Non-Hodgkin's Lymphoma of Large Multilobated Cell Type

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Non-Hodgkin's Lymphoma of Large Multilobated Cell Type A Clinicopathologic Study of Ten Cases DAVID S. WEINBERG, M.D., PHD. AND GERALDINE S. PINKUS, M.D. Weinberg, David S., and Pinkus, Geraldine S.

1 Non-Hodgkin's Lymphoma of Large Multilobated Cell Type A Clinicopathologic Study of Ten Cases DAVID S. WEINBERG, M.D., PHD. AND GERALDINE S. PINKUS, M.D. Weinberg, David S., and Pinkus, Geraldine S.: Non-Hodgkin's lymphoma of large multilobated cell type. A clinicopathologic study of ten cases. Am J Clin Pathol 6: 90-96, 9. Recently, the authors described a distinct variant of T-cell lymphoma characterized morphologically by large multilobated nuclei, and clinically by a predilection for extranodal sites and a favorable prognosis. In a retrospective study of 5 cases of "histiocytic" lymphomas observed during a 3-year period, ten additional cases of this unusual variant of non-hodgkin's lymphoma were identified. Features similar to those of the initial group of cases included a predominant extranodal distribution, particularly involving skin, subcutaneous tissue, and bone, and a favorable response to therapy. However, the retrospective cases differed in that systemic symptoms were infrequent and gonadal involvement was not observed. Recognition of this morphologically distinct subtype of non-hodgkin's lymphoma is of diagnostic, therapeutic, and prognostic significance. (Key words: Non-Hodgkin's lymphoma; Histiocytic lymphoma; T-cell lymphoma.) RECENTLY, we described four cases of a distinct variant of "histiocytic" lymphoma of T-cell type, characterized morphologically by neoplastic cells with large multilobated nuclei. 9 Clinically, these cases revealed a predilection for extranodal sites, particularly skin and subcutaneous tissue, bone, gonads, and central nervous system, and were associated with a favorable prognosis. Lymphadenopathy, if present, was not a major clinical finding, and splenomegaly was absent. These cases were morphologically and clinically distinguishable from previously described T-cell malignancies, i.e., mycosis fungoides, 4 Sezary's syndrome, 4 T-cell lymphomas of "histiocytic," lymphoblastic, 6-0 or diffuse poorly differentiated lymphocytic type, 5 T-cell leukemias of acute 2 or chronic lymphocytic type, 3,24 and the variety of non- Hodgkin's lymphoma reported by Waldron and associates. 23 Histologically, this lymphoma clearly differed from other "histiocytic" lymphomas of the Rappaport classification. 20 The multilobated nucleus was quite distinct from the round, oval, or cleaved nuclei described by Lukes and Collins for the large neoplastic lymphoid Received September 22, 90; received revised manuscript and accepted for publication October 30, 90. Address reprint requests to Dr. Pinkus: Department of Pathology, Brigham and Women's Hospital, 5 Francis Street, Boston, Massachusetts 025. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts cells of lymphomas of follicular center cell (B-cell) type, 2 and from large lymphoid cells characterizing immunoblastic sarcomas of B-cell (plasmacytoid features) and T-cell (abundant water clear cytoplasm) types. In our previous report, 9 extensive studies (surface marker studies, cytochemistry, and electron microscopy) were available in all four cases evaluated. However, since this variant of non-hodgkin's lymphoma may easily be distinguished from other "histiocytic" lymphomas by morphologic criteria alone, a retrospective study was undertaken to identify previously unrecognized cases, and to determine whether their clinical features were similar to those initially described. Materials and Methods Slides from 5 cases of "histiocytic" lymphoma observed between 966 and 99 were retrieved from the surgical pathology files of the Peter Bent Brigham Hospital. All tissues had been fixed in formalin. If available, paraffin blocks from consult cases were recut in our laboratory. Sections were reviewed without knowledge of the clinical findings. Criteria for the recognition of the variant of non- Hodgkin's lymphoma with large multilobated nuclei have been described in detail in a previous publication. 9 Briefly, the single most useful feature is the striking multilobated appearance of lymphoid nuclei, which may appear split into fragments or assume mulberry or cloverleaf shapes. The nuclear chromatin is generally fine, and nucleoli are indistinct or small. The cytoplasm is pale to weakly eosinophilic, and cell borders are poorly defined. Cases included in this study were characterized by infiltrates in which large multilobated cells constituted 50% or more of the cell population. Small lymphoid cells usually accounted for less than 0% of the lymphoid cells. Other cell types, e.g., eosinophils, plasma cells, and epithelioid histiocytes, were absent or rare //000/090 $00.5 American Society of Clinical Pathologists 90

2 Vol. 6 No. 2 LYMPHOMA OF LARGE MULTILOBATED CELLS 9 Table. Clinical Features in Ten Cases of Non-Hodgkin's Lymphoma of Large Multilobated Cell Type Case 25.F Case 2 29,M Case 3 Case 4 Case 5 Case 6 Case Patient's Age (Yrs)/ Sex Presenting History Initial Sites of Disease Clinical Course* 5,F 56,M 69,M 4,M 24,M Case 44,M Case 9 6,F Case 0 24.M Right arm pain, 2 yrs One yr history of pain, swelling, and increasing mass of medial aspect of right knee Three mp history of rapidly enlarging posterior occipital mass Night sweats and increasing right inguinal adenopathy, 6 mo duration, right buttock and thigh pain for mo Several-month history of siowly enlarging painless sternal mass Nine-mo history of tender scalp nodule (3.5 cm) Left cheek swelling and left hip pain of recent onset Four-mo history of left upper quadrant pain, anorexia, weight loss, and fatigue Intermittent hip pain for 3 yr; left inguinal mass and edema of left leg for less than mo Dyspnea, chest pain, dysphagia for 4 mo, hematuria Right humerus, soft tissues of right arm Distal right femur and adjacent soft tissue Subcutaneous tissue of scalp Right inguinal and iliac nodes; bone marrow (focal) Upper sternum (x5 cm), left cervical nodes Scalp (right parietal), right cervical nodes, equivocal periaortic nodes (lymphangiography) Left face, left zygoma, right forearm, groin, and thigh, bone marrow Spleen, omental nodes, probable periaortic nodes, mild axillary and inguinal adenopathy; liver and bone marrow negative Left pubic bone and adjacent soft tissue Right hilar mass (5x3 cm) with probable lung involvement, left kidney (nephrectomy), hepatosplenomegaly (liver biopsy negative) Excellent response to local radiotherapy Local radiotherapy with good response; yr later, recurrent disease (biopsy proven) involving supraclavicular, cervical, and axillary nodes, and multiple subcutaneous sites; remission with COP BACOP, high-dose methotrexate therapy, local radiotherapy BACOD; complete remission C-MOPP; complete remission Complete remission with MACOP Local radiotherapy- + COP with initial response; then recurrent and progressive disease involving cranial nerves, vertebrae with cord compression, multiple lytic bone lesions, scalp, oral mucosa; BACOP therapy M-BACOD, good response M-BACOP, excellent response BACOP, radiation therapy Survivalt (Mo after Diagnosis) 2 (NED) 2 (NED) 36 (NED) 34 (NED) 24 (NED) 20 (NED) (Died of disease) 2 (Receiving therapy) 2 (cause of death: massive myocardial infarction) No follow-up * M-BACOD, methotrexate-bleomycin, adriamycin, Cytoxan, vincristine, dexamethasone. COP, Cytoxan, vincristine, prednisone. MOPP, nitrogen mustard, vincristine. Clinical data were obtained from the patients' hospital and clinical records. Clinical Features Results Twelve of 5 cases (6%) of "histiocytic" lymphoma observed during a 3-year period were identified as the prednisone, procarbazine. t NED, no evidence of disease. morphologic variant with large multilobated nuclei. Two cases, one involving vertebral bone and one associated with a soft tissue mass in the cervical area (both in adults) were excluded from the study owing to lack of adequate clinical information. The clinical features of the remaining ten cases are presented in Table, and are summarized in Table 2; Extranodal involvement by lymphoma represented the most prominent clinical feature. Nine patients had

3 92 WEINBERG AND PINKUS A.J.C.P. August 9 Table 2. Clinical Features in Ten Cases of Non-Hodgkin's Lymphoma of Large Multilobated Cell Type Age (years) Range: Mean: 4 Sex (M:F) Presenting symptoms Weight loss Fever/night sweats Fatigue Local pain/tenderness Mass (soft tissue, bone) Lymphadenopathy Regional Generalized Hepatomegaly Splenomegaly Extranodal involvement Skin/subcutaneous tissue Bone (extensive) Kidney Central nervous system Extranodal involvement alone Clinical course* In remission Range: 2-2 mot Mean: 3 mo Dead* No. of Patients : Case No.,2,6,,,9, 0,2,3,5,6,,9 2,4,5,6, 0 0, 0,2,3,6,,9,2,5,,9 0,3,,9 * Clinical follow-up not available for Patient 0. t Six patients with no evidence of diease; one patient receiving therapy with good response at two months. t One death due to lymphoma at months; one patient (Case 9) died of causes unrelated to lymphoma. one or more sites of extranodal lymphoma, most commonly in bone or skin and subcutaneous tissue (seven patients). The extranodal lesions were clinically significant in all cases. Localized pain and/or the presence of a mass, particularly involving bone and soft tissue, were the most common presenting symptoms. Constitutional symptoms were present in only two often patients. Splenic and renal involvement, observed in Cases and 0, respectively, were not apparent in our initial cases. Splenomegaly alone or hepatosplenomegaly was infrequent. Patients received a variety of therapies. Six patients were treated with chemotherapy alone, one with radiation therapy alone, and three with combined chemotherapy and radiation therapy. Follow-up clinical data were available for nine patients. Six patients showed good responses to therapy and have remained in clinical remission for two to six years since the time of clinical presentation. One patient is currently receiving therapy, with a good response at two months. One patient (Case 9) died of causes unrelated to the lymphoma, and had shown a good clinical response to therapy. Another patient (Case ) died months after presentation, relapsing with widespread bone and subcutaneous involvement, after showing an initial good response to therapy. An autopsy was not performed. Histology Representative light-microscopic sections from two cases are illustrated in Figures and 2. In general, the morphologic features of these cases were similar to those described in detail previously. 9 The lymphomatous infiltrate was diffuse in all cases. Lymphoid cells with large multilobated nuclei dominated the pro T liferation, with a minor population of smaller lymphoid cells admixed. In some specimens, occasional large lymphoid cells with round or cleaved nuclei were also present. In reviewing all of our cases of "histiocytic" lymphomas, rare cases were encountered that were composed mainly of cleaved follicular center type cells associated with a conspicuous, though minor, component of lymphoid cells with multilobated nuclei. Since cell markers were unavailable for these cases, it is conjectural whether the multilobated cells represented variants of B cells (subtype of lymphoma suggested by overall morphology) or T lymphoid cells (as noted for our initial cases of multilobated cell lymphomas). In one specimen with these morphologic features, the infiltrate focally assumed a nodular growth pattern. Discussion In this retrospective study, the cases of non-hodgkin's lymphoma of large multilobated cell type that were morphologically identified revealed clinical similarities to the four well-characterized T-cell neoplasms previously reported. 9 Extranodal involvement was a prominent clinical feature in both groups, with skin/ subcutaneous tissue infiltration and destructive bone lesions consistently representing the most common extranodal manifestations of the disease. Hepatomegaly or splenomegaly was again infrequently encountered. Gonadal involvement, apparent in two of the previously described cases, was not observed in the present study. Central nervous system involvement was present in only one patient (Case ) of the current study. Renal involvement, present in one patient (Case 0), was not previously observed. Lymphadenopathy, though frequent (five of ten cases), again was usually not a prominent feature. None of our current cases exclusively involved nodes, as apparent in one previous

right) Higher magnification of neoplastic lymphoid cells. Hematoxylin and eosin. A, x600: B, x,600. case. Constitutional symptoms were less common than in the previous group.

4 vol. 6. No. 2 LYMPHOMA OF LARGE MULTILOBATED CELLS 93 FIG.. Soft tissue, pubic area, Case 9. A (left) The tissue is diffusely infiltrated by large lymphoid cells, the majority of which contain multilobated nuclei, fine chromatin, and small or indistinct nucleoli. B (.right) Higher magnification of neoplastic lymphoid cells. Hematoxylin and eosin. A, x600: B, x,600. case. Constitutional symptoms were less common than in the previous group. An important similarity to the initial group of cases was the good response to therapy; most patients experienced clinical remission. Only one of nine patients (with follow-up) has died of the disease. All other patients (with adequate followup) who experienced a remission are free of disease for periods of two to six years. The clinical and morphologic features that distinguish the variant of non-hodgkin's lymphoma with multilobated nuclei from previously reported cases of T-cell lymphoma have been discussed in detail. 9 Waldron and associates" described a variant of T-cell lymphoma that was characterized morphologically by a spectrum of lymphoid cells and associated with vascular proliferation and clusters of epithelioid histiocytes. In those cases, occasional hyperlobated or multinucleated cells were also observed, as well as large cells with clear cytoplasm, some resembling Reed-Sternberg variants. The T-cell lymphomas recently reported by Palutke and colleagues similarly revealed numerous histiocytes and prominent vascularity, features lacking in our cases. Large lymphoid cells in their group of neoplasms were characterized either by round regular nuclei or by markedly irregular nuclei. In the latter group, however, multilobated forms were not apparent. Our cases of non-hodgkin's lymphomas appear to share certain morphologic similarities with other recently described variants of T-cell lymphomas.,9 Azar and co-workers observed variable numbers of lymphoid cells with hyperlobated nuclei in two T-cell lymphomas of large cell type. In a large series of T-cell malignancies in Japan, Kikuchi and associates 9 observed lymphoid cells with hyperlobated or mulberrytype nuclei in many cases, particularly in the pleomorphic type of T-cell lymphoma that constituted a large proportion of their series. Clinical distinctions, however, do exist between our multilobated cell lymphomas and their T-cell lymphomas. Skin lesions occurred in both groups, but were more common in the cases from Japan. Other striking clinical differences in the latter cases, as compared with our group of lymphomas, include frequent leukemic involvement (6% of cases) and a poor prognosis.

B (upper, right), C (lower) Higher magnifications reveal large lymphoid cells with multilobated nuclei. Periodic acid-schiff. A, xl60; B, x00; C, x2,000.

5 94 WEINBERG AND PINKUS A.J.C.P. August 9 FIG. 2. Kidney, Case 0. A (upper, left) Lymphomatous infiltrate extensively involves the renal interstitium and surrounds residual glomeruli and tubules. B (upper, right), C (lower) Higher magnifications reveal large lymphoid cells with multilobated nuclei. Periodic acid-schiff. A, xl60; B, x00; C, x2,000. Immunologic studies have demonstrated that "histiocytic" lymphomas as defined in the Rappaport classification represent a heterogenous group of neoplasms of various origins, including B cells, T cells, null cells, and true histiocytes.2,3 Rappaport,20 in his morphologic description of "histiocytic" lymphoma, does not describe a variant with multilobated or hyperlobated nuclei. Within the group of "histiocytic"

6 Vol. 6 No. 2 lymphomas (Rappaport classification), Lukes and Collins 2 have identified several morphologic subtypes: immunoblastic sarcomas of B-cell 2 or T cell types, lymphomas of large cleaved or noncleaved follicular center cell types, and true histiocytic neoplasms. Although they do not describe a morphologic variant with large multilobated nuclei, presumably such cases have been included in the large cleaved follicular center cell (LCFCC) group of lymphomas. Although the LCFCC lymphomas are generally considered of B-cell origin, surface marker studies have shown heterogeneity within this group as well, with only 3% showing a monoclonal pattern of surface immunoglobulin (B-cell marker) and 3% negative for surface immunoglobulin. :I Identification of this morphologic variant of non- Hodgkin's lymphoma appears to have prognostic significance. Excellent clinical response to therapy was observed in all but one of nine patients with follow-up. Only one patient has died of the disease. In a clinicopathologic study comparing the Rappaport and the Lukes and Collins classification systems, 6 diffuse "histiocytic" lymphomas, in general, had a relatively poor prognosis, with a median survival of eight months (compared with 4.5 months for diffuse poorly differentiated lymphocytic lymphoma). The presence of large cleaved cells seemed to confer a more favorable prognosis, with a median survival of 22 months (compared with eight months for lymphomas of the large noncleaved follicular center type). Recently, Strauchen and associates 22 divided the "histiocytic" lymphomas into five histopathologic categories, in an attempt to correlate morphologic features with clinical behavior and prognosis. Though the subtypes described by these authors do not include a variant with large multilobated nuclei, in their study "histiocytic" lymphomas characterized by large cleaved cells were associated with the best prognosis, with six of eight patients surviving two years. Thus, the morphologic variant described in this report is similar to "histiocytic" lymphomas with large cleaved cells in its association with a better prognosis, as compared with diffuse histiocytic lymphomas as a single group, and perhaps has previously been included with that group of neoplasms. Our data suggest that the variant of "histiocytic" lymphoma with large multilobated nuclei represents a distinct clinicopathologic subtype that has not been previously recognized by other classification systems. This morphologic variant of non-hodgkin's lymphoma is characterized clinically by a predilection for extranodal involvement, particularly skin/subcutaneous tissue and bone, and shows an excellent response to therapy. Although surface markers were not available for cases in the present study, the clinical similarities LYMPHOMA OF LARGE MULTILOBATED CELLS 95 to four previously described cases 9 of T-cell lymphoma with large multilobated nuclei suggest a possible T-cell origin for these cases as well. The possibility of a B-cell origin for some of these lymphomas also cannot be excluded. Recently we examined a lymphoma involving soft tissues of the neck, composed mainly of large multilobated cells that revealed B-cell markers (complement receptors, Fc receptors, and monoclonal surface immunoglobulin of IgM, kappa type). Assessing a much larger group of cases is obviously necessary to define the immunologic and clinical characteristics of this type of lymphoma more thoroughly. However, recognition of its distinct morphologic features is of practical diagnostic importance, especially in the absence of immunologic studies. Since the main sites of clinical involvement are often extranodal, biopsy specimens with these unusual morphologic features may be confused with other neoplasms or possibly not be recognized as a variant of lymphoma. References. Azar HA, Jaffe ES, Berard CW, Callihan TR, Braylan RR, Cossman J, Triche TJ: Diffuse large cell lymphomas (Reticulum cell sarcomas, histiocytic lymphomas) Correlation of morphologic features with functional markers. Cancer 46:42-44, Berard CW, Jaffe ES, Braylan RC, et al: Immunologic aspects and pathology of the malignant lymphomas. Cancer 2: 9-92, 9 3. Brouet JC, Flandrin G, Sasportes M, et al: Chronic lymphocytic leukemia of T cell origin. Immunological and clinical evaluation in eleven patients. Lancet 2:90-93, Brouet JC, Preud'homme JL, Flandrin G, et al: Brief communication: Membrane markers in "histiocytic" lymphomas (reticulum cell sarcomas). J Natl Cancer Inst 56:63-633, Davey FR, Goldberg J, Stockman J, et al: Immunologic and cytochemical cell markers in non-hodgkin's lymphomas. Lab Invest 35:430-43, Jaffe ES, Braylan RC, Frank MM, et al: Heterogeneity of immunologic markers and surface morphology in childhood lymphoblastic lymphoma. Blood 4:23-222, 96. Jaffe ES, Braylan RC, Nanba K, et al: Functional markers: A new perspective on malignant lymphomas. Cancer Treatment Rep 6: , 9. Kaplan J, Mastrangelo R, Peterson WD, Jr: Childhood lymphoblastic lymphoma, a cancer of thymus-derived lymphocytes. Am J Clin Pathol 34:52-525, Kikuchi M, Mitsui T, Matsui N, Sato E, Tokunaga M, Hasui K, et al: T-cell malignancies in adults: Hislopathological studies of lymph nodes in 0 patients. Jpn J Clin Oncol 9: , 99 (Suppl) 0. Koziner B, Filippa DA, Mertelsmann R, et al: Characterization of malignant lymphomas in leukemic phase by multiple differentiation markers of mononuclear cells. Am J Med 63: , 9. Lukes JR: The immunologic approach to the pathology of malignant lymphomas. Am J Clin Pathol 2:65-669, Lukes RJ, Collins RD: Immunologic characterization of human malignant lymphomas. Cancer 34:4-503, Lukes RJ, Taylor CR, Parker JW, Lincoln TL, Pattengale PK, Tindle BH: A morphologic and immunologic surface marker

7 96 WEINBERG AND PINKUS A.J.C.P. August 9 study of 299 cases of non-hodgkin's lymphomas and related leukemias. Am J Pathol 90:46-45, 9 4. Lutzner M, Edelson R, Schein P, et al: Cutaneous T-cell lymphomas: The Sezary syndrome, mycosis fungoides, and related disorders. Ann Intern Med 3: , Mann RB, Jaffe ES, Braylan RC, et al: Immunologic and morphologic studies of T cell lymphoma. Am J Med 5: 30-33, Nathwani BN, Kim H, Rappaport H, Soloman J, Fox M: Non- Hodgkin's lymphomas. A clinicopathologic study comparing two classifications. Cancer 9: , 9. Palutke M, Tabaczka P, Weise RW, Axelrod A, et al: T-cell lymphomas of large cell type. A variety of malignant lymphomas: "histiocytic" and mixed lymphocytic-"histiocytic". Cancer 46:-0, 90. Pinkus GS, Said JW: Characterization of non-hodgkin's lymphomas using multiple cell markers: Immunologic, morphologic and cytochemical studies of 2 cases. Am J Pathol 94:349-30, Pinkus GS, Said JW, Hargreaves HK: Malignant lymphoma, T cell type: A distinct morphologic variant with large multilobated nuclei. Report of four cases. Am J Clin Pathol 2: , Rappaport H: Tumors of the hematopoietic system. Atlas of Tumor Pathology; Section 3, Fasc.. Washington, D. C, Armed Forces Institute of Pathology, Sen L, Borella L: Clinical importance of lymphoblasts with T markers in childhood acute leukemia. N Engl J Med 292: 2-32, Strauchen JA, Young RC, DeVita VT, Anderson T, Fantone JC, Berard CW: Clinical relevance of the histopathological subclassification of diffuse "histiocytic" lymphoma. N Engl. J Med 299:32-3, Waldron JA, Leech JH, Glick AD, et al: Malignant lymphoma of peripheral T-lymphocyte origin. Cancer 40:604-6, Uchiyama T, Yodoi J, Sagawa K, et al: Adult T-cell leukemia: Clinical and hematologic features of 6 cases. Blood 50: 4-492, 9

Non-Hodgkin lymphomas (NHLs) Hodgkin lymphoma )HL)

Non-Hodgkin lymphomas (NHLs) Hodgkin lymphoma )HL) Lymphoid Neoplasms: 1- non-hodgkin lymphomas (NHLs) 2- Hodgkin lymphoma 3- plasma cell neoplasms Non-Hodgkin lymphomas (NHLs) Acute Lymphoblastic Leukemia/Lymphoma