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CD5 T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

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CD5 T-Cell/Histiocyte-Rich Large B-Cell Lymphoma CD5؉ T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Chung-Che Chang, M.D., Ph.D., Ellen Bunyi-Teopengco, M.D., Camellia Eshoa, M.D., Christopher R. Chitambar, M.D., Bal Kampalath, M.D. Departments of Pathology (C-CC, EB-T, CE, BK) and Medicine (CRC), Medical College of Wisconsin, Milwaukee, Wisconsin to identifying more cases to understand the clinical CD5 expression in neoplastic large B-cells in T-cell/ and biologic characteristics of this variant. histiocyte-rich large B-cell lymphoma has not been reported, to the best of our knowledge. Here we KEY WORDS: CD5؉, T-cell rich/histiocyte-rich large .describe the first case of CD5؉ T-cell/histiocyte-rich B-cell lymphoma large B-cell lymphoma that is well documented by Mod Pathol 2002;15(10):1051–1057 histomorphology, immunohistochemistry, flow cy- tometry immunophenotyping and sorting, and im- T-cell/histiocyte-rich large B-cell lymphoma is cur- munoglobulin heavy-chain gene rearrangement rently categorized as a variant of diffuse large B-cell study by polymerase chain reaction. The expression lymphomas in the World Health Organization and of CD5 in large neoplastic B-cells was demonstrated revised European-American classification of lym- by immunohistochemistry and multicolor flow cy- phoid neoplasms (1, 2). Although there is no strict -tometry. The clonal nature of the CD5؉ neoplastic criteria used nor a definite agreement on the diag B-cells was confirmed by rearranged immunoglob- nosis of T-cell/histiocyte-rich large B-cell lym- ulin heavy (IgH) chain with polymerase chain reac- phoma, the majority of the cases should have the -tion (PCR) of flow cytometry–sorted CD5؉/ following characteristics: (1) a diffuse growth pat -CD19؉/␬؉ cells. The CD5؉ neoplastic large B-cells tern throughout the entire specimen on hematoxy expressed bcl-6 and MUM1/IRF4 but not CD138 by lin and eosin stain (2), scattered large neoplastic B immunohistochemistry. This suggests that the neo- cells that make up Ͻ10% of the total cell population plastic cells may be of late germinal-center B-cell/ (3), the presence of other cells that are mostly T early post–germinal center B-cell origin. The pa- cells and histiocytes, and (4) clonality of the neo- tient responded to chemotherapy, CHOP (Cytoxan, plastic B cells demonstrated by immunohistochem- doxorubicin, vincristine, and prednisone), and Rit- ical and molecular techniques (3–7). It is usually uxan very well and is currently in complete remis- associated with advanced clinical stage at presen- sion clinically. We propose that the current case, tation (3–5, 8). -CD5؉ T-cell/histiocyte-rich large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma ap represents a variant of recently reported de novo pears to be a heterogeneous group of B-cell lympho- -CD5؉ diffuse large B-cell lymphomas. Our patient mas, which may arise de novo but may also be asso has had an excellent response to treatment; how- ciated with other lymphomas such as follicular ever, the clinical and biologic significance of CD5 lymphoma and lymphocyte-predominant Hodgkin’s expression in T-cell/histiocyte-rich large B-cell lym- disease (7, 9–11). Molecular analysis of T-cell/ phoma requires further studies. Awareness of the histiocyte-rich large B-cell lymphoma has shown that -CD5؉ T-cell/histiocyte-rich large B-cell lymphoma the rearranged immunoglobulin (Ig) genes in the ma variant will prompt pathologists to perform CD5 jority of cases carry somatic mutation. This finding immunohistochemical stain in cases of T-cell/ indicates that these B cells are derived from germinal- histiocyte-rich large B-cell lymphoma. This will lead center B cells (12). Recently, de novo CD5ϩ diffuse large B-cell lym- phomas has been reported by several groups of Copyright © 2002 by The United States and Canadian Academy of investigators who proposed that this lymphoma is a Pathology, Inc. distinct subtype of diffuse large B-cell lymphomas VOL. 15, NO. 10, P. 1051, 2002 Printed in the U.S.A. Date of acceptance: June 6, 2002. (13–21). We describe here, to the best of our knowl- Address reprint requests to: Chung-Che Chang, M.D., Ph.D., Department edge, the first case of CD5ϩ T-cell/histiocyte-rich of Pathology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226; e-mail: [email protected]; fax: 414-805-8444. large B-cell lymphoma. Expression of CD5 in the DOI: 10.1097/01.MP.0000027624.08159.19 neoplastic large B cells is demonstrated by immu- 1051 nohistochemistry and by flow cytometry. Further- formalin or Bouin’s solution and paraffin embedded. more, the clonal nature of the CD5ϩ neoplastic Four-micrometer sections were stained with hema- large B-cells is confirmed by ␬ light-chain restric- toxylin and eosin. Immunohistochemical stains were tion and rearranged immunoglobulin heavy (IgH) performed on the lymph node specimen for the fol- chain using flow cytometry and polymerase chain lowing markers (Table 1): CD3, CD10, CD5, CD15, reaction (PCR), respectively. CD20, CD23, CD30, CD68, CD138, cyclin D1, Epstein- Barr virus (EBV)-LMP, MUM1/IRF4 (multiple myelo- ma-1/interferon regulatory factor-4), and bcl-6. All CASE REPORT slides were stained using the DAKO automated im- A 47-year-old white male presented to our hos- munostainer (Carpinteria, CA). CD3 and CD20 stains pital with a 4-month history of intermittent fever were also performed on the other specimens. The (99–103° F), chills, sweating, weakness, and a 25-lb slides were incubated in labeled streptavidin–biotin weight loss. He denied any significant medical his- for linking and labeled subsequently with diamino- tory. The patient worked as an assembly worker for benzidine chromogen. Appropriate positive and neg- a tractor manufacturing plant. He did not smoke ative controls were used in all cases. and occasionally drank beer. The patient’s mother had died of lymphoma; his father was living with DNA Extraction from Lymph Node of Paraffin- prostate cancer. Embedded Tissue His physical examination was unremarkable ex- The DNA of lymph node was extracted from the cept for an enlarged spleen that was confirmed by paraffin-embedded tissue with 5-␮m sections using abdominal computed tomography (CT) scan, which established protocol (22). The extracted DNA was showed the spleen measuring 17 cm in craniocau- further tested by an established ␤-globin PCR assay dal dimension. There was a palpable right inguinal to ensure that the DNA was able to be amplified by lymph node but no other lymphadenopathy veri- PCR (22). fied by chest and pelvic CT scan. His complete blood cell count was significant for normocytic/ normochromic anemia (hemoglobin: 9.8 g/dL, he- Flow Cytometry matocrit: 30%, MCV: 81 fL, MCH: 27 pg, MCHC: 33 The mononuclear cells prepared from bone mar- g/dL) and leukocytosis (white blood cell count: row aspirate were incubated with each antibody 3 19,000/mm ) with neutrophilia (72%), monocytosis coupled with various fluorochromes. The antibod- (18%), and a few atypical lymphocytes. Elevated ies studied included the following: CD2, CD3, CD5, serum levels of alkaline phosphatase (385 U/L) and CD4, CD8, CD10, CD19, CD20, ␬ light chain, and ␭ LDH (368 U/L) were also present. Other studies light chain. Three-color flow cytometry surface showed negative results for viral, fungal, and bac- marker analysis was performed with FACScan flow terial infection. He subsequently underwent a cytometer (Becton Dickinson, San Jose, CA). The lymph node biopsy, bone marrow biopsy, splenec- data analysis was done using CELLQuest software tomy, and liver biopsy. The results of pathologic (Becton Dickinson). evaluation revealed the diagnosis of CD5ϩ T-cell/ histiocyte-rich large B-cell lymphoma involving lymph node, bone marrow, spleen, and liver. The patient underwent treatment with combina- TABLE 1. Characteristics of the Antibodies Used tion chemotherapy consisting of Cytoxan, doxoru- Antibody Clone Manufacturer (location) Dilution bicin, vincristine, and prednisone (CHOP), in con- CD3 NA DAKO (Carpinteria, CA) 1Ϻ300 junction with Rituxan administrated every 3 weeks. CD5 CD5/54/F6 DAKO 1Ϻ100 CD10 56C6 Novocastra (Newcastle, 1Ϻ50 Within 2 weeks of the first cycle of treatment, his UK) symptoms of fever, chills, and sweats abated. Re- CD15 Leu-M1 Becton Dickinson (San 1Ϻ50 evaluation with CT scan and bone marrow biopsy Jose, CA) CD20 L26 DAKO 1Ϻ400 after six cycles of therapy revealed no evidence of CD23 IBI2 Novocastra 1Ϻ40 residual disease. At this time, 6 months after com- CD30 Ber-H2 DAKO 1Ϻ60 pletion of therapy, he has regained weight, feels CD68 PGM-1 DAKO 1Ϻ200 CD138 MI-15 DAKO 1Ϻ50 healthy, and remains in complete remission. MUM1/IRF4 M-17 Santa Cruz Biotechnology 1Ϻ200 (Santa Cruz, CA) Bcl-6 NA Santa Cruz Biotechnology 1Ϻ300 MATERIALS AND METHODS Cyclin D1 DSC-6 DAKO 1Ϻ25 EBV-LMP CS1-4 DAKO 1Ϻ50 Histology and Immunohistochemistry The method for epitope retrieval was a heating water bath at 100 °C with pH 6.0 citrate buffer for 35 minutes for all antibodies except EBV- The tissue specimens including lymph node, LMP, whose epitope was retrieved by proteinase K treatment. NA, not spleen, liver, and bone marrow biopsies were fixed in applicable, polyclonal; EBV, Epstein-Barr virus. 1052 Modern Pathology For flow cytometry sorting, the mononuclear The expression of CD5 in the large neoplastic cells from marrow aspirate were incubated with lymphocytes was further confirmed by flow cytom- three antibodies: CD5, CD19, and ␬ light chain in etry study performed in marrow specimen, in one tube. The sorting was performed using a FACS which involvement by lymphoma was clearly dem- Vantage flow cytometer/sorter (Becton Dickinson). onstrated by morphology and clonality studies. The CD5ϩ/CD19ϩ/␬ϩ cells and CD5Ϫ/CD19ϩ/␬ϩ marrow aspirate showed scattered large neoplastic cells were collected into two separate tubes con- lymphocytes with irregular nuclear contour, prom- taining 100 ␮L of proteinase K digestion buffer (pro- inent nucleoli, and moderate amount of cytoplasm.
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