THE----------------
`
`GEORGE P. CANELLOS,
`MD, FRCP
`William Rosenberg Professor
`of Medicine
`Harvard Medical School
`Dana-Farber Cancer Institute
`Boston, Massachusetts
`
`T. ANDREW LISTER,
`MD, FRCP, FRCPath
`Professor of ¥edical Oncology
`and Director
`ICRF Medical Oncology Unit
`Department of Medical
`Oncology
`St. Bartholomew's Hospital
`West Smithfield
`London, England
`
`JEFFREY L. SKLAR,
`MD, PhD
`Professor of Pathology
`Harvard Medical School
`
`Director, Divisions of
`Molecular Oncology and
`Diagnostic Molecular
`Biology
`Brigham and Women's Hospital
`Boston, Massachusetts
`
`W.B. SAUNDERS COMPANY
`A Divisio11 of Harcourt Brace & Co111pa11y
`Philadelphia London Toronto Montreal Sydney Tokyo
`
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`

`

`W.B. SAUNDERS COMPANY
`A Divisio11 of Harco11rl Brace & Company
`
`The Curtis Center
`Independence Sqnare ,vest
`Philadelphia, Pennsylvania 19106
`
`Library of Congress Cataloging-in-Publication Data
`
`The lymphomas / [edited by] George P. Canellos, T. Andrew Lister,
`Jeffrey L. Sklar. - 1st ed.
`
`p.
`
`cm.
`
`ISBN 0-7216-5030-9
`
`I. Canellos, George P. (George Peter)
`1. Lymphomas.
`II. Lister, T. A. (Thomas Andrew)
`Ill. Sklar, Jeffrey L.
`[DNLM: 1. Lymphoma. WH 525 L9852 1998]
`
`RC280.L9L953 1998 616.99'446-dc21
`
`DNLM/DLC
`
`97-22034
`
`THE LYMPHOMAS
`Copyright© 1998 by v,rn. Saunders Company.
`
`ISBN 0-7216-5030-9
`
`All rights reserved. No pmt of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy,
`recording, or any information storage and retrieval system, without permission in wdting from the publisher.
`
`Flinted in the United States of America.
`
`Last digit is the print number:
`
`9
`
`8
`
`7
`
`6
`
`5
`
`4
`
`3
`
`2
`
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`

`

`Chapter T
`
`• I
`
`Priillary Extranodal Lyillphoillas
`
`. .
`
`Simon B. Sutdliff'!e
`Mary K.. Gospodarowiaz
`
`The term "malignant lymphoma" refers to cancer of the
`lymphatic/reticuloendothelial system and comprises tvm
`major categories of malignant disease-Hodgkin's disease
`and non-Hodgkin's lymphoma. Both Hodgkin's disease and
`non-Hodgkin's lymphoma share the commonalities of fre(cid:173)
`quent presentation with lymphadenopathy; a common
`symptomatology of fever, night sweats, and weight loss; a
`common staging classification; and a therapeutic approach
`using radiation and/or chemotherapy. They also have impor(cid:173)
`tant distinguishing features in terms of age spectrum,
`histologic and cytologic appearances, prognosis, and the
`frequency,vith which non-Hodgkin's lymphomas present as
`plimmy extranodal tumors-a circumstance of extreme
`rarity in Hodgldn's disease.
`"Primmy extranodal lymphoma" refers to a localized
`presentation oflymphoma arising within an extranodal tissue
`and deemed to be the site of origin of the lymphoma even
`though regional lymphadenopathy may be present. The term
`implies that disseminated disease is not clinically evident,
`thus distinguishing extranodal presentation with or without
`lymphadenopathy (stages I to IIE) from disseminated or
`stage IV disease. The term also has more relevance when
`applied to the tissue of origin, for example, tonsil, paranasal
`sinus, or thyroid lymphoma, than to an anatomic region of
`the body, for example, head and neck lymphoma,
`This chapter addresses primmy extranodal lymphomas
`other than those arising in sldn or the central nervous system
`(CNS), Although it is not knmvn "(hether mediastinal large
`cell lymphoma arises from nodal or extranodal (thymic)
`tissue, it is included as a characteristic clinic entity distin(cid:173)
`guishable from nodal lymphoma of equivalent stage pre(cid:173)
`senting in nonmediastinal sites,
`Whereas Hodgldn's disease virtually always arises in nodal
`tissue and relatively less commonly involves extranodal
`tissues by extension from nodal tissue or by dissemination,
`non-Hodgkin's lymphomas have a much greater propensity
`to disseminate early through systemic circulation of lym(cid:173)
`phoma cells. In principle, therefore, it is not really surprising
`that extranodal lymphomas have been recorded in virtually
`eveiy tissue of the body, as either primmy or metastatic
`lesions, It is also clear, however, that ce1tain tissues are much
`more commonly the site of primmy extranodal lymphoma,
`for example, gastrointestinal ( GI) tract and tonsil, and that
`there are factors that determine preferential patterns of
`
`spread of lymphoma and the receptiveness of certain tissues
`or organs to accommodate metastatic growth.
`The following three principal issues are considered with
`respect to plimmy extranodal lymphoma:
`
`• Does the presentation of localized disease
`in an
`extranoclal site confer a different prognosis than a
`presentation of similar stage in a nodal site? The data
`presented in Figure 25-1 suggest that when analyzed
`by stage alone, there is no difference in survival for
`patients presenting with nodal or extranodal lym(cid:173)
`phoma. This is somewhat sm1xising given that p1immy
`extranodal lymphomas are much more commonly of
`diffuse large cell type ( or more aggressive histologic
`types) than nodal lymphomas, despite otherwise com(cid:173)
`parable prognostic attlibutes. Thus, the distinction
`between nodal versus extranodal lymphoma does not
`constitute a prognostically relevant distinction ,vithout
`fmther analysis of the subcategories of extranodal
`disease,
`• Do all primary e;,...tranoclal lymphomas have a similar
`natural history ancl prognosis? A more detailed review
`of the natural history and prognosis of extranodal
`lymphoma reveals a wide diversity that largely reflects
`the frequency with which low-grade, indolent tumors
`constitute a substantial proportion of presentations,
`conferring a "favorable" prognosis (;::,:60% 5-year sur(cid:173)
`vival rate)-for example, GI tract, ,1/aldeyer's ring,
`orbit, salivmy gland, and lungs-as opposed to sites or
`tissues where intermediate- and high-grade histologic
`types constitute the dominant proportion-for ex(cid:173)
`ample, testis or ova1y, bone, breast, or primmy CNS.
`Even with certain sites or tissues, the histologic
`spectrum and prognosis can be extremely heteroge(cid:173)
`neous, for example, p1imary cutaneous lymphoma with
`T-cell and B-cell representation through low-grade to
`high-grade malignancies (see Chapter 27). An impor(cid:173)
`tant concept in prima1y extranodal lymphoma is
`mucosa-associated lymphoid tissue (MALT) and its
`subsequent relationship to low-grade malignancy. The
`possible etiologic association with antigenic stimula(cid:173)
`tion and favorable natural histmy with low metastatic
`potential are features of MALT lymphomas. This con(cid:173)
`trasts with the more fulminant presentation and early
`449
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`450 1111 Primary Extranodal Lymphomas
`
`100
`
`.0
`
`~
`:0 co
`e a.
`"iii
`>
`.2'.
`::::,
`Cl)
`
`80
`
`60
`
`40
`
`20
`
`...... .,-.. "'"'"'"=~
`·······., ..
`
`0
`
`2
`
`4
`
`6
`
`12
`10
`8
`Time in years
`
`14
`
`16
`
`18
`
`20
`
`946W
`
`Figure 25-1. Cause-specific survival rates from the date of diagnosis for
`extranodal and nodal presentations of stages I and II non-Hodgkin's
`lymphoma. (From Sutcliffe SB, Gospodarowicz MK: Localized extranodal
`lymphomas. In Keating A, Armitage J, Burnett A, Newland A [eds]:
`Haematological Oncology. Camb1idge, Cambridge Medical Reviews, 1992,
`pp 189-222.)
`
`and widespread dissemination of disease in sites or
`tissues characterized by intermediate- or high-grade
`tumors, for example, bone or testis. Pdmaiy CNS
`lymphomas also present characteristic features related
`to the histologic type, the growth pattern (largely
`confined to the nervous system), the probability oflocal
`recurrence (high), and the etiologic role of immuno(cid:173)
`deficiency, particularly acquired immunodeficiency
`syndrome (AIDS) and post-organ transplantation (see
`Chapter 27).
`• Do the same management pdnciples apply to localized
`nodal and extranodal lymphoma? Both nodal and
`extranodal non-Hodgldn's lymphomas share a number
`of common prognostic determinants, for example,
`stage, symptoms, tumor bulk, and histologic type.
`These attiibutes define the survival probability, largely
`as a measure of the likelihood of pdmaiy tumor control
`with therapy, either as a function of recurrence after
`radiation or complete response after chemotherapy or
`combined-modality therapy. The site of extranodal
`disease provides the additional dimensions ofhistologic
`characteristics, preferential organ localization, and
`patterns of relapse or dissemination that may be
`factored into the initial management plan.
`
`GENERAL ASPECTS OF
`EXTRANODAL LYMPHOMA
`
`" 24% of all nondisseminated lymphomas in the U.S.
`Surveillance, Epidemiology, and End Results group of
`cancer regishies, 1950 to 1964 data1
`• 41 % of all patients with non-Hodgkin's lymphoma
`(stages I-IV) from a population-based regishy in the
`N etherlands2
`" 37% of all patients with non-Hodgldn's lymphoma
`(stages I-IV) from a contempormy population-based
`registiy of all new cases in western Denmark3
`• 50% of patients ,vith stages I and II non-Hodgkin's
`lymphoma or 31.5% of all patients (stages I-IV) seen at
`Princess Margaret Hospital (PMH) from 1967 to 19884
`The distribution of primmy extranodal presentation
`(stages I and IIE) in the PMH series is shown in Figure 25--3
`and in compadson ,vith the sedes of Freeman and associ(cid:173)
`ates1 and Otter and colleagues in Tables 25-1 and 25-2. 2
`
`PATHOLOGY
`Traditional classifications of non-Hodgldn's lymphoma
`derive from morphologic observations stressing architectural
`change in relation to normal tissue anatomy ( usually lymph
`node) and cytologic appearances of infiltrating malignant
`cells. Subsequently, concepts emphasizing lineage, function,
`and differentiation using phenotypic and molecular tech(cid:173)
`niques have been introduced. Morphologic classifications
`are more suited to lymph node interpretation. The four
`classic classifications, which formed the basis for clinical
`studies, are as follows:
`• Rappapmt-nodular versus diffuse; variable differen(cid:173)
`tiation of lymphocytes; histiocytic cells; mixed lympho(cid:173)
`cytic and histiocytic populations5
`• Lukes and Collins-B cell versus T cell; small lympho(cid:173)
`cyte, plasmacytoid lymphocyte, follicular center cell(cid:173)
`small and large, cleaved and noncleaved; T-cell
`tumors-small lymphocytes, convoluted or cerebriform
`cells, lymphoepithelial, imrnunoblastic lesions6
`
`100
`
`50
`
`-----Incidence
`
`--Mortality
`
`5
`
`... ---... .,,."
`
`, Male
`,.,,-;,-... -;-""'-· Female
`-,.,,.,
`1 ~Ma le
`~ Female
`0.5
`
`INCIDENCE AND DISTRIBUTION
`N on-Hodgldn' s lymphomas account for approximately 5%
`of human cancers, with an age-standardized incidence of
`around 17 per 100,000 persons. They occur more commonly
`with advancing age (Fig. 25-2) and do not show the bimodal
`adult age distribution characteristic of Hodgldn's disease.
`The frequency of occurrence of p1immy extranodal
`lymphoma has been reported as
`
`58
`
`66
`
`74
`
`82
`
`90
`
`50
`B
`Calendar year
`
`58
`
`66
`
`74
`
`82
`
`90
`
`Figure 25-2. Incidence and mortality rates e,qwessed per 100,000 of the
`population for non-Hodgkin's lymphoma (ICD 9: 200,202) for patients
`younger (A) or older (B) than 50 years of age for the Province of Ontario.
`Age is adjusted to the world standard population. ICD, International
`Classification of Diseases. Data from the Division of Epidemiology and
`Statistics, Ontaiio Cancer Treatment and Research Foundation.)
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`

`lung and pleura (1.1%)
`breast (2.0%)
`extradural (2.5%)
`bone (3.7%)
`
`skin (3.8%)
`
`eye and orbit (4.1%)
`
`testis and G.U. (4.4%)
`
`soft tissues (5.2%)
`
`GI tract (24.3%)
`
`thyroid (6.1%)
`
`Waldeyer's ring (19.4%)
`
`brain (10%)
`
`Primary Extranodal Lymphomas 1111 451
`
`Figure 25-3, Distiibution of extranodal presentations of
`stages I and II non-Ho<lgldn's lymphoma by site(cid:173)
`P1incess Margaret Hospital series, 1967-1988. GU,
`genitourinary; GI, gastrointestinal; gynae., gynecologic.
`(From Sutcliffe SB, Gospodarowicz MK: Localized
`extranodal lymphomas. In Keating A, Armitage J, Burnett
`A, Newland A [eds]: Haematological Oncology. Cam(cid:173)
`biidge, Cambridge Medical Reviews, 1992, pp 189-222.)
`
`• Kiel-lymphocytic, immunocytic, and centrocytic tu(cid:173)
`mors; centroblastic/centrocytic tumors; centroblastic,
`inununoblastic, and lymphoblastic tumors 7; subsequent
`additional distinction of B-cell and T-cell lineage8
`• Working Formulation prognostic categories-low, in(cid:173)
`termediate, and high grade, characterized predomi(cid:173)
`nately by Rappaport groupings but applicable to other
`classifications9
`
`When applied to the characterization of primaiy extra(cid:173)
`nodal lymphoma, limitations of these classifications become
`apparent.
`• The extranodal site architecture does not necessaiily
`align itself with nodal architecture, displaying a clear
`distinction of nodular (follicular) and diffuse efface(cid:173)
`ment of tissue.
`• Extranodal tissue biopsies are frequently small and
`often crushed or distorted. Issues relating to sample
`size, adequacy of material for interpretation, and
`representativeness of tissue involved by lymphoma
`aiise. There are also issues related to preservation and
`handling of small fragments or biopsy specimens and
`the adequacy of material for phenotypic and molecular
`analysis.
`" Distinction of normal physiologic lymphoid aggregates
`from localized involvement of tissue by lymphoma, for
`example, Askanazy nodules 'in bone marrow biopsy
`specimens and periportal lymphocytic infiltrates in liver
`
`biopsy specimens can be difficult. In certain sites, there
`has histmically been controversy as to tl1e nature of
`lymphoid pseudotumors, for example, orbital, pulmo(cid:173)
`naiy, and GI pseudotumors, and their distinction from
`low-grade malignant lymphoma.
`• Although tl1ese histologic classifications applied satis(cid:173)
`factorily to nodal and B-cell lymphoma, tl1e histologic
`classification of T-cell disease in nodal and extranodal
`sites posed difficulties. Additionally, the classification as
`a guide to prognostication is often limited in various
`categories of T-cell disease, for example, angioimmu(cid:173)
`noblastic lymphadenopathy, lymphomatoid granuloma(cid:173)
`tosis, and peripheral T-cell lymphomas.
`A recently proposed Revised European-American Lym(cid:173)
`phoma (REAL) classification for malignant lymphomas
`addresses some of these issues by including all the lympho(cid:173)
`proliferative disorders. 10 The REAL classification identifies
`a number of distinct disease entities not represented in
`previous classifications (Table 25-3). It is based on tl1e
`premise that B-cell malignancies are distinct from T-cell
`malignancies and attempts to desc1ibe a number of clinical
`entities, while treating the grade of disease as a variable
`within a given disease rather than the basis for classification,
`as does the Working Formulation.
`Several of the histopathologic and clinical entities are of
`particular importance to the primaiy extranodal lymphomas.
`The most common is MALT lymphoma ( discussed in the
`following section).
`
`Table 25-1. Distiibution of Patients with Non-Hodgkin's Lymphoma•
`
`Seiies
`
`Freeman et aP (1972)
`Otter et al2 (1989)
`Sutcliffe and Gospodarowicz4 (1992)
`
`Pedod
`
`1950-1964
`1981-1986
`1967-1988
`
`'Number of patients
`t Refers to nondisseminated lymphoma.
`iExclu<les 79 patients with piima1)' brain lymphoma.
`§Clinical stages IE and IIE.
`
`Total
`Number
`
`1467
`580
`2254t
`
`Stages I
`and II (No.)
`
`Pdmary
`Extranodal (No.)
`
`Percentage
`Extranodal
`
`242
`1391
`
`1467f
`236
`708§
`
`24
`40,7
`31.4
`
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`

`452 11111 Primary Extranodal Lymphomas
`
`Table 25-2. Sites of Primaiy Extranodal Non-Hodgkin's Lymphoma•
`
`Freeman et al1 (1972):
`Nondisseminated Lymphoma
`
`Otter et al2 (1989):
`Stages I-IV
`
`Sutcliffe and Gospodarowicz3 (1992):
`Stages I and IIE
`
`Series
`
`Gastrointestinal
`Waldeyer's
`Other head and neck
`Thyroid
`Eye and orbit
`Genitourinary
`G)~1ecologic
`Breast
`Berne
`Extradural
`Lung and pleura
`Soft tissue
`Sldn
`Brain
`Others
`No. of patients
`
`36.7
`13.6
`4.7
`2.5
`
`0,16
`
`2.2
`4.7
`
`3,6
`8.6
`7.5
`
`14.7
`1467
`
`16.6
`
`580
`
`24.3
`19.4
`9.5
`6.1
`4.1
`4.4
`1.0
`2.0
`3.7
`2.5
`1.1
`5.2
`.3.8
`10
`2.7
`787
`
`'E,pressed as a percentage of total.
`
`Mucosal-Associated Lymphoid
`Tissue Lymphoma
`MALT lymphomas deserve special attention. These are
`low-grade B-cell tumors of MALT predominantly in the
`GI tract, pharynx, salivmy glands, lung, and thyroid. They
`are characterized by a prolonged clinical course and
`persistent disease at the site of migin. They have a
`characteristic
`lymphoepithelial
`lesion
`consisting of
`centrocyte-like cells lying within the lamina propria and
`infiltrating the glandular epithelium of the mucosa. Tumors
`arising from MALT tissues demonstrate a clonal origin, and
`there is evidence of malignancy in otherwise "benign"
`lymphoepithelial lesions within MALT tissues. 11• 12 There
`has also been demonstration of clonality vvithin the oth(cid:173)
`erwise apparently benign lymphoepithelial lesion and sub(cid:173)
`sequent malignancy within another MALT-tissue epithelial
`system in archival material over a long natural histmy of
`illness. 13
`MALT lymphomas are usually associated with preexisting
`chronic immune system stimulation. Most MALT lympho(cid:173)
`mas arise in the stomach, but they may involve other known
`MALT sites such as thyroid and salivmy glands as well as
`other less well-described situations, ipcluding breast and
`bladder tissue. The cause of this disease has now been linked
`to infection \.vith Helicobacter pylori. Although typical
`MALT lymphomas are low-grade small B-cell neoplasms,
`they may transform into intermediate-grade large cell
`lymphomas. Current experience with these neoplasms
`suggests that MALT lymphomas tend to remain localized
`and may be cured with local therapy, even when trans(cid:173)
`formed.14
`Immunoproliferative small intestinal disease (IPSID) is an
`indolent lymphoma, probably of MALT origin, involving
`upper small intestine with associated malabs011Jtion and
`a-heavy-chain disease. 1.5 Large cell transformation may
`occur. Some early clonal IPSID lesions have been noted to
`regress after antibiotic therapy, suggesting that immune
`stimulation is involved in their pathogenesis.
`
`Peripheral T-Cell Lymphomas
`Peripheral T-cell lymphomas are a heterogeneous group
`of T-cell neoplasms, more common in Asia, usually affecting
`adults and commonly generalized at presentation. Eosino(cid:173)
`philia and pruritus are common. An aggressive clinical
`course is typical, and although the disease is potentially
`curable, some are resistant to current chemotherapeutic
`regimens. Specific subtypes of peripheral T-cell lymphoma
`should be considered because of their importance in primary
`extranodal lymphomas.
`
`Intestinal T-Cell Lymphoma (With or
`Without Enteropathy)
`Intestinal T-cell lymphoma, previously called "malignant
`histiocytosis of the intestine" is uncommon.1.5- 17 It com(cid:173)
`monly involves the jejunum, is associated with a previous
`histmy of gluten-sensitive enteropathy in approximately 50%
`of cases, and is referred to as "enteropathy-associated T-cell
`lymphoma (EATL)." Most EATLs are high-grade pleomor(cid:173)
`phic large cell lymphomas and are associated \.vith a poor
`prognosis. They are usually CD3+, CD7 +, CD4-, and CD8-
`peripheral T-cell lymphomas. They express HML-1, sup(cid:173)
`porting an origin from the intraepithelial T cells of MALT.
`Non-EATL T-cell lymphomas can occur anywhere in the GI
`tract. Most are CD4+. Some are classified as Ki-I-positive
`anaplastic large cell lymphomas.
`
`Angiocentric Lymphoma
`Angiocenhic lymphoma includes disorders previously
`known as "lethal midline granuloma," "nasal T-cell lym(cid:173)
`phoma," "lymphomatoid granulomatosis," and so forth. It is
`characterized by an angiocentiic and angioinvasive infil(cid:173)
`trate.18 The most typical example of this disease includes
`angiocentiic T-cell sinonasal lymphoma. Although less
`common in Western countiies, sinonasal lymphomas are the
`second most common group of extranodal lymphomas in
`patients in China. Many are angioinvasive T-cell lyrnphomas,
`
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`

`Table 25-3. International Lymphoma Study Group REAL
`Classification
`
`B-Cell Neoplasms
`
`I. Precursor B-cell neoplasm
`Precursor B-lymphoblastic leukemia/lymphoma
`II. Peripheral B-cell neoplasms
`• B-cell CLL/prolymphocytic lymphoma/small lymphocytic lym-
`phoma
`• Lymphoplasmacytoid lymphoma/immunocytoma
`• Mantle cell lymphoma
`• Follicle center lymphoma, follicular
`Provisional cytologic grades: I, small cell; II, mixed small and
`large cell; III, large cell
`Pro\isional subtype: diffuse, predominantly small cell type
`• Marginal zone B-ccll lymphoma
`Extranodal (MALT type ± monocytoid B cell)
`Provisional subt)1Je: Nodal (± monocytoid B eell)
`• Pro\isional entity: Splenic marginal zone lymphoma (± villous
`lymphocytes)
`• Hair cell leukemia
`• Plasmacytoma/plasma cell myeloma
`• Diffuse large B-cell lymphoma; subtype: pdmary mediastinal
`(tl1ymic) B-cell lymphoma
`• Burkitt's lymphoma
`• Provisional entity: High-grade B-cell lymphoma, Burldtt-1:ike
`
`T Cell and Putative NK-Cell Neoplasms
`
`I. Precursor T-cell neoplasm
`Precursor T-lymphoblastic lymphoma/leukemia
`II. Pe1ipheral T-cell and NK-cell neoplasms
`• T-ccll CLL/prolymphocytic leukemia
`• Large granular lymphocyte leukemia (LGL)
`T-cell l)11e, NK-cell l)']_le
`• Mycosis fungoides/Sezary syndrome
`• Peripheral T-cell l)~nphomas, unspecified
`Pro\isional cytologic categmies: Medium-sized cell, mixed
`medium and large cell, large cell, lymphoepitheliod cell
`Prmisional subl)11e: Hepatosplenic y8 T-cell lymphoma
`Provisional snbl)1Je: Subcutaneous panniculit:ic T-cell 1)~11-
`phoma
`• Angioimmunoblastic T-cell lymphoma (AILD)
`• Angiocentdc lymphoma
`• Intestinal T-cell lymphoma (± enteropathy-associatecl)
`• Adult T-cell lymphoma/leukemia (ATL/L)
`• Anaplastic large cell lymphoma, CD30+, T- and null cell l)11e
`Provisional entil)•: Anaplastic large cell l)~nphoma, Hodgkin(cid:173)
`like
`
`REAL, Revised Enropean-Ammican Lymphoma; CLL, chronic lymphocytic
`leukemia; MALT, mucosal-associated lymphoid tissue; NK, natural killer,
`
`express the CD4+ immunophenotype, and may have clonal
`T-cell receptor gene rearrangements. Sinonasal T-cell lym(cid:173)
`phomas usually follow an aggressive course. Other sites of
`angiocentric lymphoma include the skin, lung, and CNS.
`Recent studies suggest that some pulmonary cases may be
`associated with B-cell proliferation and may represent a
`distinct disease entity. 19
`
`Ana plastic Large Cell (CD30+)
`Lymphoma
`Ana plastic large cell ( CD30+) lymphoma is a distinct
`entity ,vith a predilection for skin involvement and gener(cid:173)
`alized disease. 20 The prognosis ranges from indolent for
`disease involving skin only to aggressiue for patients with
`
`Primary Extranodal Lymphomas 1111 453
`
`generalized disease. Two forms of the disease have been
`recognized: (1) a systemic form (CD30+, epithelial mem(cid:173)
`brane antigen [EMA] positive) with nodal and extranodal
`involvement including skin, and (2) a plimary cutaneous
`form (EMA-negative CLA-positive) with involvement lim(cid:173)
`ited to the skin. Primary cutaneous tumors occur predomi(cid:173)
`nantly in adults, may spontaneously regress, and are indolent
`but incurable. The systemic form appears to behave similarly
`to other large cell lymphomas and is aggressive but
`potentially curable.
`Certain studies have indicated that there may be a
`different genetic origin to large cell tumors arising in nodal
`versus extranodal sites. Raghoebier and colleagues21 have
`demonstrated that BCL2 rearrangement occurs much more
`commonly in nodal and cleaved large cell lymphoma
`compared with its infrequent occurrence and more common
`demonstration of c-myc arrangement in extranodal and
`noncleaved large cell lymphomas, implying that the funda(cid:173)
`mental changes at the genomic level between nodal and
`extranodal lymphomas may be different. This is also
`supported by the finding of a high frequency of BCL6
`rearrangement in diffuse large cell lymphoma involving
`extranodal sites. Furtl1ermore, the presence of BCL6 in
`diffuse large cell lymphoma has been associated with a
`favorable outcome independent of other recognized prog(cid:173)
`nostic factors. 22
`
`ETIOLOGY
`Despite increasingly detailed knowledge of genomic
`events underlying the progression and expression of malig(cid:173)
`nant lymphoma, information on causative agents is lacldng
`for botl1 nodal and extranodal lymphoma. Tentative evidence
`for a role for environmental factors has been reviewed. 23, 24
`An expanding literature is evolving for a potential causal
`relationship between immunodeficiency, prolonged anti(cid:173)
`genic stimulation, and the development oflymphoma. Thus,
`in cases of organ transplantation,25 AIDS,26 X-linked lym(cid:173)
`phoproliferative syndrome,27 and primaiy immunodefi(cid:173)
`ciency states,28 tl1ere is an excess risk that the patient ,vill
`develop malignant lymphoma. Such tumors are usually of
`B-cell, intermediate- or high-grade histologic type, com(cid:173)
`monly involving or presenting in extranodal sites such as the
`CNS, the GI tract, liver, and bone marrow. Although
`extranodal lymphoma is more common with conventional
`immunosuppression for organ transplantation, the more
`recent experience with cyclosporine has demonstrated
`equivalence of nodal and extranodal presentations. 25 A
`potential role for Epstein-Barr virus (EBV) has been
`intimated for lymphomagenesis in association with immu(cid:173)
`nodeficiency.
`Lymphomas also occur in excess after therapy for
`Hodgldn's disease.29 Both B- and T-cell
`tumors are
`recorded, and they are of intermediate- or high-grade
`type. There is no clear relationship to EBV: In this setting,
`both cellular immunodeficiency from disease and from
`treatment-related processes and the carcinogenic impacts of
`cytotoxic chemotl1erapy and/or radiation may be etiologically
`relevant. A potential role for infectious agents in tl1e etiology
`of GI lymphoma ( GIL) has deiived from l:\vo separate
`observations. In IPSID, or a-chain disease, a common small
`
`NOVARTIS EXHIBIT 2005
`Breckenridge v. Novartis, IPR 2017-01592
`Page 7 of 33
`
`

`

`454 1111 Primary Extranodal Lymphomas
`
`bowel lymphoma occurring in the circumstance of economic
`deprivation and poor sanitation in the Middle East and
`Mediterranean, Ben Ayed and associates reported complete
`remission in two of six patients treated with antibiotics alone
`for stage A disease.30 Various intestinal organisms in the
`context of intestinal bacterial overgrowth were noted in this
`repmt. More substantial is the evidence relating to H. pylori
`as an etiologic factor for low-grade MALT lymphoma of the
`stomach. As outlined by Isaacson,31 H. pylori is present in
`tl1e stomach of persons with gastric lymphoma, the preva(cid:173)
`lence of infection is related to the development of gastric
`lymphoma, the presence or absence of infection correlates
`with lymphoma, and infection precedes the development of
`lymphoma.31, 32 In the absence of organized lymphoid tissue
`in the stomach, H. pylori is believed to stimulate an
`accumulation of lymphoid tissue, which, in tl1e presence of
`persisting infection, antigenic stimulation, and activation of
`lymphoid cells, results in the evolution of a clonal, low-grade
`B-cell MALT lymphoma.33 Such tumors are cytokine
`sensitive and potentially reversible.34 The cytokine depen(cid:173)
`dence is lost with histologic progression of tl1e low-grade
`lesion to a large cell lymphoma.
`Although an infectious organism has not been defined for
`Sjogren's syndrome or Hashimoto's disease, botl1 disorders
`are characterized by lymphocytic infiltration at sites (salivary
`gland and thyroid gland) normally lacldng organized lym(cid:173)
`phoid tissue. In botl1 circumstances, the evolution of a
`lymphoepithelial lesion to a clonal low-grade B-cell MALT
`lymphoma is recognizecl35, 36; also recognized is a relation(cid:173)
`ship to the development of MALT lymphoma in other organ
`systems.13
`
`CLINICAL ASSESSMENT AND
`STAGING INVESTIGATIONS
`The clinical assessment of patients ,vith primary extra(cid:173)
`nodal lymphoma follows the principles established for
`assessment of patients with nodal presentations. Howeve1~
`patients with primary extranodal lymphoma, unlike those
`witl1 nodal or generalized lymphoma, may present to
`specialists not accustomed to dealing with malignant lym(cid:173)
`phoma. In such cases, assessment of the local disease extent
`may be excellent, but the assessment to exclude dissemi(cid:173)
`nated disease may be deferred until after treatment of tl1e
`local problem. In some situations this approach may be
`appropriate, but in others it may lead to inappropliately
`extensive surgical resection. The initial assessment should
`elucidate symptoms related to tl1e presenting site of disease
`and, in addition, symptoms related to generalized disease
`and specifically to lymphoma.
`The assessment of tl1e extent of disease is one of the most
`important steps in selecting approp1iate therapy. Routine
`staging investigations include a full physical examination; a
`complete blood cell count; tests for eiythrocyte sedimenta(cid:173)
`tion rate (ESR), liver function, and lactic dehydrogenase
`(LDH) levels; imaging tests; and a bone marrow biopsy. The
`minimal imaging investigations include a chest radiograph
`and computed tomography ( CT) of the abdomen and pelvis.
`Appropliate imaging tests should be performed to delineate
`the extent of extranodal disease and its size, invasiveness, and
`effect on other organs. In uncertain cases, a cytologic
`examination of an effusion, or a needle biopsy of a suspicious
`
`lesion, may help claiify the extent of disease. Traditionally,
`bipedal lymphangiography has been useful in assessing
`pelvic and paraamtic lymph nodes. The specificity and
`sensitivity of lymphangiography in expert hands have been
`repmtecl to exceed that of CT.37 However, with improve(cid:173)
`ments in CT technology and the increased use of chemo(cid:173)
`tl1erapy in early-stage disease, tl1e overall value of lymphan(cid:173)
`giography has diminished.38 In addition, the value of
`lymphangiography in other cancers has been disappointing,
`resulting in a marked decline in its use and also, tl1erefore,
`a decrease in the number of specialists with expeitise in
`inteipretation of the test. Magnetic resonance imaging
`(MRI) is useful to delineate the extent of disease in soft
`tissues, but it is especially useful in illustrating the extent of
`bone, extraclural, and brain involvement. The use of
`gadolinium enhances MRI imaging in the CNS. Gallium
`scanning, especially high-close gallium (10 mCi), is a useful
`general screening tool for malignant lymphoma. In addition
`to its use in staging, it is also valuable in assessing the
`response to therapy.39, 40 The presence of asymptomatic GIL
`should be excluded in patients with primmy lymphoma of
`Waldeyer's ling or the thyroid gland. Traditionally, imaging
`of the upper GI tract has been performed, but endoscopy
`with biopsy is now preferred.
`
`STAGING CLASSIFICATION
`The Ann Arbor staging classification originally developed
`for staging of Hodgldn's disease has been used for non(cid:173)
`Hodgldn's lymphoma for approximately 20 years.41---43 Su(cid:173)
`pradiaphragmatic lymphoid regions in the Ann Arbor
`classification include the cervical lymph nodes (including
`cervical, supraclavicular, occipital, and preauricular nodes);
`infraclavicular; right and left axillmy; epitrochlear/brachial;
`mediastinal; and hilar lymph nodes. Infradiaphragmatic
`lymph node regions include the paraaortic, mesenteric, iliac,
`inguinofemoral, and popliteal lymph nodes. In the Ann
`Arbor classification, Waldeyer's ling, thymus, spleen, appen(cid:173)
`dix, and Peyer's patches of the small intestine are considered
`lymphatic tissues, and involvement of these areas does not
`constitute an "E" lesion, which was defined originally as
`"extralymphatic" involvement. However, most clinicians
`recognize the unique pathologic and clinical characteristics
`of primmy lymphoma affecting these organs and consider
`t