SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma

Abstract

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as type II enteropathy associated T-cell lymphoma (type II EATL), is a rare, aggressive primary intestinal T-cell lymphoma with a poor prognosis and an incompletely understood pathogenesis. We collected 40 cases of MEITL and 27 cases of EATL, formerly known as type I EATL, and comparatively investigated the T-cell receptor (TCR) itself and associated signaling molecules using immunohistochemistry, amplicon deep sequencing and bisulfite pyrosequencing. The TCR showed both an αβ-T-cell origin (30%) and a γδ-T-cell derivation (55%) resulting in a predominant positive TCR phenotype in MEITL compared with the mainly silent TCR phenotype in EATL (65%). The immunohistochemical expression of the spleen tyrosine kinase (SYK) turned out to be a distinctive feature of MEITL (95%) compared with EATL (0%). Aberrant SYK overexpression in MEITL is likely caused by hypomethylation of the SYK promoter, while no common mutations in the SYK gene or in its promoter could be detected. Using amplicon deep sequencing, mutations in DNMT3A, IDH2, and TET2 were infrequent events in MEITL and EATL. Immunohistochemical expression of linker for activation of T-cells (LAT) subdivided MEITL into a LAT expressing subset (33%) and a LAT silent subset (67%) with a potentially earlier disease onset in LAT-positive MEITL.

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

“…56,60 A recent series detected spleen tyrosine kinase (SYK) expression in 95% of MEITLs but not in EATL cases. 59 Another series showed expression of c-MET in 78% of cases, which seemed to correlate with amplification of 7q31. 58 Importantly, aberrant CD20 expression has been reported in 20-24% of MEITLs.…”

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study

“…Future studies will be necessary to define whether heterogeneity in NKp46 expression may reflect heterogeneity in the cellular origin of EATL. Interestingly, NKp46 was also expressed by the four MEITL cases which, similarly to EATL, are very aggressive lymphomas that may be derived from IEL 3. In contrast, none of the indolent CD4+ or CD8+ T-LPD expressed NKp46.…”

“…Best defined entities are two highly aggressive lymphomas characterised by a 5-year survival rate shorter than 20%,2 the enteropathy-associated T-cell lymphoma (EATL), commonly associated with coeliac disease (CD), and the monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL), not associated with CD and more prevalent in Asia 1. Because of their epitheliotropism and CD103 expression, both EATL and MEITL are thought to derive from intraepithelial lymphocytes (IEL) 3. However, MEITL display a predominant positive T-cell receptor (TCR) phenotype associated with CD8, CD56 and SYK expression3 that are generally lacking in EATL.…”

“…Because of their epitheliotropism and CD103 expression, both EATL and MEITL are thought to derive from intraepithelial lymphocytes (IEL) 3. However, MEITL display a predominant positive T-cell receptor (TCR) phenotype associated with CD8, CD56 and SYK expression3 that are generally lacking in EATL. In 2016, the revised WHO classification of lymphoid neoplasms included a novel entity named indolent T-cell lymphoproliferative disease of the GI tract (indolent T-LPD) that is characterised by a good outcome 1 4–8.…”

Advances in targeted therapy for malignant lymphoma

“…175,176 BL is also characterized by tonic BCR signaling and mostly relies on SYK. 177 In T-NHLs, aberrant SYK expression was reported in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, type II EATL), 178 the follicular variant of PTCL, not otherwise specified (PTCL-NOS), and angioimmunoblastic T-cell lymphoma (AITL) due to t(5;9)(q33;q22) ITK/SYK translocation. [179][180][181] The targeted agents and clinical trials related to SYK and BTK are listed in Table 2.…”