Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome

Abstract

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males; 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e. nonmonomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ (98%) CD4- (94%) CD5- (97%) CD7+ (97%) CD8+ (90%) CD56+ (86%) CD103+ (80%) cytotoxic marker+ (98%)) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with nonmonomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%) JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signalling and encompasses genetic and morphologic variants associated with very high clinical risk.

Extranodal T- and NK-cell lymphomas

“…EATL and MEITL, formerly designated as variants of the same disease (EATL types I and II), were segregated as distinct entities in the 2017 WHO classification due to epidemiological, morphological, and immunophenotypic differences [1]. Recent molecular data reinforce this distinction [40,44,70]. The gastrointestinal tract can also be involved by any PTCL at presentation or later in the disease, especially ENKTCL.…”

“…It occurs worldwide and is the main ITCL in Asia [16,68]. A male predominance has been reported in several Asian series but not in most Western cohorts [23,70]. Most patients present with acute symptoms, mainly related to intestinal perforation and/or obstruction by an infiltrative tumor mass.…”

“…The bone marrow is rarely involved. Prognosis is poor and the median overall survival is 7-15 months [23,64,68,70].…”

“…4), a minority shows cellular pleomorphism, larger cell size, and vesicular chromatin and/or prominent nucleoli, or may have a high-grade morphological pattern with abundant apoptosis and a starry-sky appearance (Fig. 5) [23,70]. Some cases have necrosis distant from the ulcerated surface and invasion of vessel walls [70].…”

“…5) [23,70]. Some cases have necrosis distant from the ulcerated surface and invasion of vessel walls [70]. Unlike EATL, there is usually no prominent inflammatory infiltrate.…”