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`A Clinical Analysis of Two 1ndolent.Lymphoma Entities: Mantle Cell
`Lymphoma and Marginal Zone Lymphoma
`(Including the Mucosa-
`Associated Lymphoid Tissue and Monocytoid B-Cell Subcategories):
`A Southwest Oncology Group Study
`
`By Richard I. Fisher, Steve Dahlberg, Bharat N. Nathwani, Peter M. Banks, Thomas P. Miller, and Thomas M. Grogan
`
`The objectives of this study were (1) t o determine the clinical
`presentation and natural history associated with t w o newly
`recognized pathologic entities
`termed mantle cell lym-
`phoma (MCL) and marginal zone lymphoma (MZL), including
`the mucosa-associated lymphoid tissue (MALT) and mono-
`cytoid B-cell subcategories, and (2) t o determine whether
`these entities differ clinically from the other relatively indo-
`lent non-Hodgkin‘s lymphomas with which they have been
`previously classified. We reviewed the conventional pathol-
`ogy and clinical course of 376 patients who had no prior
`therapy; had stage III/IV disease; were classified as Working
`D, or E; and received cyclo-
`Formulation categories A, B, C,
`phosphamide, doxorubicin, vincristine, prednisone (CHOP)
`on Southwest Oncology Group (SWOG) studies no. .7204,
`7426, or 7713. All slides were reviewed by the three patholo-
`gists who reached a consensus diagnosis. Age, sex, perfor-
`mance status, bone marrow and/or gastrointestinal involve-
`ment,
`failure-free survival, and overall survival were
`
`M
`
`ORE THAN 10 YEARS have elapsed since the publi-
`cation of the National Cancer Institute’s Working
`Formulation (WF) that provided a common language for
`translating between the Rappaport, Lukes-Collins, Kiel, and
`World Health Organization
`lymphoma classification
`schemes.’ In the intervening years, several new pathologic
`entities have been recognized using morphologic, immuno-
`logic, and genetic methods. These new entities are not easily
`categorized in the existing classification schemes. Further-
`more, the clinical behavior of these new entities has been
`generally described only at single institutions in small series
`of patients who have been treated with a variety of therapeu-
`tic approaches.
`Among these new entities are cases of lymphoma that
`have been classified as lymphocytic lymphoma of intermedi-
`ate differentiation, intermediate lymphocytic lymphoma,
`centrocytic lymphoma, or mantle zone lymphoma.’-’ The
`term “mantle cell lymphoma” (MCL) has been recently
`proposed to replace these terms6 and will be used throughout
`this report. Lymphomas of mantle cell type have a character-
`istic morphologic appearance with both distinctive microana-
`tomic and cytologic feature^.^.^ Specifically, MCL is com-
`prised of small lymphoid cells with slightly irregular nuclear
`outlines and without admixed large transformed cells. Ini-
`tially, MCL grows around residual normal germinal centers,
`giving an expanded mantle zone pattern. This zonal or “nod-
`ular” pattern progresses to a diffuse effacing pattern. The
`MCL phenotype is also characterized by expression of Pan
`B antigens (CD20’, CD22+), monotypic Ig (IgM’ D’) and
`coexpression of the Pan T antigen CD5.’” MCL also has a
`characteristic chromosomal translocation t( 11; 14) involving
`the Ig heavy chain locus and the bcl-l oncogene that results
`in the overexpression of a gene known as PRADI, which
`encodes for cyclin Dl.’0”4
`A second group of patients have been described as having
`low-grade B-cell lymphoma of mucosa-associated lymphoid
`tissue (MALT)”-17 or monocytoid B-cell (MCBC) lym-
`
`compared among all the categories. We found that (1) MCL
`and MZL each represent approximately 10% of stage 111 or
`IV patients previously classified as Working Formulation cat-
`egories A through E and treated with CHOP on SWOG clini-
`cal trials; (2) the failure-free survival and overall survival of
`patients with MZL is the same as that of patients with Work-
`ing Formulation categories A through E, but the failure-free
`survival and overall survival of the monocytoid B-cell pa-
`tients were higher than that of the MALT lymphoma patients
`( P = .009 and .007, respectively); and (3) the failure-free sur-
`vival and overall survival of patients with MCL is significantly
`worse than that of patients with Working Formulation cate-
`gories A through E ( P = .0002 and .0001, respectively). In
`conclusion, patients with advanced stage MALT lymphomas
`may have a more aggressive course than previously recog-
`nized. Patients with MCL do not have an indolent lymphoma
`and are candidates for innovative therapy.
`0 1995 b y The American Society of Hematology.
`
`phoma.’*-*’ The term “marginal zone B-cell lymphoma”
`(MZL) has been proposed to encompass both of these subcat-
`egories and will be used here.” The MZL designation derives
`from a common microanatomic feature; both lymphomas
`involve the marginal B-cell compartment of lymphoid tissue
`outside the follicular mantle
`Both variants also
`manifest secondary involvement of benign germinal centers
`described as follicular col~nization.’~ The two entities also
`show considerable overlap with regard to cellular composi-
`tion.15-18,21 By definition, MCBC lymphoma is composed
`chiefly of clear cells with reniform or oval nuclei. MALT
`lymphoma often includes MCBCs as either a predominant
`or minority component. The two entities also have a virtually
`identical immunophenotype.” Their common immunophe-
`notype is positive for surface Ig, not of IgD type, positive
`for B-cell markers CD19, CD20, and CD22 and negative for
`CD5 and CD23. There is no genetic rearrangement for either
`bcl-l or bcl-2 loci.22
`
`From the Loyola Universiq Stritch School of Medicine, Maywood,
`IL; the Southwest Oncology Group Statistical Center, Seattle, WA:
`the University of Southern California, Los Angeles, CA; the Univer-
`sity of Texas Health Science Center, San Antonio, R: and the Uni-
`versity of Arizona Cancer Center, Tucson, AZ.
`Submitted July 28, 1994: accepted October 16, 1994.
`Supported in part by the following FS Cooperative Agreement
`grants awarded by the National Cancer Institute, Department of
`Health and Human Services: Grants No. CA38926, CA32102,
`CA46282, CA58882, CA22433, and CA13612.
`Address reprint requests to the Southwest Oncology Group
`(SWOG-7204/7426/7713) Operations OfJice, 14980 Omicron Dr,
`San Antonio, TX 78245-32 17.
`The publication costs of this article were defrayed in part by page
`charge payment. This article must therefore be hereby marked
`“advertisement” in accordance with 18 U.S.C. section 1734 solely to
`indicate this fact.
`0 1995 by The American Society of Hematology.
`0000-4971/95/8504-0010$3.00/0
`
`Blood, Vol 85, No 4 (February 15), 1995: pp 1075-1082
`
`1075
`
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`
`1076
`
`FISHER ET AL
`
`Although these numerous overlapping morphologic and
`immunophenotypic features suggest closely related lympho-
`mas, they also have microanatomic and distributional differ-
`ences reflecting the fact that the extranodal MALT
`lymphoma is mucosa-based and the MCBC lymphoma is
`node-based?* In particular, the MALT lymphoma has one
`specific, defining microanatomic feature, called a lymphoepi-
`thelia1 lesion that consists of distinctive lacunae of
`lymphoma cells within the m u c o ~ a . ’ ~ ” ~ This clustered tro-
`phism for the epithelium of affected extranodal parenchymal
`is the characteristic MALT lymphoma feature. In contrast,
`the MCBC lymphoma, which
`lacks the lymphoepithelioid
`lesion, has as its defining microanatomic property a lymph
`node growth pattern of confluent
`sinuses filled with small
`lymphoid cells with abundant clear cytoplasm.
`These new entities have now been included in the recent
`“Proposal for an International Consensus on the Classifica-
`tion of Lymphoid Neoplasms.”’’ To determine the clinical
`presentation and natural history associated with newly recog-
`nized pathologic entities termed MCL and MZL and to deter-
`mine whether these entities differ clinically from the other
`indolent lymphomas with which they have been previously
`classified, we reviewed the pathology and clinical course of
`376 previously untreated patients with advanced stage dis-
`ease and WF categories A, B, C, D, or E, who received
`cyclophosphamide, doxorubicin, vincristine, prednisone
`(CHOP) on Southwest Oncology Group (SWOG) studies no.
`7204, 7426, or 7713.
`
`PATIENTS AND METHODS
`All patients were entered on three sequential randomized clinical
`trials (SWOG no. 7204, 7426, and 7713) between 1972 and 1983,
`had stage ILI or IV non-Hodgkin’s lymphoma, and received full-
`
`dose CHOP chemotherapy or CHOP plus immunotherapy. Patient
`selection and eligibility criteria have been previously described.”
`
`Pathologic Review
`Each of the new entities in question has a distinctive microana-
`tomic and cytologic definition allowing accurate histologic diagnosis.
`It is recognized that immunophenotyping, molecular probes, and
`cytogenetics may be needed to resolve occasional classification is-
`sues in these cases. However, for multi-institutional group study
`is
`purposes, initial morphologic definition for protocol assignment
`critical. To this end a morphologic review of historic
`SWOG low
`and intermediate grade lymphomas (WF A through E) was initiated.
`Two of the authors (P.M.B., T.M.G.) are signatories of the recent
`“Proposal for an International Consensus on the Classification of
`Lymphoid Neoplasms,”’* and
`the third (B.N.N.) is a widely pub-
`lished authority on the subject of MCBC lymphomam as well as on
`low grade lymphomas in general. Thus, the newly formulated criteria
`were already familiar to these pathologists and could be applied
`readily to the microscopic and microanatomic diagnosis of these
`joint
`entities. Consensus morphologic diagnosis was achieved by
`review and agreement on all cases at a multiheaded microscope.
`The specific morphologic criteria are shown in Figs 1 to 3 and
`are described below.
`
`MCL
`MCL is morphologically homogeneous, being comprised of small,
`slightly irregular lymphocytes with small nucleoli and scant cyto-
`plasm (Fig 1). These “centrocytes” of the Kiel scheme
`are less
`irregular than the cleaved cells of follicular lymphoma (m, category
`B through D) or the diffuse small cleaved cell lymphoma (category
`E) of the W. MCL is
`further distinguished from diffuse small
`cleaved cell lymphoma
`by its near-absence of
`large transformed
`cells. It is distinguished from FL by the more scattered
`follicular
`dendritic cells relative to the tightly formed, dense follicular den-
`dritic cells or dendritic reticulum cells in FL.” Finally, MCL can be
`
`Fig 1. MCL is shown. The up-
`per panels show splenic involve-
`ment with MCL. Note expansion
`(MT) be-
`of the mantle zone
`tween the germinal center (GC)
`and outer marginal zone
`(MR).
`The lower left panel shows MCL-
`related intestinal polyposis. The
`lower right panel shows MCL in-
`filtrate characterized by homog-
`of small
`enous proliferation
`lymphoid cells with slightly ir-
`regular nuclear outlines and ele-
`vated mitotic rate.
`
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`MANTLE CELL AND MARGINAL ZONE LYMPHOMAS
`
`1077
`
`sisted of follicles infiltrated and expanded by centrocytic cells. Occa-
`further distinguished from category A (small lymphocytic leukemia
`sionally, naked germinal centers were found. This zonal or nodular
`[SLL]) by the absence of
`proliferation centers together with
`the
`greater irregularity of nuclear outlines in MCL.”~”
`pattern of expanded mantle zones often eventuated in a diffuse pat-
`of nodal effacement.
`The histologic growth pattern included both nodular and diffuse tern
`Besides the nodular and diffuse variants, a third variant was identi-
`types. The nodular pattern included cases growing
`in the mantle
`as well as those replacing
`fied, the lymphoblastoid or blastoid MCL. This blastoid variant was
`zone around residual germinal centers
`germinal centers. Most commonly, the nodular pattern observed con- characterized by small blastic lymphoid cells with finely dispersed
`
`Fig 3. MCBC lymphoma is
`shown. The upper left panel
`shows splenic involvement by
`MCBC
`lymphoma with ex-
`panded marginal zone (MR), out-
`side the mantle zone IMT) and
`germinal center (GC). This lesion
`gives a target-like effect micro-
`anatomically. The upper right
`panel shows MCBC lymphoma
`filling the outer marginal zones
`IF) of
`surrounding the follicles
`this lymph node produce a pat-
`tern of pale,
`confluent sinuses
`( C S ) . One follicle shows internal
`follicular colonization IFC). The
`lower left panel shows
`MCBC
`lymphoma infiltrate
`character-
`ized by a predominance of small
`lymphoid cells with slightly lo-
`bated nuclei and abundant pale
`cytoplasm. In the lower right
`panel, touch preparation (Wright
`Giemsa stain) shows monocy-
`
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`1078
`
`FISHER ET AL
`
`chromatin and a high mitotic rate as defined by Jaffe and cowork-
`ers.”
`
`MZL
`MALT lymphoma. All cases diagnosed as MALT lymphoma in-
`volved extranodal sites and all specifically had the distinctive micro-
`anatomic features of a lymphoepithelial lesions with several
`centrocyte-like lymphocytes clustered within epithelial lacunae (Fig
`2).’”’7.23 In addition, most showed submucosal lymphoma spread
`around reactive lymphoid follicles to produce a marginal zone pattern,
`and some showed follicular colonization by centrocyte-like cells.
`Cytologically, the lymphoid cells ranged from small round (WF
`category A) to small cleaved (WF category E) to slightly cleaved
`(centrocyte-like) cells. Typically, there were degrees of admixed
`monocytoid cells with slightly lobated (reniform) nuclei with abun-
`dant clear cytoplasm. Plasmacytoid differentiation was common. The
`various cell components were sometimes stratified in the mucosa,
`giving a multiphasic appearance.’5”7,23
`MCBC lymphoma. These lymphomas occurred in a lymph node
`distribution, the principle criterion for distinction from MALT
`lymphoma.’”’’ The distinctive microanatomic features included an
`interfollicular marginal zone nodal growth pattern with confluent
`sinuses (Fig 3). In some cases, germinal centers were filled
`with MCBCs, representing a pattern of follicular colonization
`(Fig 3).’x-20 The MCBCs are small lymphoid cells with slightly lo-
`bated (reniform) nuclei, inapparent nucleoli, and abundant clear cyto-
`plasm. Plasma cells and histiocytes were sometimes admixed. These
`nodal MCBC lymphomas were distinguished from reactive monocy-
`toid infiltrates primarily by advanced architectural effacement of
`nodal elements. Other criteria favoring malignancy were cellular
`pleomorphism, nuclear irregularity, and higher mitotic rate.2” There
`was a high association of composite lymphoma in MCBC lympho-
`mas, in particular with low grade FL components, suggesting that
`this lymphoma may evolve with varying morphologic expression.”’,”
`
`Statistical Methods
`Survival time was defined as the time from patient registration to
`the time of death from any cause. Patients last known to be alive
`were censored at the date of last contact. Failure-free survival time
`from registration to progression, relapse, or death
`was measured
`from any cause. Survival distributions were estimated using the
`method reported by Kaplan and Meier.26 Differences in survival
`between patient groups were analyzed using log-rank tests2’ All
`reported significance tests are two-sided and are not corrected for
`multiple comparisons. Data analysis is based on follow-up informa-
`tion in the SWOG Statistical Center of June l , 1994; therefore, the
`median follow-up is 16.5 years.
`
`Table 1. Pathologic Categories
`
`MCL
`6
`9
`0
`0
`21
`
`Original Diagnosis
`Total
`70
`WF A (SLVDLWD
`WF B (FSCVNLPD
`171
`40
`WF C (FM)/NM
`29
`WF D (FL)/NH
`66
`WF E (DSC)/DLPD
`Total reviewed
`376 36 (IO)
`Percentages are shown in parentheses.
`Abbreviations: SL, small lymphocytic; DLWD, diffuse lymphoma,
`well differentiated; FSC, follicular small cleaved; NLPD, nodular
`lymphoma, poorly differentiated; FM, follicular mixed; NM, nodular
`mixed; FL, follicular, large; NH, nodular histiocytic; DSc, diffuse small
`cleaved; DLPD, diffuse lymphoma, poorly differentiated.
`
`MZL
`5
`15
`5
`5
`13
`43 (11)
`
`RESULTS
`Pathologic Categorization
`The slides from 376 patients with stage Ill or IV disease
`who had been previously classified as having WF categories
`A through E by the SWOG Lymphoma Pathology Commit-
`tee were reanalyzed by three pathologists (B.N., P.B., and
`T.G.). The results are shown in Table 1 using both the origi-
`nal Rappaport and WF terminology. A diagnosis of MCL
`was made in 36 patients (10%). The majority of these pa-
`tients had been previously categorized as WF category E
`(diffuse small cleaved cell); the remaining patients were
`identified in WF A and B categories. No patients were identi-
`fied in WF C or D. A diagnosis of MZL was made in 43
`patients (1 1 %). These patients were identified in each of the
`WF categories A through E. As a result of this comprehen-
`sive pathology review, 49 additional cases were excluded
`from WF A through E as well as the MCL and MZL catego-
`ries. Thus, 248 cases remained in WF A through E.
`The 36 patients with MCL could be further subclassified
`into nodular, diffuse, or blastic variants. The results of that
`subdivision were are follows: nodular, 14 (39%); diffuse, 10
`(28%); and blastic, 12 (33%). The 43 patients with MZL
`could be further subclassified into MALT, MCBC. and not
`classifiable variants. The results of that subdivision were
`as follows: MALT, 19 (44%); MCBC, 21 (49%); and not
`classifiable, 3 (7%). Thirteen of 21 (62%) patients with
`MCBC lymphoma had
`concomitant presence of follicular
`lymphoma (“composite lymphoma”), whereas 7 of 19
`(37%) patients with MALT had composite lymphoma.
`
`Clinical Presentation
`The clinical characteristics of the patients with MCL and
`MZL were compared to the remaining 248 patients in WF
`categories A through E. The results are shown in Table 2.
`Median age of the three groups ranged from 51 to 55 years.
`There was a male predominance in patients with MCL (81 %)
`compared with those with MZL (51%) or WF A through E
`(54%; P = .009). Over 90% of the patients in each group
`were ambulatory (SWOG performance status [PS] 2). The
`percentage of patients with bone marrow involvement ranged
`from 46% to 53%. The percentage of patients with gastroin-
`testinal (GI) involvement was increased in both the mantle
`cell group (19%) and the marginal zone group (23%) com-
`pared with that of the remaining WF A through E patients
`(4%; P < .001).
`As noted previously, the subclassification of the MCLs
`three groups of between 10 and 14 patients.
`resulted in
`Therefore, it is difficult to convincingly separate the clinical
`
`Table 2. Patient Characteristics
`
`MZL
`MCL
`WF A-E
`(n = 36)
`( n = 43)
`(n = 248)
`Median age in years (range) 55 (18-81) 55 118-76) 51 (23-76)
`% Male (95% Cl)
`54 (48-61) 81 (64-92) 51 (35-67)
`5
`8
`3
`% P S > 2
`49
`46
`53
`% Bone marrow
`4 (2-7) 19 (8-36) 23 (12-39)
`% GI disease (95% Cl)
`Abbreviations: Cl, confidence interval; PS,
`
`~
`
`~~
`
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`
`MANTLE CELL AND MARGINAL ZONE LYMPHOMAS
`
`1079
`
`- - MCL
`- WF A+B+C+D+E 248
`
`A"W!!!Y!9
`36
`
`Rdapss~ 10-Ymr
`
`36
`211
`
`6%
`25%
`
`1
`
`80%
`
`60%
`
`.OOOl). In fact, the failure-free survival and overall survival
`estimates for the patients with MCL were lower than those
`for WF A, WF B, WF C, WF D, or WF E when examined
`as separate groups (data not shown).
`The subclassification of the MCLs into blastic, diffuse,
`and nodular did result in statistically different failure-free
`survival and overall survival curves ( P = .05 for both), as
`shown in Figs 5A and B, although the biologic significance
`of these differences is not clear because the 10-year failure-
`free survival estimates were 0%, lo%, and 7%, respectively.
`In contrast, the failure-free survival for the 43 patients
`with MZL was similar to that of the 248 remaining patients
`with WF A through E, as shown in Fig 6A. The 10-year
`failure-free survival estimate was 36% compared with the
`25% for WF A through E ( P = .26). The overall 10-year
`estimated survival, as shown in Fig 6B, was also not signifi-
`cantly reduced for the MZL patients (39%) as compared
`with that of the patients with WF A through E ( P = .83).
`Furthermore, if one prefers to compare the failure-free sur-
`vival and overall survival for the 43 MZL patients with
`that of the 210 patients in the classically defined low grade
`lymphomas (WF A, B, and C), the results are also similar
`( P = .22 and .89, respectively).
`The subclassification of the MZLs into the MALT
`
`100%
`
`80%
`
`Relapsas IO-Year
`At Rlsk or D . a t h 6 E s l i ~
`. . . MCLNoduiar 14
`- "CL Dmuw
`14
`7%
`10
`
`10
`10%
`"CL
`12
`0%
`
`12
`
`Blastic
`
`
`
`1 : ...
`....
`
`p = .05
`
`0
`
`15
`
`5
`
`
`
`A
`
`I
`I I I I I I I I I I I
`20
`25
`
`10
`Years Alter Registration
`
`IO-Year
`At Risk DI.thsEstllmclte
`. . . MCLNodular 14
`- "CL DmuW
`
`14%
`10%
`-"CL Blastic
`0%
`
`10
`12
`
`10
`12
`
`14
`
`Fig 5. MCL subcategories. (A) The failure-free survival curve for
`14 patientswith nodular variant, 10 patients with diffuse variant, and
`12 patients with blastic variant is shown. (B) The overall survival for
`14 patients with nodular variant, l 0 patients with diffuse variant, and
`12 patients with blastic variant is shown.
`
`'""n
`1 ":. \
`
`80%
`
`40%
`
`- - MCL
`- WF A+B+C+D+E 248
`
`10-Year
`At RiskDeatJpEltimae
`3636%
`197
`35%
`
`I - .I "-
`
`L " - ,
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`15
`20
`25
`0
`5
`10
`B
`Registration
`years
`
`L " "
`
`Fig 4. MCL. (A) The failure-free survival curve for 36 patients with
`MCL compared with 248 patients with WF A through E is shown. (B)
`The overall survival of 36 patients with MCL compared with 2 M
`patients with WF A through E is shown.
`
`characteristics of these subgroups. The blastic subgroup was
`younger; the diffuse group had fewer males; and the nodular
`group had the highest percentage with GI involvement. In
`addition to the fact that the MALT lymphomas were mucosa-
`based and all extranodal, whereas the MCBC lymphomas
`were node-based, the subclassification of the MZLs into
`MALT lymphomas and MCBC lymphomas failed to show
`any significant differences in clinical presentation except that
`the MALT lymphoma group did have more patients with GI
`involvement than the MCBC group (8 of 19 [42%] v 2 of
`21 [lo%]; P = .03). The extranodal sites of involvement for
`the MALT lymphomas included the following: 8, GI; 4,
`skin; 2, parotid; 2, lung; 2, breast; and 1, nasopharynx. Nodal
`involvement was found in 15 of 19 (79%) of MALT lympho-
`mas.
`
`Failure-Free Survival and Survival
`The failure-free survival for the 36 patients with MCL
`was significantly shorter than that of the 248 remaining pa-
`tients with WF A through E, as shown in Fig 4A. The 10-
`year failure-free survival estimate was only 6% compared
`for WF A through E ( P = ,0002). The overall
`with 25%
`10-year estimated survival, as shown in Fig 4, was also
`significantly reduced for the MCL patients (8%) as compared
`with that of the patients with WF A through E (35%; P =
`
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`1080
`
`lymphoma and MCBC categories did permit recognition of
`significant differences in failure-free survival and survival.
`The 10-year estimated failure-free survival for patients with
`MALT lymphoma was 21%, compared with 46% for MCBC
`lymphoma ( P = .009), as shown in Fig 7A. The overall 10-
`year estimated survival for patients with MALT lymphoma
`(21%) was significantly reduced compared with that of pa-
`tients with MCBC lymphoma (53%; P = .007; see Fig 7B).
`Although the failure-free survival of MALT lymphoma pa-
`tients was not significantly reduced as compared with pa-
`tients with WF A through E ( P = .12), overall survival was
`reduced ( P = .02; data not shown).
`
`DISCUSSION
`During the 1960s and 1970s. there was a proliferation of
`lymphoma classifications based primarily on morphologic
`criteria but also incorporating immunologic information on
`the cell of origin. In 1982, the National Cancer Institute-
`sponsored WF attempted to group pathologic entities based
`on an analysis of their clinical behavior and also provided
`a mechanism for translating diagnoses from one classifica-
`tion to another.' Since that time, new pathologic entities have
`been defined using morphologic, immunologic, and genetic
`methods. These new entities are not easily categorized in
`the existing classification schemes. Furthermore, the clinical
`
`Relapws 10-Year
`- - MZL
`4m!&QLl2!m?-
`- WF A+B+C+D+E 248
`4 3 3 4 3 6 %
`211
`25%
`
`40%1
`
`20Y.
`
`100%
`
`80%
`
`60%
`
`40%
`
`"""
`
`ALE"- 10-Year
`- - MZL
`- WF A+B+C+D+E 248
`4 3 3 3 3 9 %
`197 35%
`
`0
`
`B
`
`5
`
`15
`10
`Yeam After Ragisbation
`
`20
`
`25
`
`Fig 6. MZL. (AI The failure-free survival curve for 43 patients with
`MZL compared with 248 patients with W A through E is shown.
`(B) The overall survival of 43 patients with MZL compared with 248
`patients with WF A through E is shown.
`
`FISHER ET AL
`
`- -MZLM.ltrma
`
`Relilp#. 1DYmr
`eLBlrkQLcmb?eaw?
`19
`19
`
`21%
`46%
`
`14
`
`l"",
`
`I
`
`p = ,009
`
`5
`
`15
`10
`Yean After RegWmtion
`
`20
`
`25
`
`m -
`60% -
`40% -
`20% -
`
`0%
`A
`
`0
`
`StBlilt"
`- "ZLmltoma
`19
`" Z L Monocytord B 21
`
`10-Year
`
`l 9
`13
`
`21%
`53%
`
`m - L 1 \
`
`I
`I
`1
`
`2 0 % { , , , ,
`
`, , , I
`,
`p = .W7
`
`,
`
` , , ,
`
`25
`
`0%
`B
`
`0
`
`5
`
`20
`
`15
`10
`Yeam After Re@htmtion
`
`Fig 7. MZL subcategories. (A) The failure-free survival curve for
`19 patients with MALT lymphoma compared with 21 patiants with
`MCBC lymphoma. (B) The overall survival of 19 patients with MALT
`lymphoma compared with 21 patients with MCBC lymphoma
`is
`shown.
`
`presentation and natural history of these newly recognized
`pathologic entities has not been determined in large series of
`uniformly treated patients to determine whether these entities
`differ clinically from the other, relatively indolent lympho-
`mas with which they have been previously classified.
`The term MCL has now been adopted to refer to patients
`previously classified as lymphocytic lymphoma of intermedi-
`ate differentiation, intermediate lymphocytic lymphoma,
`centrocytic lymphoma, or mantle zone lymphoma.6 These
`patients have a well-characterized morphologic appearance
`and distinctive immunologic phenotype (SIgM',
`IgD+,
`CDY, CD23-, etc). The expression of CD5 helps distinguish
`these patients from those with follicular center and MZL.
`Patients with MCL also have a characteristic t(l1; 14) trans-
`location that results in overexpression of the PRADI gene
`that encodes for the cyclin D l pr~tein.''"~ Previous clinical
`studies of these patients had shown a heterogeneous natural
`history, in that some patients had very aggressive disease
`whereas others behaved similarly to patients with classic
`indolent histology? Patients classified as having centrocytic
`lymphoma in the Kiel classification have an aggressive clini-
`cal course. The patients with MCL can be further subclassi-
`fied into nodular, diffuse, or blastic variants, although the
`value of this subclassification remains unclear.
`In this study, we reviewed the conventional pathology and
`
`IPR2018-00685
`Celgene Ex. 2044, Page 6
`
`

`

`by guest
`
`
`
`www.bloodjournal.orgFrom
`
`on March 29, 2018.
`
`For personal use only.
`
`MANTLE CELL AND MARGINAL ZONE LYMPHOMAS
`
`1081
`
`higher than that of the MALT lymphoma patients ( P = .W9
`and .007, respectively). It is of interest that this group of
`advanced stage MALT lymphoma patients who were treated
`with combination chemotherapy had a median failure-free
`survival of only 2.3 years. This suggests that MALT-type
`lymphomas, after they disseminate, are not a favorable sub-
`category of low grade disease.
`We found 2 of 21 MCBC lymphomas with extranodal GI
`involvement. As pointed out by earlier
`some cases
`designated MCBC lymphoma on the basis of microscopy of
`lymph nodes may originally have been MALT-type lympho-
`mas that spread to involve nodes. Alternatively, these might
`be MCBC lymphomas that secondarily involve the gut. It
`remains uncertain whether the 2 cases of 21 MCBC
`lymphoma with GI involvement are secondary, extranodal
`MCBC or primary MALT-type lymphoma with nodal
`spread. Nonetheless, when these two cases are excluded from
`survival analysis, MCBC of nodal type remains separable
`from extranodal MALT lymphomas with regard to survival
`and time to relapse.
`In summary, patients with advanced stage MZL have a
`clinical course similar to that of other patients in WF A
`through E, although patients with advanced stage MALT
`lymphomas may have a more aggressive course than pre-
`viously recognized. However, patients with MCL do not
`have an indolent lymphoma and are candidates for innova-
`tive therapy.
`
`clinical course of 376 previously untreated, advanced stage
`patients with WF categories A, B, C, D, or E, who received
`treatment with CHOP on SWOG studies no. 7204,7426, or
`7713. We also had the advantage of a long follow-up (me-
`dian, 16.5 years). Based on conventional microscopy alone,
`that is without the benefit of immunophenotyping, we identi-
`fied 36 patients (10%) who had been previously character-
`ized as WF A through E as actually having had MCL. The
`median age, performance status, and percentage of bone mar-
`row involvement were essentially identical to the remaining
`patients with WF A through E. The median age of patients
`entered on a clinical trial is probably lower than that of the
`entire population of patients with these diseases.28 However,
`there were significant differences between the patients with
`MCL and W F A through E in the percentage of male patients
`(81% U 54%) and the percentage with GI involvement (19%
`V 4%). Furthermore, the failure-free survival and overall
`survival of patients with MCL was significantly worse than
`that of patients with WF A through E. At 10 years, 8% of
`patients with MCL were alive, and only 6% were alive with-
`out disease. The corresponding numbers for patients with
`WF A through E were 25% and 35%. With this uniformly
`poor prognosis, subclassification of these patients into the
`nodular, diffuse, or blastic variants seemed to have limited
`usefulness.
`The term MZL has been proposed to include patients with
`low grade B-cell lymphoma of MALT, MCBC lymphoma,
`and possibly splenic MZL.” These lymphomas express %g+,
`IgD-, CD19+, CD20+, CD22+, CD5-, and CD23-, and there
`REFERENCES
`is no rearrangement of bcl-l or bcZ-2. MALT lymphomas
`1. The Non-Hodgkin’s Lymphoma Pathologic Classification Proj-
`have been characterized by Isaacson and colleagues as fre-
`ect: National Cancer Institute sponsored study of classifications of
`quently presenting with localized extranodal disease involv-
`non-Hodgkin’s lymphomas. Summary and description of a working
`formulation for clinical usage. Cancer 49:2112, 1982
`ing glandular epithelial tissues, especially the stomach where
`2. Berard CW, Dorfman
`RF: Histopathology of malignant
`they have been associated with helicobacter g a s t r i t i ~ . ~ ~ , ~ ~ . ’ ~
`lymphomas. Clin Haematol 3:39, 1974
`Reportedly, localized disease could be cured in a high per-
`3. Weisenburger DD, Nathwani BN, Diamond LW: Malignant
`centage of cases with minimal local
`Dissemi-
`lymphoma, intermediate
`lymphocytic type: A clinicopathologic
`nate disease was reported in only 30% of cases, but these
`study of 42 cases. Cancer 48314