Mantle Cell Lymphoma

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1 HEMATOPATHOLOGY Original Article Mantle Cell Lymphoma Morphologic Findings in Bone Marrow Involvement JAY WASMAN, MD, 1 NANCY S. ROSENTHAL, MD,' AND DIANE C. FARHI, MD 2 Although mantle cell lymphoma (MCL), has been well described in lymph nodes, involvement of blood and bone marrow has not been well defined. The authors reviewed involved blood and marrow specimens from 13 patients with MCL to determine patterns of infiltration. These findings were compared to marrow involvement by follicular small cleaved cell lymphoma (SCCL) and small lymphocytic lymphoma (SLL). Peripheral blood involvement by MCL was present in 5 patients (38%). The circulating lymphoma cells were small (7-10M) with slightly folded nuclei. Marrow involvement ranged from 5% to 90% of the marrow space and was predominantly intertrabecular, including nodules and interstitial infiltrates (9 cases each; 68%). Paratrabecular Some lymphomas derived from small lymphocytes are not readily classifiable as either small lymphocytic lymphoma (SLL) or as small cleaved cell lymphoma (SCCL), but may show features intermediate between the two. 1 In the 1970s, the term lymphocytic lymphoma of intermediate differentiation was used to describe this entity, and in the Kiel classification the term diffuse centrocytic lymphoma was used. 23 Numerous studies have attempted to characterize more precisely this subset of lymphomas according to immunologic, cytochemical, and clinical features. 4 " 15 These studies suggest that the neoplastic cells are derived from lymphocytes of primary follicles and the mantle zones of secondary follicles; therefore, it has been suggested the term mantle cell lymphoma (MCL) be used. 16 MCL, when present in a diffuse pattern, has been shown to follow a relatively aggressive clinical course, comparable to intermediate grade lymphomas in the Working Formulation. 17 As in other lymphomas of small lymphocytes, bone marrow involvement is common in MCL 4 ' 5 ' 818 and seen in up to 65% of cases. The patterns of involvement and the possibility of From the ' Department of Pathology, University Hospitals of Cleveland. Cleveland. Ohio; and 2 Department of Pathology and Laboratory Medicine. Emory University School of Medicine. Atlanta. Georgia. Manuscript received November 14, 1995; revision accepted March 13, Address correspondence to Dr. Rosenthal: Institute of Pathology, Case Western Reserve University Adelbert Road, Cleveland, OH aggregates (6 cases; 46%) and diffuse replacement by lymphoma (3 cases; 23%) were also seen. In SCCL, paratrabecular involvement was seen as were interstitial nodules. Cases of SLL showed diffuse, interstitial or nodular involvement without paratrabecular localization. Cytologic comparison showed nuclei that were angulated in SCCL, round in SLL, and slightly irregular in MCL, with considerable overlap among the groups. The architectural and cytologic findings in marrow involved by MCL show features of both SCCL and SLL, and cannot be used to definitively diagnose MCL. (Key words: Bone marrow; Malignant lymphoma; Mantle cell lymphoma) Am J Clin Pathol 1996; 106: distinguishing features in this type of lymphoma have not been explored. Therefore, we examined 13 cases of MCL to determine the patterns and extent of bone marrow involvement and then compared our findings with SLL and SCCL to determine similarities and differences. MATERIALS AND METHODS Cases of mantle cell lymphoma (some originally diagnosed as malignant lymphoma, intermediate cell type) involving lymph node and bone marrow were retrieved from the surgical pathology records of University Hospitals of Cleveland and the Department of Pathology and Laboratory Medicine, Emory University Hospital. The diagnoses were confirmed by review of the paraffin-embedded, hematoxylin-and-eosin stained sections of lymph node and immunophenotypic studies on which the original diagnosis was made. In each case, bone marrow pathology records were reviewed for demographic and laboratory data including the complete blood count. Wright-Giemsa-stained peripheral blood smears were examined for the presence and the cellular morphology of a leukemic phase of the lymphoma. Wright-Giemsa-stained bone marrow aspirate smears were also examined for the presence, percentage, and morphology of lymphoma cells. Bone marrow clot sections and core biopsies fixed in B5, paraffinembedded, and stained with hematoxylin and eosin were also evaluated. The bone marrow clot and core biopsy sections were assessed for the presence of lymphoma, 196

2 WASMAN, ROSENTHAL, AND FARHI 197 Bone Marrow in Mantle Cell Lymphoma TABLE 1. CLINICAL AND PERIPHERAL BLOOD FINDINGS IN MANTLE CELL LYMPHOMA, SMALL LYMPHOCYTIC LYMPHOMA, AND SMALL CLEAVED CELL LYMPHOMA MCL SLL SCCL No. of patients Age (years) (mean) 33-72(54) 58-75(68) 37-70(60) Male:female 4:9 2:4 3:3 Absolute lymphocyte count Circulating lymphoma cells [no.(%)] 5/13(38) 5/6(83) 1/6(16) MCL = mantle cell lymphoma: SLL = small lymphocytic lymphoma: SCC = small cleaved cell lymphoma. percent involvement by lymphoma, pattern of marrow infiltration, and cellular morphology of the lymphomatous infiltrate. The pattern of infiltration was classified as nodular with paratrabecular or intertrabecular localization when well-defined lymphoid aggregates were present, interstitial when the lymphoid infiltrate expanded the marrow interstitium without distinct aggregates, and diffuse when the normal marrow elements were replaced by the lymphomatous infiltrate. In addition, the histologic and cytologic features of the lymphoma on aspirate smear and bone marrow biopsy specimens were compared. Peripheral blood smears, aspirate smears, clot sections, and core biopsies of cases of SLL and follicular SCCL were reviewed and the patterns of involvement were compared to MCL. Six cases each of SLL and follicular SCCL were studied as the morphologic findings are very well described.' RESULTS Thirteen matched specimens of lymph node and bone marrow involvement by MCL were available for review. Patients with MCL ranged in age from 33 to 72 years (mean 54 years), with a male:female ratio of 4:9 (Table 1). All patients were originally diagnosed by lymph node biopsy and in all cases the histology was the diffuse type of mantle cell lymphoma. Immunophenotyping studies by flow cytometry were performed on the lymph node specimen in nine of the cases. In all cases a monoclonal B-cell population with CD5 positivity was identified. The immunoglobulin heavy chain detected was IgM and CD 10 was negative in all cases. White blood cell (WBC) counts were available in 8 of 13 cases. The WBC count ranged from 1.9 to X 10 9 /L. Absolute lymphocyte counts were 0.8 to X 10 9 /L (mean 28.6 X 10 9 /L). Review of peripheral blood smears showed abnormal lymphocytes in 5 of 13 cases of MCL (38%).The WBC count in these patients ranged from 1.9 to X 10 9 /L. By comparison, five of six cases of SLL (83%), and one of six cases (16%) of SCCL showed atypical circulating lymphocytes. In MCL, the abnormal lymphocytes were small to intermediate in size with slightly irregular to cleaved nuclei (Fig. 1). The nuclear chromatin was relatively coarse and 1 to 2 small nucleoli were often present. In SLL, the abnormal lymphocytes were generally small with round nuclei, clumped chromatin, and occasional small nucleoli. In the one case of SCCL with abnormal circulating lymphocytes, the cells were intermediate in size with cleaved nuclei, coarse chromatin, and inconspicuous nucleoli. The percentage of lymphocytes in bone marrow aspirate ranged from 10% to 95% in MCL, 50% to 95% in SLL, and 5% to 30% in SCCL. In MCL, the cytologic features of the cells ranged from small round lymphocytes to small cleaved cells (Fig. 2). The percent lymphocytosis correlated well with the extent of lymphoid involvement identified on the bone marrow aspirate clot and core biopsy sections. Five of six cases with <30% lymphocytes on the aspirate smear had <25% of the core biopsy involved by lymphoma. The sixth case had 50% to 60% involvement. Two cases had greater than 70% lymphocytes on the aspirate smear and both had 90% or more involvement on the core biopsy. There was less correlation in the specimens with from 30% to 70% lymphocytes on the aspirate smear, as 2 had 15% involvement of the core biopsy and 1 had 80% involvement. In 2 cases, no aspirate smear was available for review. The bone marrow core biopsy specimens showed marked variability in overall cellularity with a range from 15% to 100%. Involvement by lymphoma ranged from 5% to 95% in MCL, from 30% to 95% in SLL, and o 'i J u o* «K * FIG. 1. Peripheral blood smear, leukemic phase of mantle cell lymphoma. Increased numbers of slightly irregular and round lymphocytes are present.(wright-giemsa). Vol. 106.No. 2

3 HEMATOPATHOLOGY 198 Origh Article from 15% to 55% in SCCL (Table 2). The patterns of involvement were more varied in MCL than in either SLL or SCCL. In the MCL group, lymphoid aggregates were present in 9 of 13 cases (69%), with intertrabecular aggregates in all 9 cases (100%) (Fig. 3), and paratrabecular localization in 6 cases (67%) (Fig. 4). An interstitial pattern was also identified in 9 of 13 cases (69%), and 8 patients had both interstitial involvement and lymphoid aggregates. The marrow was diffusely replaced by lymphoma in 3 of 13 (23%) cases. None of the cases of MCL showed the presence of proliferation centers. In the six patients with SLL, two showed interstitial lymphomatous involvement, two showed diffuse replacement of marrow elements and two showed a nodular pattern of involvement. All six cases of SCCL (100%) FlG. 3. Core biopsy showing an intertrabecular aggregate of small irregular lymphocytes. showed paratrabecular nodules, whereas intertrabecular nodules were present in two of six (33%) and a focal interstitial pattern of infiltration was identified in one of six cases (16%). Cytologic comparison, done on both aspirate smears and core biopsies, showed considerable overlap among the three groups. In all three groups the predominant cell population consisted of small lymphocytes. In MCL, the nuclei tended to range from round to cleaved with many nuclei showing slight irregularities (Fig. 5). In SLL, the nuclei generally were round and uniform, although occasional cells with cleaved nuclei were present. In SCCL, the majority of the nuclei were cleaved; however, many of the lymphocytes were similar to those seen in MCL. Rare (<5%) large, transformed lymphocytes were present in all three groups. TABLE 2. COMPARISON OF BONE MARROW FINDINGS IN MANTLE CELL LYMPHOMA, SMALL LYMPHOCYTIC LYMPHOMA, AND SMALL CLEAVED CELL LYMPHOMA lymphocytosis eaved lymphocytes [no. (%)] are biopsy Involved by lymphoma [no. (%)] Marrow replacement (%) Lymphoma distribution Nodules [no. (%)] Intertrabecular Paratrabecular Interstitial Diffuse MCL SLL SCCL /13(50) /6(0) /13(100) /13(69) 6/13(46) 9/13(69) 3/13(23) 2/6 (33) 0/6 (0) 3/6 (50) 1/6(16) 0/6 (0) MCL = mantle cell lymphoma: SLL = small lymphocytic lymphoma: SCC = small cleaved cell lymphoma. A.J.C.P.. FIG. 4. Core biopsy with a peritrabecular aggregate of small lymphocytes. Peritrabecular aggregates were seen in 46% of biopsy specimens in patients with MCL FIG. 2. Aspirate smear with small irregular lymphocytes and round lymphocytes from a patient with MCL. (Wright-Giemsa).

4 WASMAN, ROSENTHAL, AND FARHI 199 Bone Marrow in Mantle Cell Lymphoma»* # r «^r %te. * * FIG. 5. High power of a core biopsy with diffuse marrow involvement MCL. The majority of the cells are small, slightly irregular lymphocytes with rare large cells seen. DISCUSSION Bone marrow infiltration in mantle cell lymphoma is common and has been reported in up to 65% of patients. 3 In previous studies both focal and diffuse infiltration of the marrow has been described.' 8 In this study diffuse, interstitial, and nodular patterns were found. The most frequent patterns of bone marrow involvement were intertrabecular nodules and interstitial infiltration and the majority of cases showed more than one pattern of involvement. These findings in MCL, were similar to SLL, in which there was either diffuse marrow involvement, interstitial infiltration, and nodular involvement or SCCL, in which marrow involvement showed paratrabecular localization. Although the morphologic features of a bone marrow specimen may be suggestive of MCL, we were unable to identify definitive diagnostic features allowing the separation of involvement by MCL from involvement by SCCL or SLL. Therefore, lymph node biopsy is necessary to determine a diagnosis of MCL. The immunophenotypic features of CD5 positivity without CD23 may also be helpful in distinguishing SLL from MCL. Paratrabecular involvement, which is commonly associated with marrow involvement by follicular small cleaved cell lymphomas, 8 was seen in 46% of our cases of MCL. The diagnosis of a follicular center cell lymphoma should not be the only one considered in marrow specimens in which the lymphomatous infiltrate is primarily paratrabecular. Germinal centers were not seen in association with the lymphomatous involvement in our study, although they are commonly found in the lymph nodes of patients with MCL. Germinal centers in MCL are considered to be reactive in nature and not part of the malignant clone. Germinal centers are rarely seen in bone marrow clot sections or core biopsies and may be associated with underlying autoimmune disorders and drug reactions, but have also been described in association with marrow involvement by lymphoma. 19 Pombo De Olivera and colleagues 20 examined the peripheral blood findings in MCL and found that the circulating cells were pleomorphic with moderate amounts of cytoplasm, cleaved nuclei, and a conspicuous nucleolus. The morphology alone was not sufficient to classify the cells as being derived from MCL, and immunophenotyping data were required to make a definitive diagnosis. Although our findings in the peripheral blood were different than those described by Pombo De Olivera, we also found that no absolute criteria could be discerned in order to make a firm diagnosis of MCL based on peripheral blood lymphocyte morphology. The circulating cells in our patients did appear more irregular in comparison to the circulating cells of patients with CLL, but not as cleaved as those in the leukemic phase of SCCL. Bain and Catovsky 21 also thought the cells of MCL were more pleomorphic than CLL, and were more likely to be confused with circulating cells from follicular lymphomas. Immunophenotyping may be helpful as well as cytogenetic and DNA analysis for the presence of t(ll;14)(ql3;q32)inmcl. In summary, the marrow findings of mantle cell lymphoma have some of the characteristics of both small lymphocytic lymphoma and small cleaved cell lymphoma. Differentiation among the three does not appear to be possible solely according to morphologic criteria. However, the presence of bone marrow involvement by small irregular, but not cleaved lymphocytes with both paratrabecular and interstitial infiltration suggests the possibility of involvement by mantle cell lymphoma. REFERENCES 1. Brunning RD, McKenna RD. Tumors of the Bone Marrow. Washington DC: Armed Forces Institute of Pathology, Berard CW, Dorfman RF. Histopathology of malignant lymphomas. Clin Haematol 1974;3: Swerlow SH, Habeshaw JA, Murray LJ, et al. Centrocytic lymphoma: A distinct clinicopathologic and immunologic entity. Am J Pathol 1983; 113: Duggan MJ. Weisenburger DD, Ye YL, et al. Mantle zone lymphoma: A clinicopathologic study of 22 cases. Cancer 1990:66: Harris NL, Nadler LM, Bhan AK. Immunohistologic characterization of two malignant lymphomas of germinal center type (centroblastic/centrocytic and centrocytic) with monoclonal antibodies. Am J Pathol 1984; 117: Lardelli P, Bookman MA, Sundeen J, Longo DL, Jaffe ES. Lymphocytic lymphoma of intermediate differentiation Morphologic and immunophenotypic spectrum and clinical correlations. A in J Surg Pathol 1990; 14: Vol. 106-No. 2

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