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JAK-STAT pathway genes in cases of ITLPD-GIT with a CD4+ phenotype. Five of six cases, either CD4+, or dou- ble-negative in one instance, had alterations with predict- ed activation of the pathway. Interestingly, functional evidence of activation of the pathway was less convinc- ing. Cells with nuclear staining for p-STAT3 and p-STAT5 accounted for fewer than 10% of total cells in all nine cases studied. Activation of the JAK-STAT pathway is a very common finding in many forms of T-cell lymphoma, most of which have a cytotoxic phenotype. Initially reported in T-cell large granular lymphocyte leukemia,14 activation of this pathway is a regular feature of hepatosplenic T-cell lymphoma,15 intestinal T-cell lym- phomas,16,17 anaplastic large cell lymphoma (ALCL), ALK- positive and ALK-negative,18,19 and breast-implant-associ- ated ALCL.20,21 Interestingly, similar alterations were not seen in the CD8+ cases, which share a cytotoxic pheno- type with many of the above mentioned lesions. However, JAK3 mutations have been reported in NK-cell enteropathy, an indolent NK-cell derived lymphoprolifer-
ative disease of the gastrointestinal tract that has a chron- ic relapsing and remitting clinical course similar to that of ITLPD-GIT.22
Prior reports have noted that ITLPD-GIT with a CD8+ phenotype has a similar immunophenotypic profile to that of primary cutaneous acral CD8+ T-cell lymphoma, another newly recognized provisional entity in the revised WHO classification.3 This tumor presents with superficial, non-epidermotropic cutaneous lesions. Initially reported on the ear, it has subsequently been rec- ognized presenting in other acral cutaneous sites. The neoplastic cells have a cytotoxic T-cell phenotype but, as in ITLPD-GIT, are positive for TIA-1 although negative for granzyme B and perforin. Acral CD8+ T-cell lym- phoma has a similar indolent clinical course as ITLPD- GIT, with a low risk of disease beyond the skin. Given the current report by Soderquist et al., which describes structural alterations of the IL2 gene, extending these studies to other forms of indolent T-cell lymphoma is warranted. It is also notable both in this study, and in
Figure 1. Distinguishing features of primary intestinal T-cell and NK-cell neoplasms. Major biological and clinical features of enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic T-cell lymphoma (MEITL), indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (IT-LPD) and natural killer-cell enteropathy (NK-ENT) are shown. EATL and MEITL are clinically aggressive, whereas IT-LPD and NK-ENT have a chronic relapsing clinical course, with a low risk of dissemination or transformation. Common recurrent features include a cytotoxic phenotype and activation of the JAK-STAT pathway in most of the entities. EATL: enteropathy associated T-cell lymphoma; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma; IT-LPD, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract; NK-ENT, natural killer-cell enteropathy; SB; small bowel; R/D, rearrangement or deletion.
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