Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma

Abstract

EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine. EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe. Various factors are associated with an increased risk of developing EATL, such as viral infection, advanced age, being male, and the presence of the HLA-DQ2 haplotype. Clonal rearrangements in the TCR-β and γ genes have been reported in all EATL morphological variants with distinctive immunophenotypic characteristics. Although EATL can occur de novo, individuals with RCDII are at a higher risk of developing EATL. The cells of origin of EATL has been postulated to be normal small intestinal intraepithelial T-lymphocytes (IELs), and more recent evidence suggests a link between innate precursor IELs and EATL derived from refractory coeliac disease type II (RCDII). The immune microenvironment of mucosal cells within the small intestine enhances the process of neoplastic transformation of IELs into EATL. Cytokines such as IL-15 can activate and crucially deregulate the JAK-STAT signaling pathway by binding to receptors on the surface of IELs. Furthermore, mutations in the JAK/STAT pathway have been associated with RCDII-derived EATL.

Keywords: EATL; T-cell non-Hodgkin lymphoma; coeliac disease; genetics; intraepithelial T-lymphocytes; refractory coeliac disease; small intestine.

Figure 1

(A) Gross photograph of the small bowel with ulceration and haemorrhage from a patient with known coeliac disease. (B) Microscopy of ulceration and adjacent total villous atrophy increase intraepithelial lymphocytes and mural infiltration by atypical lymphoid cells (magnification: 4×). (C) Atypical lymphoid cells composed of medium to large cells with angulated nuclei, prominent nucleoli, and clear to eosinophilic cytoplasm (magnification: 100×). The cells are positive for CD3 (D), CD7 (E), and cytotoxic protein TIA1 (F).

Figure 2

Schematic diagram illustrating the proposed EATL pathogenesis: RCDII is characterized by the progressive expansion of IELs inheriting an aberrant T/NK phenotype associated with chromosomal abnormalities. The clonal expansion of abnormal IELs occurs within the lamina propria and transforms into EATL through a variety of mechanisms. IL-15, produced by enterocytes, plays a central role in RCDII transformation into EATL. IL-15 is proposed to be the initiating trigger acting on abnormal immature lymphoid precursors. One of the mechanisms proposed is the IL-15 activation of NK-like RCDII IEL cytotoxicity against epithelial cells through NK receptors expressed on RCDII IELs (pink color) and their corresponding ligands expressed on epithelial cells. This results in damage to the epithelial cells. The apoptosis of RCDII IELs is prevented via a plethora of IL-15-mediated pathways involving JAK3, STAT5, MAPK, c-Myc, and the anti-apoptotic factor BCL-xL. In addition, IL-15 plays a role in the blockage of regulatory pathways resulting in prolonged chronic inflammation, which further promotes chromosomal instability. Ultimately, the survival of RCDII IELs is facilitated by the upregulation of miR-17/92 and C19MC and the downregulation of miR-200 and miR-192/215 families via c-Myc overexpression, potentiating EATL development.