Lymphoma Program; Assistant Director for Clinical Research, The SidneyKimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD

x Hodgkin's and Non-Hodgkin's Lymphoma

Jonathan W. Friedberg, MD, Associate Director, Lymphoma ClinicalResearch, James P. Wilmot Cancer Center; Assistant Professor of Medicineand Oncology, University of Rochester Medical Center, Rochester, NY

Richard R. Furman, MD, Assistant Professor, Weill Medical College ofCornell University, Department of Medicine, Division of Hematology andOncology, New York, NY

John Gerecitano, MD, PhD, Memorial Sloan Kettering Cancer Center,Department of Medicine, New York, NY

Stanley J. Goldsmith, MD, Director, Division of Nuclear Medicine, TheNew York Presbyterian Hospital; Professor of Radiology and Medicine,Weill Medical College of Cornell University, New York, NY

Lale Kostakoglu, MD, Associate Professor of Radiology at the WeillMedical College of Cornell University, Department of Radiology, Divisionof Nuclear Medicine, The New York Presbyterian Hospital, Weill MedicalCollege of Cornell University, New York, NY

John P. Leonard, MD, Director of the Oncology Unit, New YorkPresbyterian Hospital, Assistant Professor of Medicine at the Weill MedicalCollege of Cornell University, Medical Director of the Center forLymphoma and Myeloma at NYPH-Cornell, New York, NY

Peter McLaughlin, MD, Professor of Medicine, University of Texas M.D.Anderson Cancer Center, Department of LymphomalMyeloma, Houston, TX

Enrique A. Mesri, PhD, Laboratory of Viral Oncogenesis, Divisionof Hematology-Oncology, Department of Medicine, Weill Medical Collegeof Cornell University and The New York Presbyterian Hospital, NY, NY

Sarah Montross, MD, Department of Medicine, University of California,Los Angeles Center for Health Sciences, Los Angeles, CA

Daniel Muss, Regulatory Coordinator, Weill Medical College of CornellUniversity, Department of Medicine, Division of Hematology andOncology, New York, NY

Hodgkin's and Non-Hodgkin's Lymphoma

Owen A. O'Connor, MD, PhD, Memorial Sloan Kettering Cancer Center,Department of Medicine, Division of Hematologic Oncology, Lymphomaand Developmental Chemotherapy Services, New York, NY

Carol S. Portlock, MD, Lymphoma Service, Department of Medicine,Memorial Sloan-Kettering Cancer Center, New York, New York

Christiane Querfeld, MD, Department of Dermatology, NorthwesternUniversity Feinberg School of Medicine and the Robert H. LurieComprehensive Cancer Center of Northwestern University, Chicago, IL

Steven T. Rosen, MD, Division of Hematology/Oncology, NorthwesternUniversity Feinberg School of Medicine and the Robert H. LurieComprehensive Cancer Center of Northwestern University, Chicago, IL

Avram J. Smukler, MD, Fellow, Hematology/Oncology, WashingtonUniversity, Siteman Cancer Center, Division of Medical Oncology,St. Louis, MO

xi

David J. Straus, MD, Attending Physician, Lymphoma Service, Departmentof Medicine, Memorial Sloan-Kettering Cancer Center; Professor of ClinicalMedicine, Weill Medical College of Cornell University, New York, NY

John M. Timmerman, MD, Assistant Professor of Medicine, Division ofHematology-Oncology, University of California, Los Angeles,Los Angeles, CA

Chapter 1

PATHOLOGY OF B-CELL NON-HODGKIN'S

LYMPHOMAS AND MULTIPLE MYELOMA

April Chiu, MD and Amy Chadburn, MD

Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell

University, New York, NY

1. INTRODUCTION

B-cell non-Hodgkin's lymphomas (B-NHLs) represent a heterogeneousgroup of neoplasms with respect to their clinical manifestations,histopathologic features, and biological behavior. The now widely utilizedWorld Health Organization (WHO) classification scheme incorporates ourcurrent knowledge of the clinical and pathological features of B-cellneoplasms, and categorizes them into distinct entities (Table 1),'02 It is nowgenerally accepted that B-NHLs arise from neoplastic transformation of Bcells at specific stages of differentiation, although the normal counterpartsfor some B-NHLs have not been clearly delineated (e.g. hairy cell leukemia).Furthermore, some entities, such as chronic lymphocytic leukemia/smalllymphocytic lymphoma (CLLlSLL), appear to resemble more than one Bcell differentiation stage. Nevertheless, a basic understanding of B-celldifferentiation stages and their associated immunophenotypic characteristicsfacilitates accurate diagnosis and appropriate management of B-NHLs.

2 Hodgkin's and Non-Hodgkin's Lymphoma

2. NORMAL B-CELL DIFFERENTIATION

B-lymphocytes are a key component of humoral immunity. B-cellproduction is seen first in the fetal liver by 8-9 weeks of gestation; however,this role is mostly taken over by the bone marrow for the remainder of life?Within the bone marrow, B-cells are derived from pluripotential lymphoidprecursor cells, which sequentially progress through several stages ofdevelopment. B-lymphocytes can be readily detected by flow cytometryand/or immunohistochemistry based on their expression of the pan-B cellantigens, i.e. CD19, CD20, CD22, and CD79, as well as the B-celltranscriptional factor BSAPIPAX-5. However, the pattern of expression ofthese antigens varies during stages of B-cell ontogeny.

Progenitor B cells are the earliest recognizable form of Blymphocytes. They express only a limited number of surface antigens,including terminal deoxynucelotidyl transferase (TdT), HLA-DR (la), andCD34 (Table 2). They may also express CD79 within the cytoplasm(cCD79). They are BSAPIPAX-5 positive, and have germline (i.e. nonrearranged) immunoglobulin (Ig) genes.4,5 These cells subsequently undergoimmunoglobulin heavy chain gene rearrangement and acquire the B-celllineage-associated antigens CD19 (surface) and CD22 (cytoplasmic; cCD22)to mature into pre-pre B cells.6,7 They begin to synthesize cytoplasmicimmunoglobulin heavy chain ~ (c~), and acquire expression of CDlO(cALLa) and CD20 to become pre-B cells.8-1O Progenitor B cells, pre-pre-Bcells, and pre-B cells are morphologically precursor B lymphoblasts, whichhave finely dispersed chromatin and small nucleoli.

While expression of HLA-DR and BSAP/PAX-5 is retainedthroughout B-cell ontogeny except for the terminal plasma cell stage,4.5.1l,12pre-B cells begin to lose TdT, CD34, CD10, and cytoplasmic ~ chainexpression as they enter the immature B-cell stage. They also acquire CD21and surface immunoglobulin M (sIgM) expression at this stage. A subset ofthese cells also express CD5. 13,14 They progressively increase expression ofsurface CD22 and IgD, and decrease sIgM expression to become restingmature (naIve) B cells.8-1O

•15 From this stage on, further B-cell differentiation

occurs in the peripheral lymphoid tissues (i.e. lymph nodes, spleen, andmucosa-associated lymphoid tissues [MALT]) in an antigen-dependentfashion.

Na'ive B cells, which are unexposed to antigen, express HLA-DR,CD19, CD20, CD22, CD2l, CD79, BSAP/PAX-5, sIgM, and sIgD; theyalso often express CD5 (Table 3).16 They leave the bone marrow, circulatein the peripheral blood, and eventually migrate to the peripheral lymphoidtissue and populate the primary lymphoid follicles. 16-18 Upon exposure toantigen trapped on the cell processes of CD2l(+) CD35(+) follicular

Hodgkin's and Non-Hodgkin's Lymphoma 3

dendritic cells (FOCs), the na"ive B cells undergo "blast transformation",where they proliferate to become follicular B-blasts. They furtherdifferentiate into centroblasts or "large non-cleaved cells"; these are rapidlyproliferating cells found predominantly within the "dark zone" of thegerminal center. They transiently shed expression of sIg and the antiapoptotic protein BCL-2, thus becoming susceptible to death throughapoptosis. In addition, they regain expression of COW and acquireexpression of the nuclear zinc-finger transcription factor BCL-6 (Fig. 1a-i).Centroblasts undergo somatic mutation of the Ig variable region genes tocreate more diverse antibody binding sites. As IgM has relatively lowaffinity for the stimulating antigen, centroblasts often also undergoimmunoglobulin "class switching" by producing a higher affinityimmunoglobulin, usually either IgG or IgA, during subsequent antigenexposure.19

•2D Centroblasts eventually differentiate into centrocytes, also

known as small-cleaved cells due to the characteristic angulated appearanceof their nuclei. Centrocytes retain the BCL-6(+) BCL-2(-) phenotype, andbegin to enter a resting state. They re-express sIg of variable affinity for theinciting antigen; those with insufficient affinity die by apoptosis and arecleared by tingible body macrophages, generating a "starry-sky" patternwithin the germinal center. On the other hand, centrocytes with sufficientaffinity bind the antigen trapped on the FOCs and, through a complex set ofinteractions between with FOCs and T cells, re-express BCL-2 to escape thefate of apoptosis. These survivors subsequently turn off BCL-6 expressionand, as they exit the germinal center, differentiate into memory B cells orplasma cells. 21

-26 Memory B cells, which are more responsive to repeated

antigen stimulation, are usually sIgM(+) but sIgO(-). They express on theirsurface all pan-B cell antigens (C019, C020, C022 and C079) as well asIRF4/MUM-I, and lack expression of C05, COW, and BCL-6. These cellscan usually be seen in the marginal zone at the edge of the follicles, which ismore prominent in mesenteric lymph nodes, Peyer's patches, and thespleen.2

7-3D The plasma cells seen within the lymph node medulla expressimmunoglobulin only within the cytoplasm (clg), usually of the IgG or IgAisotype. They express C019 and C079 but not other pan-B cell antigens.BSAP/PAX-5 is also down-regulated and no longer expressed by plasmacells.4

,5,1l,12 They also express C038 and C0l38 (syndecan-l), but lackexpression of HLA-OR, C045, and C056. 31-33


3. B-CELL NEOPLASMS

B-cell malignancies, including B-cell non-Hodgkin's lymphomas(B-NHLs) and plasma cell neoplasms, encompass many types of neoplasmsin the WHO classification scheme (Table 1). For the most part, they expressone or more B-cell specific antigen (i.e. CD19, CD20, CD22, CD79), the Bcell transcriptional factor BSAP/PAX-5, and either surface and/orcytoplasmic Ig. In addition, in most cases evidence of immunoglobulin generearrangement can be demonstrated, either by polymerase chain reaction(PCR) or Southern blot hybridization studies. Based on their primaryclinical presentation, natural history, and morphologic and/orimmunophenotypic resemblance to a specific stage of B-cell differentiation,B-cell neoplasms are classified into 20 distinct clinicopathological entities,the most common ten of which are discussed in this chapter. However,accurate morphologic examination and classification is highly dependent onappropriate tissue fixation, and may be severely hindered in less optimalconditions. Consequently, most pathology laboratories have becomeincreasingly reliant upon immunophenotyping, either by flow cytometry orby immunohistochemistry, for the diagnosis and classification of lymphoidneoplasms. The basic immunophenotypic criteria of the more commontypes of B-NHLs are summarized in Table 4.

3.1 Precursor B-Iymphoblastic leukemia/lymphoma(B-ALLILBL)

Precursor B-lymphoblastic leukemia/lymphoma (B-ALLILBL) is aneoplasm derived from precursor B-lymphoblasts, i.e. progenitor B cells,pre-pre-B cells, or pre-B cells. Most patients with B-ALLlLBL present withbone marrow involvement with secondary involvement of the peripheralblood; only a small number of patients initially present with disease inlymph nodes or in extra-nodal sites such as the skin.34

.35 By convention, thepresence of more than 25% lymphoblasts in the bone marrow is designatedas ALL, whereas the identification of one or more mass lesions, with lessthan 25% lymphoblasts in the marrow, establishes a diagnosis of LBL.However, as the two entities (ALL and LBL) are biologically similar, thedistinction is arbitrary and of little if any clinical relevance.

Morphologically, the lymphoblasts are medium-sized with round toconvoluted nuclei, finely dispersed chromatin, inconspicuous nucleoli, and ascant amount of cytoplasm (Fig. 2a and 2b). Within the lymph node, theneoplastic cells tend to exhibit a diffuse growth pattern, obliterating much ofthe normal nodal architecture. Frequently numerous mitotic Figures are


seen, as these tumors have a high proliferation rate. Within the bone marrowthe pattern of involvement by ALL/LBL is almost always diffuse andextensive.

Immunophenotypically, like their normal counterpart, the tumor cells areTdT (Fig. 2c) and HLA-DR positive. Virtually all cases express the B-cellassociated markers CDI9, CD79, CD22 (surface or cytoplasmic), and PAX5.5

,34 However, B-ALL/LBLs exhibit a variety of immunophenotypicpatterns with regard to CD34, CDlO, CD20, and Ig (cytoplasmic or surface)expression. B-ALL/LBLs may further be separated into immunophenotypicsubtypes based on these profiles, although the term "precursor Blymphoblastic leukemia/lymphoma" encompasses all subtypes. Thesesubtypes do not per se have prognostic significance, although someprognostically important cytogenetic aberrations are seen more frequently incertain immunophenotypic, i.e. differentiation, subtypes.

Representing the most immature stage of differentiation, early precursorB-ALL/LBLs are comprised of TdT, HLA-DR, CD34, CDI9, cCD22,cCD79a, and BSAP/PAX-5 positive lymphoblasts. 34 However, they lackexpression of CD IO. This immunophenotypic profile mirrors that of theprecursor B cell stage in B cell ontogeny. CD10 negative precursor BALL/LBLs are commonly seen in both pediatric and adult patients withchromosomal abnormalities involving the MLL gene at II q23. 36

,37 MLLgene abnormalities are particularly associated with congenital leukemias, themost common of which is the t(4; II) translocation, resulting in the fusion ofMLL gene with AF4 at chromosome 4q21.34 The majority of CDIO negativeB-ALL/LBLs with IIq23 rearrangements express CDI5; expression of othermyeloid associated antigens is also frequently found.3s

-40 In the intermediate

stage, or "common" B-ALL/LBLs, the malignant cells express CDIO inaddition to the markers expressed by the early precursor tumors. However,they lack expression of both sIg and/or cIg expression.41 Common BALL/LBLs correspond to the pre-pre-B cell stage and are the most commonimmunophenotypic subtype seen in both pediatric and adult patients,representing approximately 65% of the cases. Both favorable andunfavorable clinical and cytogenetic groups are seen within thisimmunophenotypic subtype. The pre-B-ALL/LBLs, the most differentiatedsubtype, resemble the pre-B cell differentiation stage in that the tumor cellsexpress cytoplasmic /o! (c/o!) but lack light chain or sIg expression. 35 Mostcases are TdT, HLA-DR, CDI9, CD22, BSAPIPAX-5, and CDIO positive,and show heterogeneous CD20 expression. However, the tumor cells aregenerally CD34 negative. The to; 19)(q23;p13) translocation is seen inapproximately 20% of the cases of pre-B-ALL/LBLs, where the E2A gene at19p13.3 fuses with PBX at Iq23, creating a potent transcriptional factor. 34

Patients with this translocation tend to present with high-risk clinical


features, such as high blast counts in the peripheral blood and centralnervous system involvement.42 They also tend to respond poorly to standardchemotherapeutic regimens and but may respond favorably to moreintensive regimens.43

,44

Usually B-ALULBLs do not express surface immunoglobulin (sIg);however, sIg expression can be seen rare cases.4

5-48 These so-called "mature"B-ALULBLs appear to behave like the other subtypes of B-ALULBLclinically.

A variety of other cytogenetic abnormalities are commonly seen inB-ALULBL. These can be divided into two prognostic groups--favorableand unfavorable. B-ALULBLs which are hyperdiploid (i.e. greater than 51chromosomes) are associated with a good prognosis, as are those with thet(l2;2l)(p13;q22) translocation (TEL-AMLl; ETV6-AMLl). The lattertend to be CD20 negative, but often express the myeloid associated antigenCD13.49

-51 B-ALULBLs with unfavorable prognosis include those with

translocations involving BCRlABL [t(9;22)(q34;ql1.2)], AF4/MLL[t(4; 1l)(q21 ;q23)] or MLL with other partner chromosomes [t(v; 11)(v;q23)],and E2A1PBXl [t(l;19)(q23;p13)]. However, as mentioned previously,patients with the latter cytogenetic abnormality may respond to moreintensive therapy.

3.2 Mature B-Cell Neoplasms

Mature B-cell neoplasms encompass neoplasms derived from tumor cellsthat have differentiated beyond the precursor B, pre-pre-B, and pre-B cellstages in B cell ontogeny. These are clonal proliferations of B cells atvarious stages of maturation, ranging from na'ive B cells to plasma cells.According to the WHO classification, these mature B-cell neoplasms may begrouped based on their major clinical presentation: predominatelydisseminated lymphoma/leukemias, primary extranodal lymphomas, andpredominantly nodallymphomas.52

•53 These neoplasms may also be grouped

according to their biologic behavior: indolent, aggressive, and highlyaggressive.54 Clinically, most predominately disseminatedlymphoma/leukemias and primarily extranodal lymphomas tend to beindolent neoplasms, whereas primarily nodal lymphomas may be clinicallyindolent or aggressive. The majority of the indolent B cell lymphomas arecomposed of small, relatively bland-appearing lymphocytes, with or withoutplasma cell differentiation. Some examples of indolent B-cell lymphomasinclude chronic lymphocytic leukemia/small lymphocytic lymphomas,follicular lymphoma, and marginal zone lymphoma. Although they arebiologically indolent, they also tend to be resistant to standard therapy and


are considered incurable in most instances. While theoretically subtypes ofindolent lymphoma possess distinct morphologic features that facilitate intheir classification, in practicality the tumor cells may be morphologicallyindistinguishable from one another, particularly when the tissue is poorlypreserved. However, these morphologically similar, and often clinicallysimilar, lesions can usually be categorized into to separate entities based ontheir characteristic antigen expression profiles as determined byimmunophenotypic studies (Table 4). On the other hand, in some instances,additional analyses such as molecular and/or cytogenetic studies arenecessary to classify these neoplasms. The aggressive/highly aggressivelymphomas represent a heterogeneous group of neoplasms both in terms oftheir morphology and clinical course. Two examples of aggressive/highlyaggressive B cell lymphomas are diffuse large B-cell lymphoma and Burkittlymphoma. Even within a diagnostic subtype, e.g. diffuse large B-celllymphoma, the tumor cells may exhibit significant morphologic and clinicalheterogeneity. However, efforts attempting to divide these neoplasms intosmaller, more biologically specific groups, particularly with the advent ofDNA microarray technology, are ongoing and may possibly delineateadditional clinically and biologically relevant genetic andimmunophenotypic characteristics of these neoplasms. 55

3.3 B-cell chronic lymphocytic leukemia/smalllymphocytic lymphoma

B-chronic lymphocytic leukemia/small lymphocytic lymphoma (BCLLlSLL), the prototype of predominately disseminatedlymphoma/leukemias, is the most common adult leukemia in North Americaand Western Europe.56 This neoplastic process tends to occur in older adults(>50 years of age) with a male to female ratio of 2: 1. Most patients with BCLLlSLLs present with bone marrow and peripheral blood involvement,where the absolute lymphocyte count is frequently> 10 x 109fL. In addition,the tumor cells typically disseminate widely with frequent involvement ofliver, spleen, lymph nodes, and a variety of extranodal sites. Some patientsmay also have a small amount of monoclonal protein in the serum. Rarealeukemic cases, i.e. those without bone marrow and/or peripheral bloodinvolvement, do occur, in which the designation of B-SLL is used.However, as in the case of B-ALLILBL, the tumor cells in B-CLL and BSLL are biologically similar. Like most other predominately disseminatedlymphoma/leukemias, B-CLLlSLLs are clinically indolent but not usuallycurable with available therapy.


The neoplastic cells are small in size (i.e. their nuclei are similar insize to an erythrocyte) with round nuclei, clumped chromatin, and scantycytoplasm (Fig. 3a). Some cases also show plasmacytoid differentiation.The mitotic rate is usually very low. B-chronic lymphocytic leukemia/smalllymphocytic lymphoma diffusely involves lymph nodes, however, usually avaguely nodular pattern is seen (Fig. 3b). This vague nodularity is due to thepresence of collections of cells containing increased numbers ofprolymphocytes and paraimmunoblasts known as pseudofollicles orproliferation centers. Prolymphocytes and paraimmunoblasts areintermediate to large cells with single to multiple nucleoli and areproliferating malignant cells.

In the bone marrow, the pattern of involvement may be nodular,interstitial, diffuse, or a combination of the three. Pseudofollicles aregenerally less apparent in the bone marrow than in the lymph nodes,although they can occasionally be seen. In the cases of nodular involvement,the neoplastic lymphoid aggregates tend to be randomly distributed in theinterstitial area of the marrow without a predilection for the paratrabecularregions. The patterns of bone marrow involvement by B-CLLlSLL have aprognostic significance: nodular and interstitial patterns (i.e. the tumor cellsform distinct aggregates or are admixed with hematopoietic elements,respectively) are seen in early disease, whereas a diffuse pattern ofinfiltration (i.e. complete effacement of the marrow space by sheets of tumorcells) signifies more advanced disease and worse prognosis.57.58

The peripheral blood is usually involved by B-CLLlSLL and mostpatients have an absolute lymphocytosis. The B-CLLlSLL cells in theperipheral blood are morphologically similar to those seen in the tissues; i.e.they are small and round with scant cytoplasm and clumped chromatin.Prolymphocytes usually constitute less than 10% of the circulatingmalignant lymphoid cells. Increased numbers of prolymphocytes (more than10% but less than 55%) are seen in association with p53 abnormalities andtrisomy 12, and warrant the diagnosis of CLL with increasedprolymphocytes (CLL/PL).59

Immunophenotypically, the neoplastic cells express the pan-B cellantigens CD19, CD20 (weak), CD22 (very weak or absent) and CD79a, aswell as BSAPIPAX-5; they also faintly express monotypic surfaceimmunoglobulin (usually kappa) and either sIgM alone, or sIgM and sIgDsimultaneously. In addition, they express both the T-cell antigen CD5 andthe activation marker CD23 (Fig. 4), and usually faintly express the adhesionmolecule CDllc. These neoplastic cells lack expression of CDlO and/orBCL-6, markers typically expressed by follicular lymphomas. They alsolack expression of BCL-l (cyclin-Dl), thus separating B-CLL/SLL frommantle cell lymphoma, a B-cell neoplasm which is also CD5 positive but


generally CD23 negative. Lastly, B-CLLlSLLs usually lack FMC7expression, in contrast to most other types of indolent B-celllymphoma.60,61

B-CLLlSLLs have been regarded in the past as a neoplasm arisingfrom recirculating CD5+ CD23+ IgM+ IgD+ na'ive B cells that are normallyfound in the peripheral blood, primary follicles, and mantle cell zones ofsecondary follicles; these B cells have an unmutated variable region of theimmunoglobulin gene (IgV).17,62 However, recently a second category of BCLLlSLL containing somatic mutations in IgV has emerged; these cases arethought to arise from memory B cells based on gene expression profilingstudies.63 Although the mutated cases more frequently have an "atypical"appearance (i.e. irregular nuclear contours), in general the mutated andunmutated cases of B-CLLlSLL are morphologically very similar. Thereare, however, definite differences between the mutated and unmutated casesin terms of clinical behavior, i.e. those with a mutated Ig V region tend to beassociated with a more indolent clinical course, whereas those without themutations tend to have more aggressive clinical behavior.64 Since mostlaboratories lack the resources to sequence the IgV region, two "surrogate"phenotypic markers have been identified that correlate with IgV mutationalstatus--CD38, a regulator of activation and proliferation, and ZAP-70, aprotein kinase normally expressed by T cells.65 Cases of B-CLLlSLLwithout somatic mutations, i.e. of na'ive B-cells, are more frequently CD38and ZAP-70 positive, are associated with higher stage of disease atpresentation as well as shorter survival, and are less responsive tochemotherapy.66 On the other hand, cases with mutated IgV less frequentlyexpress CD38 or ZAP-70, and are associated with a more indolent clinicalcourse and longer survival. Of the two markers, ZAP-70 is felt to be moresensitive and specific, predicting IgV mutational status in 93% of patients, incomparison to CD38 which correlates with mutation status in only 67-77%of cases.67 Furthermore, ZAP-70 expression does not change over time,while CD38 expression may change during the course of the disease. 67,68,69In addition, ZAP-70 can be detected by either flow cytometry and byimmunohistochemistry in routine formalin fixed tissue sections (Fig. 5);CD38 immunoreactivity, although reliably detected by flow cytometry, isoften faint and highly variable in paraffin tissue sections based onfixation. 65,67 ,68,70-72

Other important prognostic indicators include the proliferationassociated antigen Ki-67 (MIB-l) and p53, Typically only a small numberof CLLlSLL cells are Ki-67 positive;73 however, cases of chemotherapyresistant CLLlSLL have a higher percentage of Ki-67 positive cells in theperipheral blood.74 Expression of the p53 in B-CLLlSLLs also confers worseoutcome, with a shorter treatment free interval, poorer response to therapy,and decreased survival time,75


Transformation to high-grade lymphoma occurs not infrequently inpatients with B-CLLlSLLs.76 The most common type of B-CLLlSLLtransformation is prolymphocytic transformation, seen in 15% of patients, inwhich an increased proportion of prolymphocytes is seen. The next mostfrequent type of transformation is "Richter's syndrome", seen in 3-10% ofthe cases. Morphologically these transformations are usually diffuse largecell lymphomas (Fig. 6), although cases resembling Hodgkin lymphomamay also occur. Other types of B-CLLlSLL transformation are rare; theseinclude blastic, plasmacytoid, and paraimmunoblastic transformations. Inmost patients, when transformation occurs, the prognosis worsens and deathensues within a short period of time.

4. MANTLE CELL LYMPHOMA

Although mantle cell lymphoma (MCL) is classified as an indolentlymphoma since its survival is measured in years rather than months, themedian survival is still significantly less than the other indolent lymphoidneoplasms.77 Patients with MCL are usually elderly, male, and present withnodal disease. However, peripheral blood involvement can be seen in about25% of cases.78 The most common extranodal site of involvement is thegastrointestinal tract, which is present in approximately 30% of the cases.When the neoplastic infiltrate in the gastrointestinal tract results in multiplepolypoid mucosal lesions, it is called "lymphomatoid polyposis". Inaddition, the bone marrow and spleen are also frequently involved.

The cell of origin is postulated to be the CD5+ CD23- unstimulatedB cells of the inner mantle zone, although the precise cell type has not beendefinitively determined. The neoplastic cells are generally small to mediumin size with variably irregular nuclear contours and a scant amount ofcytoplasm. Scattered epithelioid histiocytes are also frequently seen, givingrise to a pseudo- "starry-sky" appearance (Fig. 7). Mantle cell lymphomacan be morphologically difficult to distinguish from CLLlSLL, follicularlymphoma, and marginal zone lymphoma both architecturally andcytologically (Fig. 8). However, immunophenotypically, MCL in mostinstances can be separated from these other entities. Mantle cell lymphomasare positive for the pan-B cell antigens CD19, CD20, CD22, BSAP/PAX-5and CD79a. They express high density ("bright") monoclonal surfaceimmunoglobulin, usually sIgM alone or simultaneously sIgM and sIgD. Theneoplastic cells are CD5 positive, a feature not seen in follicular lymphomaand present only in a small fraction of marginal zone lymphomas. Incontrast to CLUSLL, which is also CD5 positive, most cases of MCL lackexpression of CD23 (Fig. 9) but express FMC_7.79

•80 Furthermore, MCL

Hodgkin's and Non-Hodgkin's Lymphoma II

cells lack expression of CDlO and BCL-6, markers typically expressed byfollicular lymphoma cells.81 .84 The tumor cells are also usually CD43positive85 and are often associated with loose, ill-defined CD21 or CD35positive follicular dendritic cell meshworks. 86 In contrast to other sIgpositive mature B cell neoplasms, which usually show immunoglobulin lightchain kappa restriction, MCL cells more often express the lambdaimmunoglobulin light chain determinant,8o

Mantle cell lymphomas characteristically carry the cytogenetictranslocation t(l1 ;14)(q13;q32), in which the BCLl (PRADl, CCNDl) geneon l1q13 is juxtaposed with the Ig heavy chain gene locus on 14q32; thisresults in overexpression of the BCL-l (CYCLIN Dl) protein which can bedetected by immunostaining in the nuclei of the tumor cells in formalin fixedparaffin tissue sections (Fig. 10).87-89 Expression of BCL-l is relativelyunique to MCLs, as it is not detected in most other subtypes of B-cellneoplasia with the exception of hairy cell leukemia9o.91 and some cases ofmultiple myeloma.92 Thus, inclusion of BCL-l in the immunohistochemistrypanel can prove extremely valuable distinguishing MCLs from otherindolent lymphomas, such as B-CLUSLL, follicular lymphomas, andmarginal zone lymphomas.

The median survival of patients with MCL is 3 to 5 years. However,in the event of abnormalities/structural alterations involving other cell cycleproteins, such as p53, p16, and p18, the median survival decreases toapproximately 18 months.93-95 Overexpression of p53, p21, p16, all of whichcan be detected in paraffin tissue sections by immunohistochemical staining,is associated with more aggressive disease and a poorer prognosis.93.94 Inaddition, a high proliferation rate, which can be demonstrated by Ki-67immunostaining, also confers an adverse prognosis.96.97

Histologic transformation to a large cell lymphoma does not occurwith MCL. However, morphologic variants exist,98 The most common ofthese is the blasticlblastoid variants, in which the tumor cells either resembleIymphoblasts with dispersed chromatin, or are pleomorphic with cleavednuclei and at times prominent nucleoli. The blasticlblastoid variant of MCLis associated with high mitotic rate and a more aggressive disease course.

5. FOLLICULAR LYMPHOMA

Follicular lymphoma (FL) is the most common type of low gradenon-Hodgkin's lymphoma in the western world.99 Although primarily anodal lymphoma, FLs are characterized by widespread disease atpresentation, including frequent involvement of the bone marrow. Theaffected patients are generally older adults. Follicular lymphomas are


associated with an initially indolent disease course; however, transformationto a large cell lymphoma, generally diffuse, occurs in 25-35% of the cases. 100In these cases, the patients usually rapidly deteriorate clinically and die asthe tumor is generally refractory to treatment. 101

Typical cases of FL are characterized by a predominantly folliculargrowth pattern (Fig. 11). The neoplastic cells, centrocytes and centroblasts(Fig. 12), are thought to arise from germinal center B cells. Follicularlymphomas are graded based on the number of centroblasts present in 40xhigh-power microscopic field (hpf). Grade 1 FLs have 0-5 centroblasts/hpf,grade 2 cases have 6-15 centroblasts/hpf, and grade 3 cases have >15centroblasts/hpf.

Immunophenotypically, the neoplastic cells express the pan-B cellantigens CDI9, CD20, CD22, BSAP/PAX-5 and CD79a. They usuallyexpress sIg (IgM with or without IgD, IgG or IgA); however, a few caseslack sIg expression. 102 The tumors cells also usually express the folliclecenter cell-associated antigens CDlO and BCL-6 (Fig. 13).84.103 In contrast toB-CLUSLL and MCL, FL tumor cells are usually CD5 and CD43 negative;only rare cases of grade 3 FLs are CD43 positive.85,104.105 When a folliculargrowth pattern is present, the neoplastic follicles are associated with CD21positive follicular dendritic cell (FDC) meshworks. The FDC meshworksare usually relatively intact around the periphery but are often centrallyfragmented.106.107 The tumor cells, in general, express the anti-apoptoticprotein BCL-2 (Fig. 13); this is in sharp contrast to normal germinal centerB cells, which normally turn off BCL-2 expression (Fig. Ih). Thus,overexpression of the BCL-2 protein distinguishes neoplastic follicles fromreactive ones. The abnormal expression of the BCL-2 protein is due to thet(l4;18) translocation where the BCL-2 gene on chromosome 18 isjuxtaposed to the 19H gene chromosome 14. Consequently, BCL-2 genetranscription comes under the control of the immunoglobulin heavy chaingene promoter, resulting in overexpression of the BCL-2 protein andconferring upon the tumor cells a survival advantage. The incidence ofBCL-2 expression tends to vary according to the cytologic grade, rangingfrom nearly 100% in grade 1, greater than 80% in grade 2, and 70% of grade3 FL. 108 Approximately 15% of FLs lack a t(l4;18) translocation but bearother cytogenetic abnormalities.109-lll

Primary cutaneous FL is currently a distinct variant of FL in theWHO classification scheme. In contrast to FLs with nodal presentation,primary cutaneous FLs frequently lack BCL-2 overexpression and lack thet(l4;18) rearrangement. l12,m They are frequently localized to the head andneck region or trunk, treatable by local therapy, and associated with an evenmore indolent clinical behavior compared to conventional FLs. The


biological relationship between primary cutaneous FLs and those with nodalpresentation remained to be elucidated.

6. MARGINAL ZONE LYMPHOMA

Marginal zone lymphoma (MZL) was recognized as a distinct subtype ofB-NHLs in the REAL and WHO classification schemes. Marginal zonelymphomas are divided into three subtypes: nodal MZL, extra-nodal MZL ofmucosa-associated lymphoid tissue ("MALT" lymphoma), and splenic MZL(SMZL) / splenic lymphoma with villous lymphocytes (SLVL). Theseneoplasms, for the most part, are morphologically andimmunophenotypically similar. The neoplastic cells, small to medium insize, are postulated to be derived from the marginal B-cell compartment ofthe secondary lymphoid tissue, representing post-germinal center B cells. 114

The cellular composition of these lymphomas shows considerable variation,however; the neoplastic cells may exhibit centrocytic, monocytoid (clearcells with moderate amount of pale cytoplasm), immunoblastic,centroblastic, and/or plasmacytic differentiation (Fig. 14).114-116 In all typesof MZL, "follicular colonization," where residual reactive germinal centersare invaded by neoplastic cells, may be present. 114

Immunophenotypically, MZL cells express pan B-cell associatedantigens, such as CD20 and CD79a. In cases with plasmacyticdifferentiation, the tumor cells may express monotypic cytoplasmicimmunoglobulin (Fig. 15). The neoplastic cells in general lack expression ofCDS, CDlO, CD23, BCL-l, and BCL-6. The cells are FMC7 positive andsometimes CD43 positive; however, SMZLs are usually CD43negative.85.104.117,118 These immunophenotypic findings help facilitate therecognition of MZLs. However, there is not a marker that clearlydemonstrates the marginal zone cell origin of the neoplastic cells. Thus, theimmunoarchitectural features of the specimen are often crucial in reachingthe diagnosis of MZL. Immunostaining for CD21 and CD35 often showsthe presence of follicular dendritic cell (FDC) meshworks with extensivefragmentation at the edges, "broken-down" by the infiltrating neoplasticMZL cells (Fig. 16a), a pattern unlike that seen in FLs (i.e. intact edges; Fig.13b). The neoplastic MZL cells, which are usually BCL-2 positive, mayextensively infiltrate among the BCL-2 negative residual benign germinalcenter cells (Fig. 16b), simulating the BCL-2 positive follicles seen in FLs.However, the MZL cells lack immunoreactivity for both CDlO and BCL-6;the serpiginous areas of CDI0/BCL6 negative staining are not seen in eitherreactive follicles or FL follicles.8I,108,119


Despite their morphologic and immunophenotypic similarities,SMZLs, nodal MZLs, and MALT lymphomas differ in terms of their clinicalpresentation and behavior, and thus are best considered separateclinicopathologic entities.

6.1 Splenic marginal zone lymphoma

Splenic marginal zone lymphoma (SMZL) is a rare neoplasm,representing less than 1% of lymphoid neoplasms. 120 The tumor involves thespleen, splenic hilar lymph nodes, bone marrow, and peripheral blood. Mostpatients are over 50 years of age who present with splenomegaly,autoimmune thrombocytopenia or anemia, and/or peripheral blood villouslymphocytes. In the spleen, the neoplastic cells involve both the white andred pulp (Fig. 17). Within the white pulp, the neoplastic cells surround orreplace the germinal centers, often with effacement of the mantle cell zone,and infiltrate the marginal zone. In the red pulp, the tumor cells formnodules and sheets, and infiltrate the sinuses. 121

.122 In the peripheral blood,

the circulating neoplastic cells usually have relatively abundant cytoplasmand polar villous projections.

Immunophenotypically the neoplastic cells, aside from theaforementioned markers, express surface IgM and IgD. 123

•126 Splenic

marginal zone lymphomas in general lack expression of CD43; in contrast,this antigen is occasionally expressed by nodal or extranodal MZLs. 85 Due toclinical splenomegaly and the frequent prominent red pulp infiltration seenon routine morphologic examination, hairy cell leukemia is an importantdiagnostic consideration. However, the tumor cells in SMZL lackexpression of the hairy cell leukemia-associated markers CD25, CDllc,CDI03, HC-2, and TRAP.125.127

Although a small number of cases of SMZL progress to large celllymphoma, in contrast to CLLlSLL and MCL, this progression is not usuallyassociated with p53 mutation or overexpression, but rather with a higherproliferation rate as indicated by Ki-67 expression. 128 However, the smallnumber of patients with transformed SMZLlSLVL in which p53 mutationshave been identified have significantly worse survival. 129

6.2 Nodal marginal zone lymphoma

Nodal MZLs are also rare, comprising less than 2% of lymphoidneoplasms.99 Patients with nodal MZLs present with peripherallymphadenopathy, and occasionally bone marrow and peripheral bloodinvolvement.


Within the lymph node a variety of growth patterns may be seen.These include parafollicular, perisinusoidal, nodular, and diffuse patterns ofinfiltration. As in other types of MZLs, the neoplastic cells may assume avariety of morphologic appearances. Nodal MZL with a prominentmonocytoid B-cells component has been described and classified asmonotyoid B-cell lymphoma of the lymph node in the past, 130-132

Nodal MZLs are generally immunophenotypically similar to othertypes of MZLs. In contrast to SMZLs, however, nodal MZL cells usuallyexpress surface immunoglobulin IgM, IgG, or IgA, and are usually IgDnegative. However, some IgD positive cases have been reported. 123

6.3 Extra-nodal marginal zone lymphoma of mucosaassociated lymphoid tissue (MALT)

Extra-nodal marginal zone lymphoma of mucosa-associatedlymphoid tissue (MALT lymphoma) is an indolent B-cell neoplasm virtuallyalways presenting in extranodal sites. These neoplasms comprise 7-8% ofall B-cell lymphomas99 and up to 50% of primary gastric lymphomas. 133

•134

Although frequently diagnosed in the stomach, MALT lymphomas alsooccur in other sites, such as the orbit,135 salivary glands,136 and skin. 137 Manycases of MALT lymphoma appear to be associated with chronicinflammatory conditions, such as Helicobacter pylori (H. pylori) infectionwhich is frequently seen in association with gastric MALT lymphomasl38.139and Chlamydia psittaci infection in ocular MALT lymphomas. 135.140

Furthermore, patients with autoimmune diseases, such as Sjogren'ssyndromel41.142 and Hashimoto's thyroiditis,143.144 are also at an increased riskfor MALT lymphoma.

The tumor cells often arise in the marginal zone of the reactivefollicles in mucosa-associated lymphoid tissue and extend into theinterfollicular areas. In epithelial tissues, the tumor cells may extend into theepithelium, forming Iymphoepithelial lesions-a feature characteristic, butnot diagnostic, of MALT lymphomas (Fig. 18).145.146

Immunophenotypically, MALT lymphomas are similar to nodalMZL with respect to surface immunoglobulin heavy chain expression, i.e.IgM, IgA, or IgG. They do not generally express IgD. 123 In contrast tosplenic MZL, many cases of MALT lymphoma are CD43 positive. Themalignant cells are otherwise immunophenotypically similar to other typesof MZLs. They may also express CD21 and CD3S. MALT lymphomasgenerally lack expression of CDS; however, occasional CDS positive caseshave been reported. These have been reported to be associated with aclinically aggressive course and tendency for dissemination.147-149 As in


other types of MZLs, infiltration of FDC meshworks by CDlO negative,BCL-6 negative, BCL-2 positive neoplastic cells is frequently seen inMALT lymphomas. In addition, the characteristic lymphoepithelial lesionscan be accentuated by immunostaining for cytokeratin and B cell markers(Fig. 18). In gastric MALT, identification of H. pylori, which can befacilitated by immunostaining for the organism, may direct treatment, sincesome cases of gastric MALT lymphoma can be cured by antibiotictherapy. 150,151

A variety of cytogenetic aberrations have been described in MALTlymphoma. The t(11;18)(q21;q2l) translocation is detected in 14% ofMALT lymphomas of all sites, but is more common in gastric (24%) andpulmonary (53%) MALT lymphomas, and is least common in ocular (3%)and salivary gland (2%) lesions. 152 In this translocation, the APJ2 gene onchromosome 11 is fused to the MALT1 gene on chromosome 18 to produce achimeric APJ2-MALT1 fusion transcript. 153 MALT lymphomas confined tothe stomach (Stage IE) with t(11; 18) do not respond to H. pylorieradication.154.155 The recently described t(14; 18)(q32;q21) translocation isdetected in 11 % of MALT lymphomas overall but is seen more frequently inocular (24%), skin (14%), and salivary gland (12%) cases. 152 In addition,these cases frequently harbor additional cytogenetic abnormalities. 156

The t(1;14)(q22;q23) translocation is encountered in <2% of MALTlymphomas of all sites, but is more commonly seen in the intestine (13%)and the lung (7%).152 This involves translocation of BeLl0, a tumorsuppressor gene, to the IgH locus at 14q32, resulting in overexpression ofthe BCL-I0 protein in the nucIeus. 157 BCL-lO may also be expressed ingastric MALT lymphomas with t(11 ;18) but without t(1 ;14); the expressionof BCL-l 0 in these cases is associated with higher stage disease. 158 Numericchromosomal aberrations such as trisomy 3 and trisomy 18 are alsocommonly encountered in MALT lymphomas. 159

7. HAIRY CELL LEUKEMIA

Hairy cell leukemia (HCL) is a rare type of lymphoid neoplasm withleukemic presentation, accounting for 2% of all leukemias. 160,161 The medianage at diagnosis is 55 years, with a male to female ratio of 4-5: 1.162.163 Mostpatients present with splenomegaly and pancytopenia. Monocytopenia isalso nearly always present in untreated patients. 164 The leukemic cellstypically infiltrate the splenic red pulp; peripheral blood and bone marroware also usually involved at presentation. The tumor may also be seeninfrequently in the liver, lymph nodes, and skin. 161 ,163 The cell of origin is


unknown, but is thought to be derived from a B-cell of a post-germinalcenter stage of differentiation.

Morphologically, the neoplastic cells are medium in size and blandappearing (Fig. 19a). They have oval or indented (bean-shaped) nuclei andrelatively abundant cytoplasm with circumferential "hairy" cytoplasmicprojections.

Immunophenotypically, BCL cells are CD19, CD20, CD22, CD79apositive B cells which express relatively bright monotypic surfaceimmunoglobulin (lgM, IgMD, IgG or IgA). They are CD5, CD10 and CD23negative, but brightly express CDllc, CD25, CD103, BC-2 andFMC7. 125

•127,165 They also are tartrate resistant acid phosphatase (TRAP),

DBA.44, and CD25 positive by immunohistochemical staining (Fig. 19b-d).As most patients with BCL have a "dry-tap" on bone marrow aspirate, theconcomitant expression of these three latter markers are extremely helpful inmaking the diagnosis on paraffin-embedded sections. 166,167

8. BURKITT LYMPHOMA

Burkitt lymphoma (BL) is highly aggressive, frequently involvingextranodal sites, peripheral blood, and bone marrow at presentation. 168,169 BLmay be seen in an endemic form occurring in equatorial Africa and NewGuinea, arise sporadically throughout the world, or be associated withhuman immunodeficiency virus (BIV) infection. The abdomen is involvedin the majority of sporadic BLs,170.171 while involvement of the jaws, orbit,and other head and neck structures is seen more often in the endemicform. 168.172 In BL arising in the setting of BIV infection, the neoplasticinfiltrate more often presents in lymph nodes and the bone marrow. Thepostulated cell of origin is thought to be the B-blast from early in thegerminal center reaction.

The neoplastic infiltrate is composed of monotonous medium-sizedlymphoid cells. These cells have round nuclei, multiple nucleoli, andrelatively abundant basophilic cytoplasm. A large number of tingible bodymacrophages (macrophages containing phagocytic debris) is usually present,imparting a starry-sky pattern (Fig. 20a). Numerous mitotic Figures arepresent, reflecting the extremely high growth fraction of the tumor cells.

The tumor cells express CD19, CD20, CD22, CD79a, CDI0, BCL6, and sIgM; they lack expression of CD5, CD23, and BCL-2. 27.108.173-175Many of the cases are CD43 positive.108.176 The majority of the endemiccases are CD21 positive, the receptor for both C3d and the Epstein-Barrvirus (EBV).177 Nearly 100% of the cells are Ki-67 positive (Fig.20b).53.175.178


Virtually all endemic cases, 25-40% of the immunodeficiencyassociated cases, and a variable number of the sporadic cases are associatedwith the Epstein Barr virus.179-184 All cases have a translocation involving theMYC gene at chromosome 8 and an immunoglobulin gene, either the heavychain (on chromosome 14) or a light chain (kappa on chromosome 2 orlambda on chromosome 22).184-186

9. DIFFUSE LARGE B-CELL LYMPHOMA

Diffuse large B-cell lymphoma (DLBCL) accounts for 30-40% ofadult NHLs in the western countries. These clinically aggressive tumorsmay present in lymph nodes or in extra-nodal sites.53.187 A variety ofextranodal sites may be involved, including the gastrointestinal tract, bone,skin, central nervous system, liver, and spleen. Presentation in the bonemarrow and/or peripheral blood, however, is rare. 188 DLBCLs can occur inpatients of all ages, including children.99.12o.189 Most cases arise de novo;however, some cases represent transformation from a previous low-gradelymphoma, e.g. B-CLLlSLL, FL, MZL.

Diffuse large B-cell lymphomas have a diffuse growth pattern,obliterating the normal architecture of the involved lymph node orextranodal site. However, DLBCLs are heterogeneous with regards tocellular morphology (Fig. 21a-f). In most cases the neoplastic largelymphoid cells resemble centroblasts (large non-cleaved cells) orimmunoblasts (large lymphoid cells with a single, centrally-placed nucleoli).They may also appear multilobated, Reed-Sternberg cell-like, and/oranaplastic (i.e. cells with bizarre pleomorphic nuclei). Another morphologicvariant is T cell/histiocyte rich B cell lymphoma, where the neoplastic Bcells account for only 10% or less of the malignant cell population.190-192There are also distinct forms of DLBCL, including mediastinal (thymic)large B-cell lymphoma, intravascular large B cell lymphoma, and primaryeffusion lymphoma (PEL). The latter two lymphomas are extremely rare; inaddition, PEL occurs primarily in HIV-positive individuals. 193 Mediastinallarge B-cell lymphoma is thought to arise from thymic B cells, and isclinically, immunophenotypically, and genetically distinct from otherDLBCLs.194-196

Diffuse large B-cell lymphomas usually express the pan-B cellantigens, such as CDI9, CD20, CD22, BSAP/PAX-5, and CD79a.However, some cases may lack expression of one or more of theseantigens.176.188.197 The cells may express surface and/or cytoplasmic Ig; thelatter is usually seen in cases that exhibit plasmacytic differentiation. 198,199Some cases may also express CD30.198.199 Approximately 30% and 80% of


the cases express CDlO and BCL-6, respectively. BCL-2 is positive inapproximately 50% of the cases express. CD138 expression is only rarelyseen. Expression of IRF4IMUMI is frequently found. Approximately onethird of cases express CD43, including a number of those that lackexpression of all pan-B cell antigens. In these "CD43 only" cases, it isimportant to perform additional studies, including immunoglobulin and Tcell receptor chain gene rearrangement analyses to determine the celllineage, since CD43 can be expressed by myeloid tumors as well as by T andB cell neoplasms.

Occasional cases of DLBCLs are CD5 positive. These may ariseeither de novo or represent transformed cases of CLLlSLL or MCL; atransformed case of MCL usually expresses BCL_I,200 while many of thetransformed CLLlSLL cases retain CD23 expression.201.202 De novo CD5positive DLBCLs are associated with a more aggressive clinical course anddecreased survival.203 ,204 Other adverse prognostic indicators include BCL-2and/or p53 overexpression.205.206 Recent gene profiling studies haveidentified two categories of DLBCLs according to patterns of geneexpression: germinal center cell-like and activated B cell-like.55 Patientswith the former type had a better overall survival than the latter. CDIO andBCL-6 are two markers commonly associated with germinal center B celllike DLBCLs, whereas IRF4/MUMI expression is associated with theactivated B-cell type (Fig. 22).207

10. PLASMA CELL NEOPLASM

The broad diagnostic category of plasma cell neoplasm (PCN)includes many clinicopathological entities according to the WHOclassification scheme: plasma cell myeloma (including the variants nonsecretory myeloma, smoldering myeloma, indolent myeloma, and plasmacell leukemia), plasmacytoma (solitary or extramedullary type),immunoglobulin deposition diseases (primary amyloidosis, systemiclight/heavy chain deposition disease), osteosclerotic myeloma (POEMSsyndrome), and heavy chain disease (gamma, mu, and alpha).208 The mostcommon type of PCN, however, is plasma cell myeloma.

Plasma cell myeloma (i.e. multiple myeloma) usually presents as amultifocal bone marrow neoplasm, although solitary bone or extramedullary(i.e. tissue) presentation may be seen. Peripheral blood and/or lymph nodeinvolvement is only rarely present. The incidence of plasma cell myeloma ishigher in blacks than whites, and tends to increase with advancing age.2°9

The afflicted patients have one or more of a myriad of clinicalmanifestations of the disease process, including serum or urine "M"


(monoclonal) protein, pathologic fractures, bone pain, hypercalcemia,anemia, recurrent infections, and renal failure in addition to havingneoplastic plasma cells?08,21O The diagnosis is based on a constellation ofclinical, radiologic and pathologic findings. In general, a diagnosis ofplasma cell myeloma can be made when at least two of the following criteriaare met: marrow plasmacytosis, lytic bone lesions, monoclonal protein (Mcomponent) in the serum or urine, plasmacytoma on tissue biopsy, andreduced production of normal immunoglobulins?08

Bone marrows involved by plasma cell myeloma show an excessnumber of plasma cells, These plasma cells often form large aggregates andsheets, in contrast to normal plasma cells that tend to be scattered or formsmall clusters around vessels, The myeloma plasma cells may have variablemorphologic appearances (Fig, 23), including mature formsindistinguishable from normal plasma cells ("clock-face" chromatin withoutnucleoli, perinuclear hof, eccentric nucleoli), immature forms with moredispersed chromatin and prominent eosinophilic nucleoli, and those with"plasmablastic" features such as high nuclear to cytoplasmic ratio,prominent nucleoli, and blastic nuclei. The latter morphologic appearancehas been associated with a poor prognosis?11,212 These differentmorphologic variations may be seen together in a single patient and even inthe same biopsy.

The neoplastic plasma cells, like their normal counterpart, lacksurface expression of most antigens, including sIg, However, they expressclg that is monotypic, mostly commonly IgG and less commonly IgA,213Expression of the other Ig isotypes, i.e, IgD, IgM, and IgE, is rare.Regardless the isotype, the M component in most cases is secreted as awhole Ig molecule, complete with heavy and light chain, However, in about15% of cases only immunoglobulin light chains are produced ("BenceJones" myeloma), Most myeloma plasma cells lack expression the B-cellmarkers CD20 and CD22; however, they express cCD79a. CD20 expressionis detected in 20% of the cases of plasma cell myeloma; these malignantplasma cells are usually small in size and contain t(l1;14) (Fig, 24).214Patients with CD20-positive plasma cell myeloma may benefit from antiCD20 monoclonal antibody therapy, Although normal plasma cells areCD19 positive and express the B-cell transcription factor PAX-5, neoplasticplasma cells are negative for both.215 As the PAX-5 gene is a regulator ofCDl9 transcription, the lack of PAX-5 expression may be responsible forthe lack of CD19 expression by the myeloma cells,32,215,216 Myelomaplasma cells express CD38, CD138 (syndecan-1), and sometimes CD56 (NCAM), As CD56 is not expressed by normal plasma cells, CD56 expressionby plasma cells is indicative of their malignant nature.32,217,218 In addition,CD56 expression is frequently associated with lytic bone lesions in myeloma

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HODGKIN’S AND NON-HODGKIN’S · HODGKIN’S AND NON-HODGKIN’S LYMPHOMA edited by JOHN P. LEONARD, MD ... pathology and imaging have provided a better understanding of the pathogenesis