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

The history of intestinal T-cell lymphomas begins with the early work of Peter Isaacson and Dennis Wright who described cases of “malignant histiocytosis” of the intestine that they linked to malabsorption and ulcerative jejunitis.1 Subsequent work showed that “malignant histiocytosis of the intestine” was a form of T-cell lymphoma, later named enteropathy-associated T-cell lymphoma (EATL).2 Since then, we have come to understand the distinction between EATL, closely linked to celiac disease, and monomorphic epitheliotropic T-cell lymphoma (MEITL), formerly EATL type II (Figure 1).3 The work of Isaacson and Wright shaped the modern classification of both T-cell and B-cell intestinal lymphomas, giving us not only EATL, but also mucosa-associated lymphoid tissue (MALT) lymphoma. Sadly Dennis Wright passed away on April 08, 2020 at the age of 88.

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.

Most cases of intestinal T-cell lymphoma were highly aggressive, but in the 1990s there was a series of reports of low-grade intestinal T-cell neoplasms, some of which mimicked lymphomatous polyposis.84 The nature of this rare form of T-cell lymphoma was better defined in sub sequent reports,109 and incorporated into the Revised 4 Edition of the World Health Organization (WHO) classification3 as a provisional entity under the term indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (ITLPD-GIT) (Figure 1). Most patients had a chronic, relapsing clinical course, although in both of the above series late instances of large-cell transformation were described.1110

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 authors also examined the expression of T-bet (TBX21) and GATA3, but any conclusions regarding the functional or clinical significance of these markers, which have been examined more extensively in nodal peripheral T-cell lymphomas,13 remain premature.

This study confirms the importance of alterations in JAK-STAT pathway genes in cases of ITLPD-GIT with a CD4 phenotype. Five of six cases, either CD4, or double-negative in one instance, had alterations with predicted activation of the pathway. Interestingly, functional evidence of activation of the pathway was less convincing. 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 lymphomas,1716 anaplastic large cell lymphoma (ALCL), ALK-positive and ALK-negative,1918 and breast-implant-associated ALCL.2120 Interestingly, similar alterations were not seen in the CD8 cases, which share a cytotoxic phenotype 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 chronic 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 recognized 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 lymphoma 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 prior work, that the molecular pathogenesis of the CD4 and CD8 cases of ITLPD-GIT appears distinct.2310 Thus, more formal separation of these phenotypic variants may be warranted in the future.

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. Most of the patients had a very protracted clinical course, with two patients being alive 19 and 21 years after diagnosis. There is a small but significant risk of transformation, with disease progressing in two patients after 11 and 27 years of follow-up. A variety of treatments were employed, with no patient stated to attain a complete remission.

In prior series, all patients had disease confined to the gastrointestinal tract, with extraintestinal dissemination seen only in patients with histological progression.109 However, Soderquist et al. report bone marrow involvement in three cases, all of which were detected prior to transformation. In one case bone marrow involvement was detected only through an unidentified cytogenetic abnormality; the bone marrow was morphologically normal and lacked evidence of a monoclonal T-cell receptor gene rearrangement. This patient is alive with disease at 7 years after presentation, so the presence of bone marrow involvement, if real, has had little clinical impact. Two additional patients were reported to have inguinal lymph node involvement, one of whom also had positive bone marrow. This latter case is the only patient classified as having Ann Arbor Stage IV disease. This 41-year old male was asymptomatic at presentation, and is untreated, being alive with disease at 1 year. Curiously, the remaining three patients said to have “biopsy-proven” involvement of lymph node or bone marrow were classified as stage IE at diagnosis. Presumably, the stated bone marrow or lymph node involvement occurred at some later point during the clinical course. More data are needed to understand the clinical and biological significance of this extraintestinal dissemination, including molecular data to confirm involvement.

A remaining issue is the optimal therapy for ITLPD-GIT. Most of the data are anecdotal. A number of patients have been treated with a variety of chemotherapy regimens used in both B-cell and T-cell lymphomas.9 Most patients have failed to achieve any long-term benefit from conventional chemotherapy. The JAK-STAT pathway appears to be an attractive target, especially in patients with CD4 disease, and in recent years there has been interest in the use of targeted agents for a variety of mature T-cell and NK-cell malignancies.24 Ruxolitinib is a JAK-inhibitor approved for use in myeloproliferative neoplasms, and has shown some activity in cutaneous T-cell lymphomas with activation of the JAK-STAT pathway.24 Other agents under evaluation for T-cell and NK-cell lymphomas include tofacitinib, pacritinib, and the histone deacetylase inhibitor, chidamide. The use of targeted agents in combination with either chemotherapy or immunotherapy may offer promise in the future.