A cytomorphological and immunohistochemical profile of aggressive B-cell lymphoma: high clinical impact of a cumulative immunohistochemical outcome predictor score

Journal of Hematopathology - Tập 2 - Trang 187-194 - 2009
Sylvia Höller1,2, Heike Horn3, Andreas Lohr1, Uwe Mäder4, Tiemo Katzenberger1, Jörg Kalla3, Heinz-Wolfram Bernd5, Philip Went2, M. Michaela Ott6, Hans Konrad Müller-Hermelink1, Andreas Rosenwald1, German Ott3,7
1Department of Pathology, University of Würzburg, Würzburg, Germany
2Department of Pathology, Kantonsspital Basel, University of Basel, Basel, Switzerland
3Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany
4Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
5Department of Pathology, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
6Department of Pathology, Caritas-Krankenhaus, Bad Mergentheim, Germany
7Abteilung Pathologie, Robert-Bosch-Krankenhaus, Stuttgart, Germany

Tóm tắt

We analyzed morphological and immunohistochemical features in 174 aggressive B-cell lymphomas of nodal and extranodal origin. Morphological features included presence or absence of a follicular component and cytologic criteria according to the Kiel classification, whereas immunohistochemical studies included expression of CD10, BCL-2, BCL-6, IRF4/MUM1, HLA-DR, p53, Ki-67 and the assessment of plasmacytoid differentiation. Patients were treated with a CHOP-like regimen. While the presence or absence of either CD10, BCL-6 and IRF4/MUM1 reactivity or plasmacytoid differentiation did not identify particular cytomorphologic or site-specific subtypes, we found that expression of CD10 and BCL-6, and a low reactivity for IRF4/MUM1 were favourable prognostic indicators. In contrast, BCL-2 expression and presence of a monotypic cytoplasmic immunoglobulin expression was associated with an unfavourable prognosis in univariate analyses. Meta-analysis of these data resulted in the development of a cumulative immunohistochemical outcome predictor score (CIOPS) enabling the recognition of four distinct prognostic groups. Multivariate analysis proved this score to be independent of the international prognostic index. Such a cumulative immunohistochemical scoring approach might provide a valuable alternative in the recognition of defined risk types of aggressive B-cell lymphomas.

Tài liệu tham khảo

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) (2008) World Health Organization Classification of Tumours of Haematopoietic and Lymphoid tissues. International Agency for Research on Cancer, Lyon Engelhard M, Brittinger G, Huhn D, Gerhartz HH, Meusers P, Siegert W, Thiel E, Wilmanns W, Aydemir U, Bierwolf S, Griesser H, Tiemann M, Lennert K (1997) Subclassification of diffuse large B-cell lymphomas according to the Kiel classification: distinction of centroblastic and immunoblastic lymphomas is a significant prognostic risk factor. Blood 89:2291–2297 Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Muller-Hermelink K, Feller A, Heinz R (1999) Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group. Blood 94:3114–3120 Grogan TM, Lippman SM, Spier CM, Slymen DJ, Rybski JA, Rangel CS, Richter LC, Miller TP (1988) Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67. Blood 71:1157–1160 Silvestrini R, Costa A, Boracchi P, Giardini R, Rilke F (1993) Cell proliferation as a long-term prognostic factor in diffuse large-cell lymphomas. Inter J Cancer 54:231–236 Wilson WH, Teruya-Feldstein J, Fest T, Harris C, Steinberg SM, Jaffe ES, Raffeld M (1997) Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood 89:601–609 Gascoyne RD, Adomat SA, Krajewski S, Krajewska M, Horsman DE, Tolcher AW, O’Reilly SE, Hoskins P, Coldman AJ, Reed JC, Connors JM (1997) Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin’s lymphoma. Blood 90:244–251 Hermine O, Haioun C, Lepage E, d’Agay MF, Briere J, Lavignac C, Fillet G, Salles G, Marolleau JP, Diebold J, Reyas F, Gaulard P (1996) Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 87:265–272 Hill ME, MacLennan KA, Cunningham DC, Vaughan HB, Burke M, Clarke P, Di SF, Anderson L, Vaughan HG, Mason D, Selby P, Linch DC (1996) Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin’s lymphoma: a British National Lymphoma Investigation Study. Blood 88:1046–1051 Kramer MH, Hermans J, Parker J, Krol AD, Kluin-Nelemans JC, Haak HL, van GK, van Krieken JH, De JD, Kluin PM (1996) Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study. J Clin Oncol 14:2131–2138 Kramer MH, Hermans J, Wijburg E, Philippo K, Geelen E, van Krieken JH, De JD, Maartense E, Schuuring E, Kluin PM (1998) Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. Blood 92:3152–3162 Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511 Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937–1947 Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR (2002) Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8:68–74 Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, Vose J, Bast M, Fu K, Weisenburger DD, Greiner TC, Armitage JO, Kyle A, May L, Gascoyne RD, Connors JM, Troen G, Holte H, Kvaloy S, Dierickx D, Verhoef G, Delabie J, Smeland EB, Jares P, Martinez A, Lopez-Guillermo A, Montserrat E, Campo E, Braziel RM, Miller TP, Rimsza LM, Cook JR, Pohlman B, Sweetenham J, Tubbs RR, Fisher RI, Hartmann E, Rosenwald A, Ott G, Muller-Hermelink HK, Wrench D, Lister TA, Jaffe ES, Wilson WH, Chan WC, Staudt LM (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359:2313–2323 Barrans SL, Carter I, Owen RG, Davies FE, Patmore RD, Haynes AP, Morgan GJ, Jack AS (2002) Germinal center phenotype and bcl-2 expression combined with the International Prognostic Index improves patient risk stratification in diffuse large B-cell lymphoma. Blood 99:1136–1143 Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Muller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282 Lossos IS, Jones CD, Warnke R, Natkunam Y, Kaizer H, Zehnder JL, Tibshirani R, Levy R (2001) Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood 98:945–951 Uherova P, Ross CW, Schnitzer B, Singleton TP, Finn WG (2001) The clinical significance of CD10 antigen expression in diffuse large B-cell lymphoma. Am J Clin Pathol 115:582–588 Berglund M, Thunberg U, Amini RM, Book M, Roos G, Erlanson M, Linderoth J, Dictor M, Jerkeman M, Cavallin-Stahl E, Sundstrom C, Rehn-Eriksson S, Backlin C, Hagberg H, Rosenquist R, Enblad G (2005) Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis. Mod Pathol 18:1113–1120 Biasoli I, Morais JC, Scheliga A, Milito CB, Romano S, Land M, Pulcheri W, Spector N (2005) CD10 and Bcl-2 expression combined with the International Prognostic Index can identify subgroups of patients with diffuse large-cell lymphoma with very good or very poor prognoses. Histopathology 46:328–333 Colomo L, Lopez-Guillermo A, Perales M, Rives S, Martinez A, Bosch F, Colomer D, Falini B, Montserrat E, Campo E (2003) Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. Blood 101:78–84 Haarer CF, Roberts RA, Frutiger YM, Grogan TM, Rimsza LM (2006) Immunohistochemical classification of de novo, transformed, and relapsed diffuse large B-cell lymphoma into germinal center B-cell and nongerminal center B-cell subtypes correlates with gene expression profile and patient survival. Arch Pathol Lab Med 130:1819–1824 Muris JJ, Meijer CJ, Vos W, van Krieken JH, Jiwa NM, Ossenkoppele GJ, Oudejans JJ (2006) Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma. J Pathol 208:714–723 Natkunam Y, Farinha P, Hsi ED, Hans CP, Tibshirani R, Sehn LH, Connors JM, Gratzinger D, Rosado M, Zhao S, Pohlman B, Wongchaowart N, Bast M, Avigdor A, Schiby G, Nagler A, Byrne GE, Levy R, Gascoyne RD, Lossos IS (2008) LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. J Clin Oncol 26:447–454 Nyman H, Adde M, Karjalainen-Lindsberg ML, Taskinen M, Berglund M, Amini RM, Blomqvist C, Enblad G, Leppa S (2007) Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Blood 109:4930–4935 Sjo LD, Poulsen CB, Hansen M, Moller MB, Ralfkiaer E (2007) Profiling of diffuse large B-cell lymphoma by immunohistochemistry: identification of prognostic subgroups. Eur J Haematol 79:501–507 Xu Y, McKenna RW, Molberg KH, Kroft SH (2001) Clinicopathologic analysis of CD10+ and. Am J Clin Pathol 116:183–190 Zinzani PL, Dirnhofer S, Sabattini E, Alinari L, Piccaluga PP, Stefoni V, Tani M, Musuraca G, Marchi E, Falini B, Baccarani M, Pileri SA (2005) Identification of outcome predictors in diffuse large B-cell lymphoma. Immunohistochemical profiling of homogeneously treated de novo tumors with nodal presentation on tissue micro-arrays. Haematologica 90:341–347 Rimsza LM, Roberts RA, Miller TP, Unger JM, LeBlanc M, Braziel RM, Weisenberger DD, Chan WC, Muller-Hermelink HK, Jaffe ES, Gascoyne RD, Campo E, Fuchs DA, Spier CM, Fisher RI, Delabie J, Rosenwald A, Staudt LM, Grogan TM (2004) Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 103:4251–4258 Visco C, Canal F, Parolini C, Andreoli A, Ambrosetti A, Krampera M, Lestani M, Pizzolo G, Chilosi M (2006) The impact of P53 and P21(waf1) expression on the survival of patients with the germinal center phenotype of diffuse large B-cell lymphoma. Haematologica 91:687–690 Ott G, Katzenberger T, Lohr A, Kindelberger S, Rudiger T, Wilhelm M, Kalla J, Rosenwald A, Muller JG, Ott MM, Muller-Hermelink HK (2002) Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 99:3806–3812 Lennert K, Feller A (1992) Histopathology of Non-Hodgkin´s Lymphomas. Springer Verlag, New York Rudiger T, Hofler H, Kreipe HH, Nizze H, Pfeifer U, Stein H, Dallenbach FE, Fischer HP, Mengel M, von WR, Muller-Hermelink HK (2002) Quality assurance in immunohistochemistry: results of an interlaboratory trial involving 172 pathologists. Am J Surg Pathol 26:873–882 de Jong D, Rosenwald A, Chhanabhai M, Gaulard P, Klapper W, Lee A, Sander B, Thorns C, Campo E, Molina T, Norton A, Hagenbeek A, Horning S, Lister A, Raemaekers J, Gascoyne RD, Salles G, Weller E (2007) Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications–a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 25:805–812 de Jong D, Voetdijk BM, Beverstock GC, van Ommen GJ, Willemze R, Kluin PM (1988) Activation of the c-myc oncogene in a precursor-B-cell blast crisis of follicular lymphoma, presenting as composite lymphoma. N Engl J Med 318:1373–1378 Diebold J, Anderson JR, Armitage JO, Connors JM, MacLennan KA, Muller-Hermelink HK, Nathwani BN, Ullrich F, Weisenburger DD (2002) Diffuse large B-cell lymphoma: a clinicopathologic analysis of 444 cases classified according to the updated Kiel classification. Leuk Lymphoma 43:97–104 Filipits M, Jaeger U, Pohl G, Stranzl T, Simonitsch I, Kaider A, Skrabs C, Pirker R (2002) Cyclin D3 is a predictive and prognostic factor in diffuse large B-cell lymphoma. Clin Cancer Res 8:729–733 Kuttler F, Valnet-Rabier MB, Angonin R, Ferrand C, Deconinck E, Mougin C, Cahn JY, Fest T (2002) Relationship between expression of genes involved in cell cycle control and apoptosis in diffuse large B cell lymphoma: a preferential survivin-cyclin B link. Leukemia 16:726–735 Jerkeman M, Johansson B, Akerman M, Cavallin-Stahl E, Kristoffersson U, Mitelman F (1999) Prognostic implications of cytogenetic aberrations in diffuse large B-cell lymphomas. Eur J Haematol 62:184–190 Offit K, Lo CF, Louie DC, Parsa NZ, Leung D, Portlock C, Ye BH, Lista F, Filippa DA, Rosenbaum A (1994) Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med 331:74–80 de Paepe P, Achten R, Verhoef G, Wlodarska I, Stul M, Vanhentenrijk V, Praet M, De Wolf-Peeters C (2005) Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas. J Clin Oncol 23:7060–7068 van Imhoff GW, Boerma EJ, van der HB, Schuuring E, Verdonck LF, Kluin-Nelemans HC, Kluin PM (2006) Prognostic impact of germinal center-associated proteins and chromosomal breakpoints in poor-risk diffuse large B-cell lymphoma. J Clin Oncol 24:4135–4142 Dogan A, Bagdi E, Munson P, Isaacson PG (2000) CD10 and BCL-6 expression in paraffin sections of normal lymphoid tissue and B-cell lymphomas. Am J Surg Pathol 24:846–852 de Jong D, Xie W, Rosenwald A, Chhanabhai M, Gaulard P, Klapper W, Lee A, Sander B, Thorns C, Campo E, Molina T, Hagenbeek A, Horning S, Lister A, Raemaekers J, Salles G, Gascoyne RD, Weller E (2009) Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium). J Clin Pathol 62:128–138 Falini B, Fizzotti M, Pucciarini A, Bigerna B, Marafioti T, Gambacorta M, Pacini R, Alunni C, Natali-Tanci L, Ugolini B, Sebastiani C, Cattoretti G, Pileri S, la-Favera R, Stein H (2000) A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood 95:2084–2092 Falini B, Mason DY (2002) Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. Blood 99:409–426 Simonitsch-Klupp I, Hauser I, Ott G, Drach J, Ackermann J, Kaufmann J, Weltermann A, Greinix HT, Skrabs C, Dittrich C, Lutz D, Potter R, Mannhalter C, Lechner K, Chott A, Jaeger U (2004) Diffuse large B-cell lymphomas with plasmablastic/plasmacytoid features are associated with TP53 deletions and poor clinical outcome. Leukemia 18:146–155