Pathogenesis of Enteropathy-Associated T Cell Lymphoma

Abstract

EATL frequently evolves from RCD type II (RCD II) but can occur "de novo" in individuals with celiac disease. Recurrent activating mutations in members of the JAK/STAT pathway have been recently described in EATL and RCD II, which suggests deregulation of cytokine signaling to be an early event in lymphomagenesis. Intraepithelial T cells are presumed to be the cell of origin of EATL (and RCD II). Recent in vitro molecular and phenotypic analyses and in vivo murine studies, however, suggest an origin of RCD II from innate IELs (NK/T cell precursors), which could also be the cell of origin of RCD II-derived EATL. The immune microenvironment of the small intestinal mucosa in celiac disease fosters the development of EATL, often in a multistep pathway.

Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential

“…The mean ages of patients in different CD groups varied, in line with previous observations. RCD I was diagnosed more frequently in older individuals and 17% were seropositive for anti‐tTG immunoglobulin (Ig)A antibodies. Biopsies from CD patients showed differences in the distribution of Marsh scores or severity of villous atrophy in the different disease groups.…”

T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update

“…4 The reported incidence of EATL in coeliac disease patients ranges from 0.22 to 1.9/100 000. 6 Accordingly, EATL is more common in Western countries which have a higher seroprevalence of coeliac disease. 6,7 Many patients have a documented history of coeliac disease, though in others the diagnosis is made concomitantly with EATL, often on surgical resection specimens obtained at emergency laparotomy or sometimes at autopsy.…”

“…6 Accordingly, EATL is more common in Western countries which have a higher seroprevalence of coeliac disease. 6,7 Many patients have a documented history of coeliac disease, though in others the diagnosis is made concomitantly with EATL, often on surgical resection specimens obtained at emergency laparotomy or sometimes at autopsy. 5,[8][9][10] Poor adherence to gluten-free diet, advanced age (>50 years) and homozygosity for HLA-DQ2 are associated with an increased risk for developing EATL.…”

“…[11][12][13] Furthermore, the development of refractory coeliac disease (RCD) may herald a more ominous phase in the evolution of coeliac disease, particularly in those patients who develop aberrant and clonal intraepithelial T-cells (i.e., type II RCD, discussed in greater detail below). 6,[14][15][16][17] Interestingly, patients with coeliac disease may also be at increased risk of lymphomas other than EATL involving the GI tract, including diffuse large B-cell lymphoma, extranodal marginal zone lymphoma and unspecified peripheral T-cell lymphomas. 18 Epidemiology EATL is rare, comprising approximately 5% of all peripheral T-cell lymphomas.…”

Extranodal T/NK Lymphomas

“…It is defined by histological changes associated with enteropathy in cases with strict diet for >12 months or severe and persistent symptoms that require a clinical intervention regardless of the duration of the strict diet. There is a sub-classification, RCD type I, if the intraepithelial lymphocytes show a normal phenotype and constitute a polyclonal population, and RCD type II, if the intraepithelial lymphocytes immunophenotype is aberrant and clonal products are detected on TCR gene rearrangement analysis [34].…”