Top

Published in:

01-09-2018 | Original Article

Round-robin test for the cell-of-origin classification of diffuse large B-cell lymphoma—a feasibility study using full slide staining

Authors: Sarah Reinke, Julia Richter, Falko Fend, Alfred Feller, Martin-Leo Hansmann, Katrin Hüttl, Ilske Oschlies, German Ott, Peter Möller, Andreas Rosenwald, Harald Stein, Michael Altenbuchinger, Rainer Spang, Wolfram Klapper

Published in: Virchows Archiv | Issue 3/2018

Abstract

Diffuse large B-cell lymphoma (DLBCL) is subdivided by gene expression analysis (GEP) into two molecular subtypes named germinal center B-cell-like (GCB) and activated B-cell-like (ABC) after their putative cell-of-origin (COO). Determination of the COO is considered mandatory in any new-diagnosed DLBCL, not otherwise specified according to the updated WHO classification. Despite the fact that pathologists are free to choose the method for COO classification, immunohistochemical (IHC) assays are most widely used. However, to the best of our knowledge, no round-robin test to evaluate the interlaboratory variability has been published so far. Eight hematopathology laboratories participated in an interlaboratory test for COO classification of 10 DLBCL tumors using the IHC classifier comprising the expression of CD10, BCL6, and MUM1 (so-called Hans classifier). The results were compared with GEP for COO signature and, in a subset, with results obtained by image analysis. In 7/10 cases (70%), at least seven laboratories assigned a given case to the same COO subtype (one center assessed one sample as not analyzable), which was in agreement with the COO subtype determined by GEP. The results in 3/10 cases (30%) revealed discrepancies between centers and/or between IHC and GEP subtype. Whereas the CD10 staining results were highly reproducible, staining for MUM1 was inconsistent in 50% and for BCL6 in 40% of cases. Image analysis of 16 slides stained for BCL6 (N = 8) and MUM1 (N = 8) of the two cases with the highest disagreement in COO classification were in line with the score of the pathologists in 14/16 stainings analyzed (87.5%). This study describes the first round-robin test for COO subtyping in DLBCL using IHC and demonstrates that COO classification using the Hans classifier yields consistent results among experienced hematopathologists, even when variable staining protocols are used. Data from this small feasibility study need to be validated in larger cohorts.

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H (2008) Thiele J (2017) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC Press, Lyon

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, 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(6769):503–511. https://doi.org/10.1038/35000501 CrossRefPubMed

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, López-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM, Project LLMP (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346(25):1937–1947. https://doi.org/10.1056/NEJMoa012914 CrossRefPubMed

Lenz G, Staudt LM (2010) Aggressive lymphomas. N Engl J Med 362(15):1417–1429. https://doi.org/10.1056/NEJMra0807082 CrossRefPubMed

Scott DW, Wright GW, Williams PM, Lih CJ, Walsh W, Jaffe ES, Rosenwald A, Campo E, Chan WC, Connors JM, Smeland EB, Mottok A, Braziel RM, Ott G, Delabie J, Tubbs RR, Cook JR, Weisenburger DD, Greiner TC, Glinsmann-Gibson BJ, Fu K, Staudt LM, Gascoyne RD, Rimsza LM (2014) Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123(8):1214–1217. https://doi.org/10.1182/blood-2013-11-536433 CrossRefPubMedPubMedCentral

Masqué-Soler N, Szczepanowski M, Kohler CW, Spang R, Klapper W (2013) Molecular classification of mature aggressive B-cell lymphoma using digital multiplexed gene expression on formalin-fixed paraffin-embedded biopsy specimens. Blood 122(11):1985–1986. https://doi.org/10.1182/blood-2013-06-508937 CrossRefPubMed

Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Müller-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(1):275–282. https://doi.org/10.1182/blood-2003-05-1545 CrossRefPubMed

Choi WW, Weisenburger DD, Greiner TC, Piris MA, Banham AH, Delabie J, Braziel RM, Geng H, Iqbal J, Lenz G, Vose JM, Hans CP, Fu K, Smith LM, Li M, Liu Z, Gascoyne RD, Rosenwald A, Ott G, Rimsza LM, Campo E, Jaffe ES, Jaye DL, Staudt LM, Chan WC (2009) A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 15(17):5494–5502. https://doi.org/10.1158/1078-0432.CCR-09-0113 CrossRefPubMed

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(5):714–723. https://doi.org/10.1002/path.1924 CrossRefPubMed

10.

Gutiérrez-García G, Cardesa-Salzmann T, Climent F, González-Barca E, Mercadal S, Mate JL, Sancho JM, Arenillas L, Serrano S, Escoda L, Martínez S, Valera A, Martínez A, Jares P, Pinyol M, García-Herrera A, Martínez-Trillos A, Giné E, Villamor N, Campo E, Colomo L, López-Guillermo A, Grup per l'Estudi dels Limfomes de Catalunya I Balears (GELCAB) (2011) Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood 117(18):4836–4843. https://doi.org/10.1182/blood-2010-12-322362

11.

Sehn LH, Gascoyne RD (2015) Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood 125(1):22–32. https://doi.org/10.1182/blood-2014-05-577189 CrossRefPubMed

12.

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, Consortium LLB (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(7):805–812. https://doi.org/10.1200/JCO.2006.09.4490 CrossRefPubMed

13.

Lawrie CH, Ballabio E, Soilleux E, Sington J, Hatton CS, Dirnhofer S, Tzankov A (2012) Inter- and intra-observational variability in immunohistochemistry: a multicentre analysis of diffuse large B-cell lymphoma staining. Histopathology 61(1):18–25. https://doi.org/10.1111/j.1365-2559.2012.04179.x CrossRefPubMed

14.

Paul U, Richter J, Stuhlmann-Laiesz C, Kreuz M, Nagel I, Horn H, Staiger AM, Aukema SM, Hummel H, Ott G, Spang R, Rosenwald A, Feller AC, Cogliatti S, Stein H, Hansmann ML, Moller P, Szczepanowski M, Burkhardt B, Pfreundschuh M, Schmitz N, Loeffler M, Trümper L, Siebert R, Klapper W (2018) Advanced patient age at diagnosis of diffuse large B-cell lymphoma is associated with molecular characteristics including ABC-subtype and high expression of MYC. Leuk Lymphoma 59(5):1213–1221. https://doi.org/10.1080/10428194.2017.1365851

15.

Staiger AM, Ziepert M, Horn H, Scott DW, Barth TFE, Bernd HW, Feller AC, Klapper W, Szczepanowski M, Hummel M, Stein H, Lenze D, Hansmann ML, Hartmann S, Möller P, Cogliatti S, Lenz G, Trümper L, Löffler M, Schmitz N, Pfreundschuh M, Rosenwald A, Ott G, G. H.-G. L. S. Group (2017) Clinical impact of the cell-of-origin classification and the MYC/ BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German high-grade non-Hodgkin's lymphoma study group. J Clin Oncol 35(22):2515–2526. https://doi.org/10.1200/JCO.2016.70.3660 CrossRefPubMed

16.

Meyer PN, Fu K, Greiner TC, Smith LM, Delabie J, Gascoyne RD, Ott G, Rosenwald A, Braziel RM, Campo E, Vose JM, Lenz G, Staudt LM, Chan WC, Weisenburger DD (2011) Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 29(2):200–207. https://doi.org/10.1200/JCO.2010.30.0368 CrossRefPubMed

17.

Salles G, de Jong D, Xie W, Rosenwald A, Chhanabhai M, Gaulard P, Klapper W, Calaminici M, Sander B, Thorns C, Campo E, Molina T, Lee A, Pfreundschuh M, Horning S, Lister A, Sehn LH, Raemaekers J, Hagenbeek A, Gascoyne RD, Weller E (2011) Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg lymphoma biomarker consortium. Blood 117(26):7070–7078. https://doi.org/10.1182/blood-2011-04-345256 CrossRefPubMed

18.

Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung R, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS (2017) Genetic and functional drivers of diffuse large B cell lymphoma. Cell 171(2):481–494.e15. https://doi.org/10.1016/j.cell.2017.09.027 CrossRefPubMed

Title: Round-robin test for the cell-of-origin classification of diffuse large B-cell lymphoma—a feasibility study using full slide staining
Authors: Sarah Reinke
Julia Richter
Falko Fend
Alfred Feller
Martin-Leo Hansmann
Katrin Hüttl
Ilske Oschlies
German Ott
Peter Möller
Andreas Rosenwald
Harald Stein
Michael Altenbuchinger
Rainer Spang
Wolfram Klapper
Publication date: 01-09-2018
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 3/2018
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-018-2367-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Round-robin test for the cell-of-origin classification of diffuse large B-cell lymphoma—a feasibility study using full slide staining

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2018

Tumour origin and R1 rates in pancreatic resections: towards consilience in pathology reporting

Misses and near misses in diagnosing nodular fasciitis and morphologically related reactive myofibroblastic proliferations: experience of a referral center with emphasis on frequency of USP6 gene rearrangements

Book review—Rosai and Ackerman’s surgical pathology-2 volume set, 11th edition

In this issue

Comparison of targeted next generation sequencing (NGS) versus isolated BRAF V600E analysis in patients with metastatic melanoma

Eosinophils in the gastrointestinal tract: how much is normal?