Poor Concordance among Nine Immunohistochemistry Classifiers of Cell-of-Origin for Diffuse Large B-Cell Lymphoma: Implications for Therapeutic Strategies

Abstract

Purpose The opportunity to improve therapeutic choices on the basis of molecular features of the tumour cells is on the horizon in Diffuse Large B-cell Lymphoma (DLBCL). Agents such as bortezomib exhibit selective activity against the poor outcome activated B-cell type DLBCL. In order for targeted therapies to succeed in this disease, robust strategies that segregate patients into molecular groups with high reliability are needed. While molecular studies are considered gold standard, several immunohistochemistry (IHC) algorithms have been published that claim to be able to stratify patients according to their cell-of-origin and to be relevant for patient outcome. However results are poorly reproducible by independent groups. Experimental design We investigated nine IHC algorithms for molecular classification in a dataset of DLBCL diagnostic biopsies, incorporating immunostaining for CD10, BCL6, BCL2, MUM1, FOXP1, GCET1 and LMO2. IHC profiles were assessed and agreed among three expert observers. A consensus matrix based on all scoring combinations and the number of subjects for each combination allowed to assess reliability. The survival impact of individual markers and classifiers was evaluated using Kaplan-Meier curves and the log-rank test. Results The concordance in patient’s classification across the different algorithms was low. Only 4% the tumors have been classified as GCB and 21% as ABC/non-GCB by all methods. None of the algorithms provided prognostic information in the R-CHOP treated cohort. Conclusion Further work is required to standardize IHC algorithms for DLBCL cell-of-origin classification for these to be considered reliable alternatives to molecular-based methods to be used for clinical decisions.

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

“…In addition, determining the COO by IHC does not seem to be the ideal approach, and gene expression profiling studies might be needed to identify patients with ABC DLBCL [53,54].…”

Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Is It a Valid Treatment Option?

“…Several attempts have been made to correlate the two subtypes with immunohistochemical (IHC) markers [6][7][8].The Hans algorithm is the most commonly used and distinguishes non-GCB and GCB patients [8]. Although these algorithms provide a practical method for designating subtypes, they are a suboptimal alternative to GEP [9]. COO subtypes are characterized by distinct oncogenic driver pathways, such as the dysregulation of nuclear factor (NF)-kB pathway in ABC, resulting in variable susceptibility to different antineoplastic drugs and variable prognoses [10,11].…”

Case report. A rare case of triple-hit diffuse large B-cell lymphoma of the parotid gland in a patient with Sjogren’s syndrome

“…Patients with GCB or ABC DLBCLs may benefit from different therapeutic approaches with the ABC subtype responding to novel drugs (bortezomib, lenalidomide or ibrutinib) 14 . Among the published immunohistochemical algorithms, the Hans algorithm was most widely used in routine practice and prognostic significance has been questioned, especially in the chemoimmunotherapy era [15][16][17][18][19] . As described before, this case with MYC, BCL 2 and BCL 6 translocations was classified as a triple hit lymphoma (THL), which has the worst outcome 20,21 .…”