Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract

Abstract

Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of 10 indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4+ (n=4), CD8+ (n=4), CD4+/CD8+ (n=1) and CD4-/CD8-(n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) lymphoproliferative disorders. The CD4+, CD4+/CD8+, and CD4-/CD8-cases harbored frequent alterations of the JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8+ cases exhibited structural alterations involving the 3' untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case were a harbinger of disease transformation. The CD4+ and CD4+/CD8+ lymphoproliferative disorders displayed heterogeneous Th1 (T-bet+), Th2 (GATA3+) or hybrid Th1/Th2 (T-bet+/GATA3+) profiles, while the majority of CD8+ disorders and the CD4-/CD8-disease showed a type-2 polarized (GATA3+) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8+ cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the 4 gastrointestinal tract and confirm the heterogeneous nature of these diseases.Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract: a tricky diagnosis of a gastric case

“…All cases of ITLPD show clonal rearrangement of TCR genes, either TCRβ or TCRγ [1][2][3][4][5]. Recent data suggest that ITLPD are genetically heterogeneous and share some pathogenetic mechanisms with other intestinal T-cell lymphomas as mutations in the JAK-STAT signaling pathway [11]. Genetic abnormalities involving TET2, DNMT3A, KMT2D genes have also been recently reported [11].…”

Oncogenetic Landscape Of Lymphomagenesis In Coeliac Disease

“…[23] The role of TNIP3, a partner of TNFAIP3/A20 in the ubiquitin editing complex[22] is much less known, but TNIP3 inversion was reported in one case of indolent intestinal CD4+ T lymphoma. [40] CeD pathogenesis has been mainly linked to cytokines such as IFNγ, IL-15 or IL-21 that trigger the JAK-STAT pathway. [41,42] Yet, some studies have pointed to a potential role of NFκB signalling.…”

T-cell and NK-cell neoplasms of the gastrointestinal tract – recurrent themes, but clinical and biological distinctions exist

“…10,11 In the current issue of Haematologica, Soderquist et al expand our knowledge regarding the immunophenotypic spectrum of ITLPD-GIT and provide new insights into its molecular pathogenesis. 12 As with prior reports, all cases were derived from αβ T cells with an equal proportion of cases expressing either CD4 or CD8. One case each had either a double-positive or double-negative phenotype.…”

“…The current series presents both similarities with and differences from prior clinical reports. 12 Endoscopic findings included multiple mucosal lesions, often with nodularity or polyps. Only one case was associated with mucosal ulceration.…”