Yeşim ERTAN, Saliha SOYDAN, MURAT TOMBULOĞLU, Seçkin ÇAĞIRGAN, Ayhan DÖNMEZ, Güray SAYDAM, Mine HEKİMGİL

Mitotic activity, p53 and bcl-2 protein immunoreactivity difference between morphological variants and subtypes of diffuse large B cell lymphoma

Bu çalışmada, antiapopitotik bcl-2 gen ve p53 tümör supresör gen proteinlerinin, diffüz büyük B hücreli lenfomaların (DBBHL) morfolojik varyantları ve alt gruplarındaki immunreaktivite farklılıklarının değerlendirilmesi ve sözü edilen proteinler ve mitoz sayısı ile olguların sağ kalım süresi arasındaki ilişkinin ortaya konması amaçlanmıştır. Retrospektif çalışmamızda, ana bilim dalımızda 1995 yılı Ocak ayı ve 2001 yılı Aralık ayı arasında non-Hodgkin Işnfoma tanısı almış materyalimiz gözden geçirilmiş ve DBBHL tanısı almış 123 olgu saptanmıştır. Bunlardan yalnızca 53 olgu morfolojik varyant ve alt grup ve mitoz yanı sıra p53 ve bcl-2 immunohistokimyasal özellikleri bakımından değerlendirilmiştir. Elli altı olgunun 31'inin klinik takibi elde edilebilmiş olup, bu olgular yukarıda sözü edilen parametreler yanı sıra sağ kalım süreleri bakımından da değerlendirilmiştir.53 olgu Dünya Sağlık Örgütü (WHO) sınıflamasındaki kriterlere göre morfolojik varyant ve alt gruplara ayrılmış ve 22'si (%41.5) sentroblastik, 13'ü (%24.5) anaplastik, 7'si (%13.3) immunoblastik, 6'sı (%11.3) T hücreden zengin B hücreli lenfoma (THZBHL) ve 5'i (%9.4) primer mediastinal B hücreli lenfoma olarak değerlendirilmiştir. Plazmablastik lymphoma ve lenfomatoid granülomatozis tanısı alan morfolojik varyantlar saptanmamıştır. P53 ekspresyonu anaplastik lenfomada (%92.3), THZBHL (%16.7) ile karşılaştırıldığında yüksek oranda saptanmıştır (p < 0.0008 ). Bcl-2 ekspresyonu immunoblastik lenfomada (%85.7), anaplastik lenfoma ile karşılaştırıldığında yüksek oranda saptanmıştır. Sentroblastik lenfomada ortalama mitoz oranı ve 20'nin üzerinde mitoz değeri diğer lenfomalara göre yüksek bulunmuştur. Morfolojik varyantlar ve alt gruplara ayrılmaksızm genel olarak DBBHL'lar yanısıra morfolojik varyantlar ve alt gruptaki p53, bcl-2 ve mitoz değerlerinin sağ kalım süresini etkilemediği belirlenmiştir.

Anahtar Kelimeler:

Genler, p53, Mitoz, Lenfom, büyük hücreli, difüz, Genler, bcl-2

Diffüz büyük B hücreli lenfoma morfolojik varyant ve alt gruplarında mitotik aktivite, p53 ve bcl-2 protein immunreaktivite farklılığı

The aim of this study is to assess the antiapoptotic bcl-2 gene protein and p53 tumor supressor gene protein immunoreactivity difference between the morphological variants and subtypes of diffuse large B cell Iymphoma (DLBCL) and the relationship between the aforementioned proteins, mitotic activity and survival.In this retrospective study, we examined the pathologic material which were diagnosed as non-Hodkin Iymphoma (NHL) from January 1995 to December 2001 in our pathology department. Among these Iymphomas, 123 cases were diagnosed as DLBCL. Of 123 cases, we were able to analyze the morphological variants and subtype, mitotic activity and the expression of p53 and bcl-2 proteins in only 53 cases of which in 31 cases clinical data were available. We examined the relation of aforementioned parameters and survival of these 31 cases. The diagnosis of DLBCL was established according to the criteria referred in World Health Organization (WHO) classification. Of 53 cases, 22 (41.5%) were centroblastic, 13 (24.5%) anapiastic, 7 (13.3%) immunoblastic, 6 (11.3%) T cell rich B cell Iymphoma (TCRBCL) and 5 (9.4%) primary mediastinal B cell Iymphoma (PMBCL). We had no cases diagnosed as plasmablastic Iymphoma and lymphomatoid granulomatosis. We found some relationships between the morphological variants and subtype of DLBCL and mitotic activity, the expression of p53 and bcl-2 proteins: The expression of p53 protein was observed more frequently in anapiastic Iymphomas compared to TCRBCL (92.3% versus 16.7%, p< 0.0008). The expression of bcl-2 protein was observed more frequently in immunoblastic Iymphoma compared to anapiastic Iymphoma (85.7% versus 53.8%, p< 0.001). In centroblastic Iymphoma, median mitotic activity was higher and mitotic figures higher than 20 were observed more frequently. In DLBCL, with or without subclassification, no correlation was found between survival and p53, bcl-2 expression and mitotic activity.

Keywords:

Genes, p53, Mitosis, Lymphoma, Large-Cell, Diffuse, Genes, bcl-2,

PDF

___

1. Non-Hodgkin's lymphoma pathologic classification project National Cancer Institute sponsored study of classifications of non- Hodgkin's lymphomas: Summary and description of a Working Formulation for clinical usage. Cancer 1982; 49:2112.
2. Shipp et al. a predictive model for aggresive non-Hodgkin's lymphoma. N Engl J Med 1993; 329:987-994.
3. Fisher Rl, Hubbard SM, DeVita VT, et al. factors predicting long-term survival in diffuse mixed, histiocytic, or undifferentiated lymphoma. Blood 1981; 58:45-51.
4. Jagannath S, Velasquez WS, Tucker SL, et al. Tumor burden assessment and its implication for a prognostic model in advanced diffuse large-dell lymphoma. J Clin Oncol 1986; 4:859-865.
5. Danieu L, Wong G, Koziner B, Clarkson B. Predictive model for prognosis in advanced diffuse histiocytic lymphoma. Cancer Res 1986; 46:5372-5379.
6. Coiffier B, Gisselbrecth C, Vose JM, et al. Prognostic factors in agressive malignant lymphomas: description and validation of prognostic index that could identify patients requiring a more intensive therapy. J Clin Oncol 1991; 9:211-219.
7. Coiffier B, Lepage E. Prognostic factors in agressive lymphomas: a study of five prognostic models with patients included in the LNH-84 regimen. Blood 1989; 74:558-564.
8. Shipp MA, Yeap BY, Harrington DP, et al. The M-BACOP combination chemotherapy regiamen in large-cell lymphoma: analysis of the completed trial and comparison with the M-BACOP regimen. J Clin Oncol 1990; 8:84-93.
9. Kramer MH, Hermans J, Wijburg K, et al. Clinical relevance of bcl-2, bcl-6, and myc rearrengements in diffuse large B-cell lymphoma. The American Society of Hematology 1998; 92:3152-3162.
10. Ichikawa A, Kınoshıta T, Watanabe T, et al. Mutations of the p53 gene as a prognostic factor in aggressive B-cell Lymphoma. N Engl J Med 1997; 337:529-534.
11. Nakamine H, Bagin RG, Vose J, et al. Prognostic significance of clinical and pathologic features in diffuse large B-cell Lymphoma. Cancer 1993; 71:3130-3137.
12. Randy D, Gascoyne MD. Pathologic prognostic factors in diffuse aggressive non-Hodgkin Lymphoma. Hematology Clin of North America 1997; 11:847-862.
13. Kramer MH, Hermans J, Parker J, et al. Clinical significance of bcl-2 and p53 protein expression in diffuse large B-cell Lymphoma: A population-based study. J of Clin Oncology 1996; 14:2131-2138.
14. Zhang A, Ohshimo K, Sato K, et al. Prognostic clinicopathologic factors, including immunologic expression in diffuse large B-cell lymphomas. Pathology international 1999; 49:1043-1052.
15. Priss MA, Pezzalla F, Martinez JC, et al. P53 and bcl-2 expressions in high-grade B cell lyphomas: correlation with survival time. Br J Cancer 1994; 69:337-341.
16. Gascoyne RD, Adomat SA, Krajewski S, et al. Prognostic significance of bcl-2 protein expression and bcl-2 gene rearrangement in diffuse agressive non-Hodgkin's Lymphoma. Blood 1997; 90:244-251.
17. Tang SC, Visser L, Hepperie B, et al. Clinical significance of bcl-2 MBR gene rearrengement and protein expression in diffuse agressive non-Hodgkin's Lymphoma: an analysis of 83 cases. J Clin Oncol 1994; 12:149-154.
18. Harris NL, Jaffe ES, Diebold J, et al. The World Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: report of the clinical advisory committee meeting, 1997. Histopathology 2000; 36:69-87.
19. Vago JF, Weisenburger DD, Armitage J. Do pathologic features predict prognosis in diffuse large B-cell Lymphoma? Hematol Pathol 1987; 1:217-255.
20. Warnke RA, Stauchen JA, Burke JS. Morphologic types of diffuse large cell Lymphoma. Cancer 1981; 50:690-695.
21. Oudejans JJ, Dukers DF, Berge RL, et al. T cell rich large B cell lymphomas contain non-activated CD8+ cytolytic T cells, show increased tumor cell apoptosis, and have lower bcl-2 expression than diffuse large B-cell lymphomas. Am J Pathol 1999;155(1):325-326.
22. Tsang P, Lesarman E, Chadburn A, et al. Molecular characterization of primary mediastinal B-cell lymphoma. Am J Pathol 1996; 148(6):2017-2025.
23. Scarpa A, Moore PS, Riqaud G, et al. Molecular features of primary mediastinal B- cell lymphoma: Involvement of p 16INK4A,p53 and c-myc. Br J Hematol 1999; 107(1): 106-113.
24. Piris MA, Pezzella F, Martinez-Montero JC et al. P53 and bcl-2 expression in high grade B-cell lymphomas. Cancer 1994; 69:337-341
25. Sander CA, Yano T, Clark HM, et al. P53 mutation is associated with progresion in follicular Lymphoma. Blood 1993; 1994-2004.
26. Kramer MHH, Hermans J, Parker J, et al. Clinical significance of bcl-2 and p53 protein expression in diffuse large B-cell Lymphoma. J Clin Oncol 1996; 14:2131-2138.
27. Hernandez L, Fest T, Cazorla M, et al. P-53 gene mutations and protein overexpression are associated with agressive variants of mantle cell lymphomas. Blood 1996; 87:3351-3359.
28. Sohn SK, Jung JT, Kim DH.et al. Prognostic significance of bcl-2,bax, and p53 expression in diffuse large B cell lymphoma. Am J Hematol 2003; 73 (2): 101-107.
29. Zhang A, Ohshimo K, Sato K, et al. Prognostic clinicopathologic factors, including immunologic expression in diffuse large B-cell lymphomas. Pathology international 1999; 49:1043-1052.
30. Sanchez E, Chacon MM, Plaza M, et al. Clinical outcoma in diffuse large B-cell Lymphoma is dependent on the relationship between different cell-cycle regulator proteins. J Clin Oncol 1998; 5:1931-1939.
31. Hermine O, Haiooun C, Lepage E, et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin Lymphoma. Blood 1996; 87:265-272.
32. Gascoyne RD, Adomat SA. Prognostic significance of bcl-2 protein expression and bcl-2 gene rearrengement in diffuse agressive B-cell Lymphoma. Blood 1997; 90:244.
33. Miller TP, Levy N, Bailey NP, et al. The bcl-2 gene translocation t(14;18) identifies a subgruop of patient with diffuse large cell Lymphoma having an indolecent clinical course with late relapse. Am Soc Clin Oncol 1994; 13:370