Pathologist’s perspective on the challenges of CD30 detection: an interactive case discussion Laurence de Leval Institute of Pathology, Lausanne, Switzerland Wolfram Klapper Institute of Pathology, Kiel, Germany CD30 as a diagnostic marker for haematological malignancies ● Hodgkin lymphoma – classical Hodgkin lymphoma ● B-cell lymphomas – frequent CD30 expression in some DLBCLs ● T-cell lymphomas – Anaplastic large cell lymphomas – CD30+ cutaneous lymphoproliferations DLBCL, diffuse large B-cell lymphoma. ALCL CD30 sALCL ALK+ ALK+ SYSTEMIC sALCL ALK− ALK− PTCL-NOS cALCL CD30 ALK− LyP ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; cALCL, cutaneous anaplastic large cell lymphoma; LyP, lymphomatoid papulosis; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; sALCL, systemic anaplastic large cell lymphoma. CUTANEOUS LyP de Leval L, Gaulard P. Haematologica. 2010;95:1627−30. The challenges of CD30 detection ● CD30 expression as a diagnostic marker – interpretation of CD30 expression as part of a panel in the diagnostic approach – interactive cases illustrating how CD30 can be useful… and also misleading! ● CD30 expression as a therapeutic target Case 1 ● A 79-year-old man with multiple left cervical lymphadenopathies ● A 3 cm lymph node was excised What are the diagnostic possibilities? ● Carcinoma ● Melanoma ● Anaplastic lymphoma ● Hodgkin lymphoma CK, S100, MelanA CK, cytokeratin; EMA, epithelial membrane antigen. EMA CD45 CD20 CD3 CD30 Pax5 MUM1 CD15 CD2 CD5 CD8 CD4 GZB TiA1 ALK Diagnosis: ALK− ALCL A provisional entity in the 2008 WHO classification A CD30+ PTCL that is not reproducibly distinguishable on morphological grounds from ALK+ ALCL, but lacks ALK expression ● Morphologically indistinguishable from ALK+ ALCL ● Prerequisite – Hallmark cells – Cohesive growth – Strong homogeneous CD30 expression ● Desirable – Reduced T-cell surface markers – Cytotoxic phenotype – EMA positivity – Sinusoidal growth Attygalle AD, et al. Histopathology. 2014;64:171-99. Case 2 ● A 55-year-old man with inguinal lymphadenopathy ● A 4 cm lymph node was excised CD2 CD8 CD30 CD15 TIA-1 EMA/ALK Diagnosis: PTCL-NOS (CD30+) A category comprising all PTCLs that do not fulfill criteria for a more specific entity, a heterogeneous category thought to comprise several subgroups ● Not all large-cell PTCLs with CD30 expression are ALK− ALCLs! ● This distinction has clinical implications PTCL-U, peripheral T-cell lymphoma, unspecified. Savage KJ, et al. Blood. 2008;111:5496-504. Case 3 ● Large cervical mass was excised in a 62-year-old man CD45 CD20 ALK/EMA- CD30 CD79a Diagnosis: Diffuse large B-cell lymphoma (DLBCL), anaplastic variant A morphologic variant of DLBCL characterized by large round, oval or polygonal cells with bizarre pleomorphic nuclei that may resemble HRS cells. The cells may show a sinusoidal/cohesive growth pattern and mimic undifferentiated carcinoma ● Anaplastic DLBCL is often CD30+ ● In the International DLBCL R-CHOP consortium, 14% of DLBCL express CD30 (cut-off 20%) – GCB or ABC subtypes – better OS and PFS ABC, activated B cell-like; GCB, Germinal center B cell-like; HRS, Hodgkin and Reed−Sternberg; PFS, progression free survival; OS, overall survival. Case 4 ● 35-year-old man with large sinonasal mass CD3 −/+ CD4 − Also: CD20 − CD5 − CD8 − CD30 + EMA − GZB PCR TCR gamma polyclonal ALK − CD56− EBER, Epstein-Barr encoded RNA. EBER Diagnosis: extranodal NKTCL, nasal type An aggressive lymphoma derived from NK or less commonly from T cells, in which the tumour cells are infected by EBV, characterized by angiocentric features, often complicated by necrosis. Most commonly arises in the upper aerodigestive tract but also in other extranodal sites. ● Anaplastic features and/or CD30 expression not uncommonly occur in extranodal PTCLs ● ENKTCL, in cases with large cell morphology ● EATL type I is almost always variably CD30+ EATL, enteropathy-associated T-cell lymphoma; EBV, Epstein– Barr virus; ENKTCL, extranodal natural killer/T-cell lymphoma, nasal type. The challenges of CD30 detection ● CD30 expression as a diagnostic marker – interpretation of the staining – interpretation of CD30 expression in the diagnostic approach ● CD30 expression as a therapeutic target – the use of brentuximab vedotin has been reported for non-anaplastic T-cell lymphomas with promising efficacy – CD30 assessment is critical for therapeutic decision A study to assess CD30 expression at the protein and mRNA levels in PTCLs 238 PTCLs CD30 IHC & mRNA expression (GEP affymetrix) 374 PTCLs CD30 IHC EATL ATLL HSTL ALCL ALK+ ENKTL 28 14 9 7 97 AITL 61 EATL ALCL ALK− HSTL ATLL ALCL ALK+ ENKTL 14 6 4 5 17 61 64 141 ALCL ALK− 19 65 AITL PTCL-NOS AITL, angioimmunoblastic T-cell lymphoma; ATLL, adult T-cell leukaemia/lymphoma; GEP, gene expression profiling; HSTL, hepatosplenic T-cell lymphoma. PTCL-NOS Bossard C, et al. Blood. In press 2014. CD30 IHC scoring IHC score CD30+ tumour cells (%) 0 0– < 5% 1 5–24% 2 25–49% 3 50–75% 4 > 75% PTCL NOS Score 0 AITL PAX5/CD30 score 2 PTCL NOS Score 1 PTCL NOS Score 3 EPTCL NOS Score 2 EATL Score 4 CD30 protein expression in PTCLs 100% of ALCL and 58% of other PTCLs express CD30 100% 58% 63% 46% 50% 55.5% 0% 100% 90% 80% 70% score 4 (>75%) score 3 (50-75%) score 2 (25-49%) score 1 (5-24%) score 0 60% 50% 40% 30% 20% 10% 0% ALCL PTCL NOS AITL ENKTL EATL N = 97 ATLL N = 78 N = 141 N = 97 N = 28 N = 14 N=9 HSTL N=7 Bossard C, et al. Blood. In press 2014. CD30 protein expression in PTCLs Strong expression of CD30 is observed in 20% of non-anaplastic PTCL 96% 23% 5% 28.5% 50% 11% 0% 100% 90% 80% 70% score 4 (>75%) score 3 (50-75%) score 2 (25-49%) score 1 (5-24%) score 0 60% 50% 40% 30% 20% 10% 0% ALCL PTCL NOS AITL ENKTL EATL N = 97 ATLL N = 78 N = 141 N = 97 N = 28 N = 14 N=9 HSTL N=7 Bossard C, et al. Blood. In press 2014. Extent and intensity of CD30 staining correlates with tumour cell size Small Large 100% Percentage 80% CD30 status Small N = 157 Large N = 139 p CD30− PTCLs 85 (54.1%) 43 (30.9%) 6.3e-05 CD30+ PTCLs 72 (45.9%) 96 (69.1%) Intensity Small N = 72 Large N = 96 p weak 30 (41.7%) 25 (26.0%) 5.3e-0.4 moderate 34 (47.2%) 36 (36.5%) strong 8 (11.1%) 35 (36.5%) 60% 40% 20% 0% <5 5-25 26-50 51-75 >75 Immunohistochemical score (%) Bossard C, et al. Blood. In press 2014. Significant correlation between CD30 protein and mRNA expression levels AITL ρ = 0.8, p < 2e10-16 ALCL ALKALCL ALK+ 10 EATL ATLL ENKTL mRNA expression PTCL NOS HSTL 8 6 4 0 1 2 3 Immunohistochemistry scores 4 Bossard C, et al. Blood. In press 2014. IMMUNOHISTOCHEMISTRY AS A VALUABLE TOOL TO ASSESS CD30 EXPRESSION IN PERIPHERAL T-CELL LYMPHOMAS: HIGH CORRELATION BETWEEN PROTEIN AND MRNA EXPRESSION C Bossard, MP Dobay, M Parrens, L Lamant, E Missiaglia, C Haioun, A Martin, B Fabiani, R Delarue, O Tournilhac, M Delorenzi, P Gaulard, and L de Leval Conclusions ● Strong CD30 expression is characteristic of Hodgkin lymphoma and ALCL but can be seen in other B-cell or NK/T cell derived lymphomas ● There is a broad heterogeneity of CD30 expression across and within PTCL entities ● CD30 mRNA and protein expression are highly correlated for all PTCL entities ● IHC is a valuable clinical tool for assessing CD30+ PTCL patients who may be eligible for CD30-targeted therapies ● Prospective clinical studies are needed to determine the appropriate cut-off value(s) of CD30 expression correlating with antitumour activity of brentuximab vedotin
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