Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2.

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations.

Enteropathy-associated T-cell lymphoma (EATL), a rare and aggressive intestinal malignancy of intraepithelial T lymphocytes, comprises two disease variants (EATL-I and EATL-II) differing in clinical characteristics and pathological features. Here we report findings derived from whole-exome sequencing of 15 EATL-II tumour-normal tissue pairs. The tumour suppressor gene SETD2 encoding a non-redundant H3K36-specific trimethyltransferase is altered in 14/15 cases (93%), mainly by loss-of-function mutations and/or loss of the corresponding locus (3p21.31). These alterations consistently correlate with defective H3K36 trimethylation. The JAK/STAT pathway comprises recurrent STAT5B (60%), JAK3 (46%) and SH2B3 (20%) mutations, including a STAT5B V712E activating variant. In addition, frequent mutations in TP53, BRAF and KRAS are observed. Conversely, in EATL-I, no SETD2, STAT5B or JAK3 mutations are found, and H3K36 trimethylation is preserved. This study describes SETD2 inactivation as EATL-II molecular hallmark, supports EATL-I and -II being two distinct entities, and defines potential new targets for therapeutic intervention.

Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies.

The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (αß-type T cell, γδ T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy-associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented.

Classic versus type II enteropathy-associated T-cell lymphoma: diagnostic considerations.

Enteropathy-associated T-cell lymphoma is a rare type of peripheral T-cell lymphoma that characteristically involves the jejunum or ileum. Awareness of the histologic and immunophenotypic features of this subtype of lymphoma is important for accurate subclassification. Enteropathy-associated T-cell lymphoma has 2 forms, classic and type II, with different clinical and pathologic features. The 2 types will be described and discussed, with an emphasis on how to differentiate these entities in routine practice.

Enteropathy-associated T-cell lymphoma: epidemiology, clinical features, and current treatment strategies.

Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma of T-cell origin. The recent 2008 World Health Organization classification of hematologic malignancies distinguishes between two types of EATL. The disease is associated with celiac disease, particularly with its late, adult onset. Currently, there are no standardized diagnostic or treatment protocols for EATL, mostly because of its rarity. Historically, the patients have been treated with anthracycline-based chemotherapy with or without surgery. The outcome of patients with EATL treated with these approaches is poor. The reported death rates in the biggest studies are approximately 80-84%, with median progression-free survival (PFS) of 3.4-6.0 months and overall survival of 7.1-10.0 months. The 5-year PFS ranged from 3.2% to 18% and OS from 19.7% to 20%. The results of a novel induction regimen with ifosfamide, etoposide, and epirubicin alternating with intermediate-dose methotrexate followed by autologous stem cell transplantation (ASCT) are more promising, with a 5-year PFS of 52% and OS of 60%. The alternative approach, with a more common induction with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone followed by ASCT has also delivered promising results, with a 3-year PFS of 52% and OS of 47%. This review summarizes recently published data on epidemiology and clinical features, as well as standard and novel treatments including high-dose chemotherapy with ASCT and their outcome in EATL.

Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project.

Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.

[Salient clinical features of lymphoma and related lymphoproliferative disorders]. / Steckbriefe einzelner lymphoproliferativer Erkrankungen.

The literature on malignant lymphomas has grown to an extent which is hardly palatable for general practitioners and non-lymphoma aficionados. Nevertheless some lymphomas exhibit typical clinical and radiological features which permit to suspect the correct histopathological diagnosis even before a pathology report becomes available. The present article points out such "case vignettes" of particular types of malignant lymphoma.