Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma

690

608

• The clinically based NCCN-IPI is a robust prognostic tool for the rituximab era that better discriminates low-and high-risk DLBCL patients compared with the IPI.• The NCCN-IPI outperforms the IPI by refined categorization of age and LDH, and the identification of disease involvement at specific extranodal sites. : 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n 5 1138), it also demonstrated enhanced discrimination for both low-and high-risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era. (Blood. 2014;123(6):837-842)

Section: Discussionmentioning

confidence: 97%

An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era

Zhou

Sehn

Rademaker

et al. 2014

690

608

“…[28][29][30][31] In adults, the outcome for patients with GCB disease is superior to that seen in patients with the ABC subtype. 1 In patients of all ages, relapsed disease offers a much worse prognosis, with second-line therapies able to salvage only a fraction of patients.…”

Section: Discussionmentioning

confidence: 99%

UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma

Bedekovics

Hussain

Feldman³

et al. 2016

• The neuronal marker UCH-L1 is induced in, and specifically augments the oncogeneinduced transformation of, GCB cells.• High levels of UCHL1 identify patients with GC DLBCL with an increased risk for poor outcomes.Gene expression profiling has identified 2 major subclasses of diffuse large B-cell lymphoma (DLBCL). Cases resembling germinal center (GC) B cells (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-GC cells (activated B-cell DLBCL). We previously found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. The cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown. Here, we show that UCH-L1 reflects GC lineage in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL. We find that UCH-L1 is specifically induced in GC B cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. We also find that UCH-L1 cooperates with BCL6 in a mouse model of GC B-cell lymphoma, but not with the development of multiple myeloma derived from post-GC cells. Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biological diversity in this subset of disease. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in GC B cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication. These data demonstrate a novel role for UCH-L1 outside of the nervous system and suggest its potential use as a biomarker and therapeutic target in DLBCL. (Blood. 2016;127(12):1564-1574

“…45 These findings are in agreement with recent data indicating that aging is an important determinant of lymphoma biology. 46 In an effort to explain the proportional increase of ABC DLBCL with age, Mareschal et al 45 speculated that either there is a change in B-cell population during aging or there is putative pathological specificity of EBV in elderly patients with DLBCL. Not BLOOD, 18 JULY 2013 x VOLUME 122, NUMBER 3 EBV-POSITIVE DLBCL OF THE ELDERLY 331 …”

Section: Immunophenotypementioning

confidence: 99%

EBV-positive diffuse large B-cell lymphoma of the elderly

Papathomas

Medeiros

et al. 2013

198

178

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly, initially described in 2003, is a provisional entity in the 2008 World Health Organization classification system and is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in patients >50 years of age and in whom there is no known immunodeficiency or history of lymphoma. These tumors are more common in Asia but also occur in North America and Europe at a low frequency. These neoplasms exhibit a morphologic continuum, from polymorphous to monomorphous, but morphologic features do not correlate with prognosis as all patients have a clinically aggressive course. Most EBV-positive DLBCL of the elderly patients have an activated B-cell immunophenotype and are characterized by prominent nuclear factor-κB activation. Cytogenetic complexity is usually low. In this review, we comprehensively delineate the data emerging from analyses of EBV latency program, microRNA-mediated EBV viral oncogenesis, functional genomics of EBV and its biology, and differential diagnosis challenge for EBV-positive DLBCL of the elderly. It is hoped that the improved understanding of these tumors will lead to the development of novel therapeutic approaches, enhance the effectiveness of clinical trials, and improve prognosis.