ITLPD of the GI tract is a rare low-grade clonal lymphoid proliferation, included as a provisional entity in the current World Health Organization (WHO) classification . The etiology is unknown, although few cases are reported in patients with inflammatory bowel disease and autoimmune disorders [2,3,4,5,6,7]. Any part of the GI tract can be involved with single or multiple lesions [2,3,4,5,6,7]. The small intestine and colon are the sites most frequently affected. Involvement of the stomach, as occurred in our case, is uncommon as well as esophageal and oral involvement . ITLPD can show heterogeneous phenotype: most cases express CD8, some express CD4 and rare are double negative . The identification of clonal rearrangement of TCR (αβ or γ) is essential for the diagnosis . ITLPD remains localized to the GI tract often for a long duration, with chronic relapsing clinical course. Prolonged survival with persistent disease is common; conventional chemotherapy is usually not effective [1, 7]. Dissemination to other organs can be observed with disease progression [1, 4]. Bone marrow involvement has been infrequently reported [5, 9, 10]. Higher-grade T-cell lymphomas may rarely develop in a subset of cases .
Our case underlines how challenging can be the recognition of this entity for both clinicians and pathologists. ITLPD of the GI tract can be either overlooked or misdiagnosed as an aggressive lymphoma. Firstly, the symptoms are non-specific (abdominal pain, diarrhea, vomiting, food intolerance, dyspepsia, bleeding) and commonly lasting for long time before diagnosis. ITLPD is often clinically misinterpreted as refractory celiac disease or inflammatory bowel disease (IBD) with delay in diagnosis [1,2,3,4,5,6,7]. Secondly, the endoscopic features are non-specific as well. The mucosa can appear normal or slightly hyperemic, as in our case. Sometimes prominent folds, erosions or nodules are present [2,3,4,5,6,7]. Lastly, the mucosal lymphoid infiltrate is subtle, generally limited to the mucosa and rarely extending to the submucosa, without forming tumor masses [2,3,4,5,6,7]. The infiltrate can be easily overlooked, if appropriate immunohistochemical and molecular analyses are not performed. A misleading aberrant expression of B-cell markers, such as CD20, has been reported in one case of ITLPD by Wang et al. . It needs to be emphasized that ITLPD diagnosis always requires clonality testing. 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 . Genetic abnormalities involving TET2, DNMT3A, KMT2D genes have also been recently reported .
It is mandatory to distinguish ITLPD from aggressive T-cell lymphomas, which can involve the GI tract, in order to avoid unnecessary therapy. In aggressive lymphomas, such as monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) and enteropathy associated T-cell lymphoma (EATL), about half of the patients present acutely with intestinal obstruction or perforation, although others have an insidious presentation with abdominal pain and diarrhea, more similar to ITLPD [1, 6, 7]. In EATL and MEITL, the lymphoid infiltrate is generally transmural, with a destructive pattern of growth. Pleomorphism is more common in EATL, whereas in MEITL the cells have a more uniform appearance. The proliferation index is high [1, 6, 7]. Both EATL and MEITL are aggressive neoplasms not responding to current therapy. Differently, in ITLPD the infiltrate is often limited to the mucosa, without forming a mass, it is bland-looking with a low proliferative fraction. Extranodal, NK/T-cell lymphoma, nasal-type, needs to be ruled out. It arises mostly in the upper aerodigestive tract. GI involvement can occur generally later in the course of the disease or more rarely the GI tract represents the primary site of the disease [1, 5]. Necrosis, angiocentricity, angioinvasion and EBER positivity are characteristics features of this aggressive lymphoma, typically absent in ITLPD. To be mentioned the indolent NK-cell proliferation of the GI tract, variably labelled as NK-cell enteropathy and lymphomatoid gastropathy . The clinical course is often indolent and protracted, like in ITLPD. EBER negativity is helpful to rule out extranodal-NK/T-cell lymphoma, nasal type, which represents the major diagnostic pitfall. Other entities, typically presenting outside the GI tract, as peripheral T-cell lymphoma not otherwise specified or anaplastic large cell lymphoma may sometimes present as intestinal disease . Clinico-pathological correlation is essential to reach the correct diagnosis.
In conclusion, we report a case of CD4-positive ITLPD with gastric presentation, an uncommon site compared to small and large bowel. In absence of chemotherapy, the disease remained confined to the stomach, at 12 months from the initial biopsy. Despite bone marrow appeared disease-free histologically, T-cell clonal rearrangement was identified in bone marrow. ITLPD usually remains localized to the GI tract for years and involvement of other sites such as bone marrow is rare and usually observed with disease progression. Clinicians and pathologists need to be aware of ITLPD as, in order to make the correct diagnosis, clinico-pathological correlation is essential. After having ruled out autoimmune disorders, a crucial point in the diagnosis of ITLPD is the identification of a bland T-cell infiltrate, usually limited to the mucosa, resulting monoclonal with molecular analysis.