Cytogenetic studies of composite lymphomas: Monocytoid B-cell lymphoma and other B-cell non-Hodgkin's lymphomas

Cytogenetic Studies of Composite Lymphomas: Monocytoid B-Cell Lymphoma and Other B-Cell Non-Hodgkin’s Lymphomas MARILYN L. SLOVAK, PHD, LAWRENCE M. WEISS, MD, BHARAT N. NATHWANI, MD, LESLIE BERNSTEIN, PHD, AND ALEXANDRA M. LEVINE, MD Monocytoid

B-cell lymphoma

phologically

(MBCL)

and immunologically

is a newly recognized,

distinct, low-grade

mor-

B-cell neo-

plasm that may exist as a pure morphologic

entity or as a component

of a composite

whether cytogenetic ah-

lymphoma. To determine

normalities exist in cases of MBCL, fresh tissue from four lymphoma specimens in which MBCL

was a substantial component

alyzed by classic cytogenetics; no pure MBCL

were an-

cases were available

for study. One monoclonal neoplastic population was found in each case by immunophenotyping

studies and classic cytogenetics. Clonal

cytogenetic abnormalities

included

del(6q), t(ll;l4)(q13;q32),

dup(l2q),

der(S)t(S;g)(pll.2;q13). underlying [t(l4;18)],

lymphomatous

process,

or +X, t(14;18)(q32;qZl),

dup(lq),

The abnormal

mantle cell lymphoma

lymphoma

-X

t(2;3)(q13;q29),

and

clone usually reflected the

namely, follicular

[t(ll;l4)],

lymphoma

or small lymphocytic

(partial trisomy 12). There were no cytogenetic abnor-

malities common to all neoplasms. Taken together, the cytogenetic and immunologic

data suggest that although MBCL

may exist as a

pure entity, it also may commonly represent a morphologic or a component PATHOL

of other primary lymphomatous

24:1086-1094.

Copyright

variant

processes.

H~hl

0 1993 by W.B. Saunders Com-

pany

Monocytoid B-cell lymphoma (MBCL), also known as parafollicular B-cell lymphoma,’ has been described as the neoplastic counterpart of the reactive monocytoid B-cell component found within a variety of lymphoproliferative disorders, ranging from inflammatory responses (such as those seen in toxoplasmosis) to malignant lymphoma, yet the pathobiology of these cells has not been resolved.‘-4 Monocytoid B cells are moderately sized lymphocytes with abundant, clear cytoplasm and bland-appearing, oval or reniform nuclei. Neutrophils and plasma cells usually are present within the monocytoid B-cell proliferation. When found as a reactive component, the monocytoid B cells are polyclonal cells of B lineage that are CD20+, CDllc+, CD21-, and

From the Departments of Cytogenetics and Anatomic Pathology, City of Hope National Medical Center, Duarte, CA; and the Departments of Internal Medicine (Hematology). Pathology, and Preventive Medicine, University of Southern California School of Medicine, Los Angeles, CA. Accepted for publication May 3, 1993. Supported in part by grants no. CA-33572, CA-50850, and CA50341. Key words:monocytoid B-cell lymphoma, immunophenotype, cytogenetics,

composite

lymphoma,

low-grade

B-cell lymphomas.

Address correspondence and reprint requests to Marilyn L. Slovak, PhD, Department of Cytogenetics, City of Hope National Medical Center, Northwest Bldg. Room 2255, 1500 E Duarte Rd. Duarte, CA

91010-0269. Copyright 0 1993 by W.B. Saunders

Company

0046-8177,‘93/2410-0007$5,00/O

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CD25-.5-7 However, a rare malignant lymphoma has been described in which the proliferating cells have morphologic and immunophenotypic features similar to reactive monocytoid B cells but are monoclonal, as determined by the detection of monoclonal surface immunoglobulin and monoclonal immunoglobulin gene rearrangements. These data led to the proposal of a new B-cell neoplasm designated by some investigators as MBCL.s-‘? Monocytoid B-cell lymphoma may present either as a pure entity or in combination with other types of lymphoma, most commonly, small lymphocytic, mantle cell, and/or follicular lymphomas.‘” The existence of these composite lymphomas raises the possibility of a close lineage relationship among them. Additionally, hairy cell leukemia and MBCL share similar morphologic and immunophenotypic features, suggesting a closely related histogenesis. IJ.15 However, unlike small lymphocytic lymphoma (SLL) or hairy cell leukemia, bone marrow involvement with circulation of MBCI. is rare.16 Furthermore, nodal MBCL bears a close resemblance to the mucosal-associated lymphoid tissue-derived lymphomas, suggesting that equivalent cytologic entities localize to different tumor sites.” Cytogenetic analysis has been useful in determining the lineage affiliation of various leukemias and lymphomas. Most notably, t(14; 18)(q32; q21) has been found to be the cytogenetic hallmark of follicular lymphoma.” Recently, a close association between t( 11; 14)(ql3;q32) and mantle cell/intermediate lymphocytic lymphoma has been proposed.‘“,20 These data suggest that a combined morphologic, immunophenotypic, and cytogenetic classification system may lead to a better understanding of the pathogenesis of the malignant lymphomas and their clinical management. We provide the results of cytogenetic studies of four cases of lymphoma in which MBCL is a significant component. In all four cases only one monoclonal neoplastic population was identified by classic cytogenetics. MATERIALS

AND METHODS

Case Selectionand PathologicAssessment The patients included in this study were identified as part of an ongoing case-control study of B-cell lymphomas (human immunodeficiency virus-positive and -negative). This project has been approved by the Institutional Review Boards of the University of Southern California School of Medicine and the City

CYTOGENETICS

TABLE 1. Case NO.

Age (yr)/ Sex

1

41/M

2

63/F

3

4

OF COMPOSITE

MBCL (Slovak et al)

Clinicopathologic Characteristics of Monocytoid B-Cell Lymphoma Patients

Clinical

Lymphoma

History

Immunology

Diagnosis*

Cytogenetics

Constitutional Xlinefelter’s syndrome; stage IIB Hodgkin’s disease 10 yr prior Small lymphocytic lymphoma

MBCL/small lymphocytic with plasmacytoid features

CD20+; kappa+; CD5-; CDlO-

47,XXY,dir

MBCL/mantle lymphoma

CDZO+; lambda+; CD5+: CDl O-

26/F

Follicular, small cleaved cell lymphoma for 8 years

Follicular MBCL

63/M

Alcoholic ascites

44,X,-X,der(3)t(3;13)(p25;q14),de1(6) (q15q25),t(l1;14)(q13;q32),-13 [16]/46,XX,t(ll;l4)(q13;q32) [11/46,Xx ]31 49,XX,+X,t(2;3)(q13;q29),+der(Z) t(2;3)(ql3;q29),der(S)t(8;9) (p11.2;q13), t(14;18)(q32;q21), +18 [19]/49,idem,de1(9)(q13) 48,XY,der(l)t(l;Z)(p34;q31)dup(l) (ql2 + q25).add(l6)(q24),+fxZ [23]/46,XY [4]

* Major component

stated

liver disease

with

cell

small cleaved/

MCBL with transformation to small, non-cleaved

CDZO+; lambda+; CD5-; CD1 O-

+

q21) [2]/

dup(lZ)(q13 + q21)

[l]

first

of Hope National Medical Center. Since fresh tumor material is needed for cytogenetic analysis, no selection criteria other than the availability of tumor material after pathologic diagnosis were applied. Pathology review was performed by two of the authors (B.N.N. and L.M.W.). Cases selected for the current study had morphologic features of lymphoma in which MBCL accounted for at least 25% of the neoplastic population. No pure MBCL cases were encountered. Paraffin and frozen section immunophenotyping was performed in all four cases using established methods2’ All cases were studied in paraffin sections using L26 (CD20), UCHLl (CD45RO), and immunoglobulin light chains. All cases were studied in frozen sections using CD20 or CD22, CD3, CD5, CDlO, and immunoglobulin light chains.

Cytogenetic

CDZO+; kappa+; CD5-; CD10 weak+

dup(lZ)(q13

46,XY,-X,dir I191

Methods

were incubated overnight in a 37°C incubator. No mitogen stim-

ulation was used. After a 40-minute exposure to 0.05 pg/mL of Colcemid (Gibco, Grand Island, NY) the preparations were resuspended in 0.4% KC1 for 20 minutes and fixed with Camoy’s fixative (3:l methanol to glacial acetic acid). Giemsa-trypsin banding (GTG) was used to identify the chromosomes. C-banding by barium hydroxide using Giemsa was performed in cases no. 3 and 4. At least 20 metaphases were analyzed per patient. An abnormal clone was defined as two or more cells with the same structural abnormality or the same extra chromosome or the presence of three or more cells with the same missing chromosome. The chromosomes were classified according to the Guidelines for Cancer Cytogenetics supplement to the International System for Human Cytogenetic Nomenclature.”

RESULTS

On receipt,

the lymph node tissue was minced with a scalpel to obtain a single cell suspension. Cultures were seeded with 1 X lo7 cells/mI, in RPM1 1640 medium containing 10% fetal

bovine serum, 1% t.-glutamine, penicillin, and streptomycin, and

FIGURE 1. Case no. I. Composite MBCL (left) and small lymphocytic lymphoma with plasmacytoid features (right). Note the admixed neutrophils within the MBCL and the presence of Dutcher bodies within some of the neoplastic cells in the small lymphocytic lymphoma. (Hematoxylin-eosin stain; magnification x600.)

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Clinical Findings The clinicopathologic are summarized in Table

characteristics of the patients 1. There were two men and

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1993)

FIGURE 2. Case no. 2. Composite mantle cell lymphoma/MBCL (left). A central atrophic germinal center is surrounded by a thickened mantle (dark area), which in turn is surrounded by MBCL (pale area). (Hematoxylin-eosin stain; magnification X100.) (Right) The mantle cell component of the lymphoma is seen above, while the MBCL component is seen below. (Hematoxylin-eosin stain; magnification X600.)

two women whose ages ranged from 26 to 63 years. None of the patients were positive for the human immunodeficiency virus. Patient no. 1 had the known constitutional cytogenetic abnormality of Klinefelter’s syndrome (47,XXY) and had a history of stage IIB nodular sclerosing Hodgkin’s disease diagnosed 10 years earlier, which had been successfully treated with chemotherapy and radiotherapy. Patient no. 2 was diagnosed 2 years earlier in the Philippines with small lymphocytic lymphoma. Patient no. 3 had an g-year history of stage IV follicular, predominantly small cleaved cell lymphoma. Pathologic Assessment The histologic appearance of the four lymph nodes varied from case to case, although all four cases had a component of MBCL exceeding 25% of the tumor population. In case no. 1 MBCL was the major component, with other areas comprising approximately 20% of the neoplasm, showing features of SLL with plasmacytoid differentiation (Fig 1). Other investigators may have considered this case to represent MBCL with plasmacytic differentiation.’ In case no. 2 the mantle zones of the lymph node demonstrated mantle cell lymphoma, while the marginal zones contained cells with differentiation

toward MBCL. Monocytoid B-cell lymphoma comprised approximately 60% of the area (Fig 2). In case no. 3 both the lymph node biopsy analyzed for cytogenetics and the lymph node biopsy examined 8 years earlier showed similar histologic features (Fig 3). Both specimens showed follicular, predominantly small cleaved cell lymphoma comprising the majority of the tumor, with MBCL present in the interfollicular areas. Monocytoid B-cell lymphoma comprised approximately 25% of the area in the original biopsy and 40% of the area in the current specimen analyzed for cytogenetics. In case no. 4 MBCL was the predominant component and it had an interfollicular and sinusoidal distribution, but some of the sinuses also contained a population of cells of medium size with prominent nucleoli and a high mitotic rate, consistent with transformation to a high-grade MBCL (Fig 4). The lymphomatous areas represented approximately 60% of the area, of which approximately 50% represented typical MBCL and 50% showed highgrade areas. The bone marrow showed involvement by malignant lymphoma with the cytologic features of SLL. lmmunophenotypic

Analysis

The immunophenotypic studies are summarized in Table 1. In all cases all components of the lymphoma

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CYTOGENETICS

OF COMPOSITE

MBCL (Slovak et al)

FIGURE 3. Case no. 3. Composite follicular, small cleaved cell IymphomaIMBCL. (Left) A follicular pattern is seen at low magnification, although the follicles appear somewhat ill-defined because the interfollicular areas are also somewhat pale. (Hematoxylin-eosin stain; magnification x100.) (Right) The interfollicular areas show features characteristic of MBCL. (Hematoxylin-eosin stain; magnification x600.)

appeared to stain similarly, although assessment was difficult in frozen sections. B lineage was demonstrated in all cases, with strong expression of CD20. In addition, all cases demonstrated monoclonal light chain restriction, kappa in two cases and lambda in two cases. In each case the light chain restriction was present in the MBCL areas as well as in the areas showing other components. In case no. 2, the case of MBCL/mantle cell lymphoma, CD5 was positive in the areas of mantle cell lymphoma. In case no. 3, the case of follicular small cleaved/MBCL lymphoma, CD1 0 was weakly positive in areas of follicular small cleaved cell lymphoma. The Tlineage markers CD45RO and CD3 were negative in the neoplastic cells in all four cases. Cytogenetic

Data

The cytogenetics are summarized in Table 1. Detailed descriptions follow. In case no. 1 all cells (n = 2 1) analyzed by cytogenetics were abnormal. The mainline, the most frequent chromosome constitution of a tumor cell population and a subclone of the stemline, contained a direct duplication of 12ql3+ 12q2 1 of the long arm of chromosome 12 and the loss of an X chro1089

mosome. The stemline, the most basic clone of the tumor cell population, was characterized by duplication of the 12ql3+ 12q2 1 chromosomal segment only. The karyotypic designation of the mainline was 46,XY,-X,dir dup (12)(q13+q21) (Fig 5). Of the 20 cells collected for cytogenetic analysis in case no. 2, 17 cells were abnormal. The hypodiploid stemline contained 44 chromosomes. Monosomy X was a clonal numerical change. Structural aberrations included an unbalanced 3; 13 translocation, an interstitial deletion of the long arm of chromosome 6, and an 11; 14 translocation. One pseudodiploid cell contained the 11; 14 translocation only, suggesting that this translocation was the primary cytogenetic abnormality. Three normal 46,Xx female cells also were collected. The stemline was 44,X,-X,der(3)t(3; 13)(p25;q14),de1(6) (q15q25),t(11;14)(q13;q32),-13 (Fig 6). Case no. 3 was completely abnormal karyotypically. The hyperdiploid stemline contained trisomy X and trisomy 18. Structural aberrations included an apparently balanced translocation between chromosomes 2 and 3, a 14; 18 translocation, an unbalanced 8; 9 translocation, and an extra copy of the derivative chromosome 2 of

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FIGURE 4. Case no. 4. Composite MBCL/high-grade lymphoma. (Left) The paracortical and sinusoidal areas are expanded, surrounding reactive follicles. (Hematoxylin-eosin stain; magnification x 100.). (Right) Although this field has some features reminiscent of MBCL, the degree of cytologic atypia and the high mitotic rate identify it as a high-grade lymphoma. (Hematoxylin-eosin stain; magnification x600.)

the 2;3 translocation. C-banding by barium hydroxide using Giemsa was performed to rule out the possibility of a dicentric 8;9 translocation; however, the results were equivocal. One cell derived from the stemline contained a deletion of the long arm of chromosome 9 [del(9)(q 13)]. The karyotypic designation of the stemline was 49,XX,+X,t(2;3)(q13;q29),+der(2)t(2;3)(q13;q29), der(8)t(8;9)(p11.2;q13),t(14;18)(q32;q21),+18(Fig7). A cytogenetic study at presentation was not performed. In case no. 4,23 of the 27 cells collected for analysis were abnormal; four cells with a 46,XY normal male karyotype were observed. The hyperdiploid stemline contained 48 chromosomes, with structural rearrangements affecting chromosomes 1, 2, and 16. The derivative chromosome 1 was involved in a translocation between chromosome lp and 2q and contained a duplication of the long arm of chromosome 1 involving the 1q 12+ 1 q25 chromosomal segment. A derivative chromosome 16 contained additional chromosomal material of unknown origin at band 16q24. Two centric fragments, confirmed with C-banding by barium hydroxide using Giemsa, also were identified. The stemline was designated as 48,XY,der(l)t(l;2)(~34;q3l)dup(l) (q12-*q25),add(l6)(q24),+fx2 (Fig 8). 1090

DISCUSSION Classic cytogenetic analyses were performed on four lymph node biopsy specimens in which MBCL was a significant component of a composite lymphoma. In three of the four cases cytogenetic aberrations common to various low-grade lymphomas were observed. Trisomy or partial trisomy 12 is the most frequently reported chromosomal abnormality in chronic lymphocytic leukemia or SLL, 18,?.7-26and thus appears to represent a primary cytogenetic change in B-cell chronic lymphocytic leukemia/SLL development. In case no. 1 a duplication of the long arm of chromosome 12 was observed in all cells sampled. Since two cells retained the additional X chromosome of the patient’s Klinefelter’s constitutional abnormality, the duplication of the long arm of chromosome 12 appears to be the primary cytogenetic change in the genesis of this malignant process. These cytogenetic results also support the hypothesis that MBCL and SLL may be closely related, at least in some cases. Alternatively, a 20-cell cytogenetic study may not be sensitive enough to recognize two independent clones due to either a proliferative advantage of a particular neoplastic population or to in vitro cell cycle

CYTOGENETICS

OF COMPOSITE

MBCL (Slovak et al)

FIGURE 5. A GTG-banded karyotype from case no. 1. The mainline contained a direct duplication of the long arm of chromosome 12 (12q13+12q21) (open arrowhead) with the loss of an X chromosome. Karyotypic designation: 46,Xx,-X,dir dup(i2)(q13+q21). Constitutional karyotype: 47,XXY (Klinefelter’s syndrome).

aberrations associated with neoplastic B cells that perhaps may require mitogenic stimulation. Case no. 2 was characterized by an 11; 14 translocation with clonal abnormalities affecting chromosomes 3, 6, and 13. At the molecular level this translocation disrupts the immunoglobulin heavy chain (IgH) gene

FIGURE 6. A GTG-banded karyotype from case no. 2. Stemline: 44,X,-X,der(3)t (3:13)(p25;ql4).del(6) (q1!5q25),t(ll: 14)(q13;q32), - 13. Structural aberrations are indicated with arrowheads

on band 14q32 and the M-1 (PRAD/cyclin Dl) oncogene located on band 11 ql3.” The physiologic function of the M-1 gene is not clear, as is its role in the genesis of tumors displaying the t(ll; 14) translocation. Although this translocation is characteristic of mantle cell lymphoma, rgS2’it also has been described in other B-cell

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1993)

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malignancies, including SLL, chronic lymphocytic leukemia, prolymphocytic leukemia, diffuse large cell lymphoma, plasma cell leukemia, and multiple myeloma.25 In addition, case no. 2 was characterized by an unbalanced 3; 13 translocation affecting band 13q14, the normal cellular locus for the retinoblastoma tumor sup-

FIGURE 7. A GTG-bonded kan/otype from case no. 3. Stemline karyotypic designation: 49,XX;+X,t(2;3)(q13; q29),+der(2)t(2:3)(ql3; q29),der(8)t(8:9)(pl1.2;q13). t ( 14: 18 > ( q32:q21 ) , +18. Chromosomal aberrations are indicated with arrows

pressor gene. Recently, abnormalities of 13q involving band 13ql4 have been described as a nonrandom cytogenetic abnormality in B-cell chronic lymphocytic leukemia.24.27 Deletions of 6q are frequent secondary changes in both lymphoid malignancies28~2g and solid tumors.25

FIGURE 8. A GTG-banded karyotype from case no. 5. Stemline: 48,XV,der(l)t(l:2) (p34;q3l)dup(l)(ql2q25).add(16)(q24).+fx2. Structural aberrations are indicated with arrowheads.

pt 1092

[i?‘@ 22

x/Y

CYTOGENETICS

OF COMPOSITE

Case no. 3 was comprised of a composite follicular small cleaved lymphoma and MBCL, with the latter component increasing in the second biopsy performed 8 years later. Cytogenetic studies show a t( 14; 18)-bearing clone with multiple structural abnormalities. The 14; 18 translocation is seen in over 85% of the follicular lymphomas, strongly indicating follicular origin. Although 20% of the diffuse large cell lymphomas may possess this translocation,“,“’ many of these patients have a prior history of follicular lymphoma,31 suggesting that these diffuse lymphomas may represent progression of preceding or occult follicular lymphoma. The natural course of low-grade lymphomas includes transformation to high-grade diffuse large cell lymphoma.32 Furthermore, bcl-2 gene rearrangements have been reported previously in MBCL when a pre-existing follicular lymphoma was present.33 Since all B-cell lymphomas with bcl-2 rearrangements demonstrate high levels of bcl-2 proteins”” and deregulation of the bcl-2 gene selectively expands and extends the survival of small resting IgM/ IgD B-cell populations,““.“” secondary genetic abnormalities may play a critical role in progression to a higher-grade malignancy. The additional abnormalities of trisomy 18 and +X observed in case no. 3 have been described as nonspecific yet nonrandom changes in the whereas chromosomal non-Hodgkin’s lymphomas, 20*37.38 aberrations of 2q, 3q, and 9q have been associated with diffuse, large non-cleaved cell lymphoma.“7~‘“-“’ In case no. 3 duplication of 2p[+der(2)] was associated with an accelerated clinical course and a poor response to treatment as previously reported.““.” The pathology of case no. 4 was a low-grade MBCL that has transformed to a high-grade lymphoma. Apparently, MBCL has a propensity to transform to a higher grade of malignancy.‘J Cytogenetically, the data also suggest an evolving process based on the presence of a duplication of the long arm of chromosome 1 and 2q aberrations. Duplication of lq is a nonrandom cytogenetic change frequently observed in malignant lymphoma.‘” These additional karyotypic abnormalities considered secondary in nature may be more closely related to the biologic behavior and phenotypic aspects of the disease course. Thus, case no. 4 provides evidence that the transformation of MBCL to a higher-grade malignancy may be accompanied by cytogenetic changes. Taken together, these morphologic, immunologic, and cytogenetic data provide support for the concept that a close histogenetic relationship exists between MBCL and several other low-grade B-cell lymphoid malignancies. Although a larger sample size is needed before a definitive conclusion can be drawn, our data suggest that although MBCL may exist as a pure entity, it may also commonly represent a morphologic variant or a component of another primary lymphomatous process, which may later transform to higher-grade disease. Additional cytogenetic and molecular characterization of low-grade B-cell lymphoma this newly recognized, should help clarify the pathogenesis of MBCL and other low-grade B-cell neoplasms. Acknowledgment. The expert technical contributions of Jennifer Pelkey-Ho and the quality secretarial services of Debra Godwin are gratefully acknowledged. We thank Dr Eileen

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MBCL (Slovak et al)

Smith for kindly providing the clinical information for case no. 1 and Jane Sullivan-Halley for the providing the clinical histories for cases no. 2 to 4.

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33. Ngan BY, Warnke RA, Wilson M, et aI: Monocytoid B-cell lymphoma: A study of 36 cases. HLI~I PATHOI. 22:4(K)--42 I, 1!)
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