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., non-monomorphic 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 non-monomorphic 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 signaling and encompasses genetic and morphologic variants associated with very high clinical risk.

Figure 1.

Heatmap representation of morphological, immunophenotypical and molecular features of 71 monomorphic epithelio-tropic intestinal T-cell lymphoma patients. TCR: T-cell receptor; IHC: immunohistochemistry; FISH: fluorescence in situ hybridization; OS: overall survival; NA: not available; NGS: next-generation sequencing.

Figure 2.

Typical monomorphic epitheliotropic intestinal T-cell lymphoma cases #30 (A to C) and #51 (D to L). (A) The intestinal tumor comprises a central transmural zone and a peripheral zone with intramucosal tumor spread. (B) The tumor cells are medium-sized and monomorphic with clear and ample cytoplasm and invade the epithelium of the crypts. (C) The tumor recurrence after 5 years shows an identical cytomorphology. (D) Intramucosal tumor spread is associated with shortening and widening of the villi. (E) Broadly expanded villi comprise a heavy epitheliotropic tumor cell infiltrate. (F) The tumor cells are strongly positive for CD3, (G) negative for CD5, (H) positive for CD8, (I) CD56, and (J) TCRβ. (K) CD103 is strongly positive in the superficial intramucosal tumor compartment and gradually decreases in the infiltrating part. (L) Lymphoma cells in the mucosa (upper part of panel figure) and submucosa (lower part of panel figure) are strongly and moderately positive for CD103. Original magnifications x10 (A), x40 (K), x100 (E), x125 (D), x400 (B, C, F to J, L).

Figure 3.

Atypical monomorphic epitheliotropic intestinal T-cell lymphoma cases #31 (A to L), #15 (M) and #59 (N to O). (A) The tumor is composed of medium–sized pleomorphic cells and comprises scattered histiocytes with apoptotic debris. (B) A vein is infiltrated by lymphoma cells. (C) The lymphoma cells are weakly positive for TCRγ. (D) FISH with SETD2 probe shows 1 red (SETD2) and 2 green (control) signals per nucleus, indicating deletion of 1 allele. (E) The lymphoma cells show strong nuclear positivity for H3K36me2 and (F) are completely negative for H3K36me3, while reactive histiocytes are positive. (G) The lymphoma cells are diffusely positive for TIA-1, (H) show a high Ki67 index (>80%), and (I) are strongly positive for p53. (J) A gastric biopsy performed during follow-up showed recurrent tumor with a more blastoid morphology, invading the glandular epithelium. (K) Post-mortem liver showed lymphoma infiltrating in the sinusoids and within hepatocytes. (L) A cytokeratin immunostains confirmed emperipolesis of lymphoma cells into hepatocytes. (M) This case features marked angiotropism and angioinvasion. (N) This tumor contains large necrotic areas in its invasive portion, and (O) is composed of pleomorphic large cells. Original magnifications: x25 (N), x100 (B and M), ×400 (A, C, E to K, L, O), x630 (D).

Figure 4.

Overview of the genetic alterations in monomorphic epitheliotropic intestinal T-cell lymphoma. (A) Heatmap representation of mutations in a selected panel of genes examined by whole-exome sequencing and targeted deep sequencing in 65 monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) tumors. Patients are displayed as columns and mutations (named on the left) are coloured by the type of alteration. The percentage of mutated samples is represented on the right. First row shows the expression patterns of T-cell receptor (TCR) isoforms, second row shows the status of H3K36me3 trimethylation and third row displays the results of SETD2 fluorescence in situ hybridization (FISH) study. (B) Schematic representation of somatic mutations in SETD2 (top), STAT5B (central) and JAK3 (bottom) genes identified in this study. Domains of the protein are represented according to the Uniprot database (http://www.uniprot.org) in different colors. Exact positions of mutations found in MEITL cases are given, which are colored by the type of alteration.

Figure 5.

Overall survival for monomorphic epitheliotropic intestinal T-cell lymphoma patients. (A) Overall survival (OS) in months of the all cohort; and according to (B) age at diagnosis, (C) performance status (PS) score, (D) Lugano stage at diagnosis, (E) the presence of atypical histological features, (F) cytological atypia, (G) TP53 mutational status, (H) STAT5B mutational status, (I) the concurrent presence of TP53 and STAT5B mutations and (J) MYC expression (>25% immunohistochemistry). Age in years. MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma; # at risk: number at risk; mut: mutated; WT: wild-type.