EATL is a rare type of peripheral T-cell lymphomas in gastrointestinal tract and seldom occurs in stomach. O’Farrelly et al. firstly proposed the term EATL owing to the close association of this lymphoma with villous atrophy of the jejunal mucosa adjacent to EATL in 1986
. EATL accounts for less than 1% of non-Hodgkin’s lymphoma and was most common in Europe, followed by North America and Asia
. The small intestine is the most common site of involvement. Presentation in the duodenum, stomach, colon or outside the gastrointestinal tract may occur but is rare
[5, 6]. Delabie et al. has reported approximately 8% of the EATL arising in stomach
. In spite of its low prevalence, EATL is one of the main causes of death in patients with long-lasting untreated refractory celiac disease, due to its aggressive nature and unresponsiveness to therapies currently available. Most of the lymphomas occur in stomach are of B cell origin
[8–10]. Therefore, B cell lymphomas and other rare T cell lymphomas should be excluded when the diagnosis of gastric EATL is made. In addition, peptic ulcer and poorly-differentiated adenocarcinoma should also be considered in the differential diagnosis.
Although EATL has two subtypes with different histological features and mimics various gastric neoplasms, it can still be recognized or suspected on morphologic grounds. Histologically, the tumor forms an ulcerating mucosal lesion that invades the wall of gastrointestinal tract. Most commonly, the tumor cells are relatively monotonous, medium to large in size, with round or angulated vesicular nuclei, prominent nucleoli. The cytoplasm is moderate to abundant and pale-staining. Less commonly, the tumor exhibits marked pleomorphism with numerous inflammatory cells in the background. In the monomorphic form of EATL type II, the neoplastic cells have medium-sized round, darkly staining nuclei with a rim of pale cytoplasm. An inflammatory background is absent, and necrosis is usually less evident than in classical EATL type I. Immunohistochemically, the tumor cells are CD3+, CD4-, CD5-, CD7+, CD8−/+, CD103+, TCRβ+/−, and contain cytotoxic granule associated proteins. In almost all cases, a varying proportion of tumor cells express CD30. In contrast to EATL type II, EATL type I seldom expresses CD8 and CD56.
The differential diagnosis includes peptic ulcer, poorly differentiated adenocarcinoma, B cell lymphomas and other types of T cell lymphomas that present in the stomach. In some cases of EATL, the inflammatory cells may be so abundant as to obscure the relatively small number of tumor cells and therefore resembles the lesion of peptic ulcer. However, the intraepithelial lymphocytes of peptic ulcer are polyclonal and typically show no atypia. The pleomorphic cells in EATL indicate the property of poorly differentiated adenocarcinoma, but negative for AE1/AE3 staining will be helpful to distinguish between them.
The most common types of lymphomas involving the stomach are of B cell origin, and include MALT lymphoma, diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma, and occasionally, follicular lymphoma. Mantle cell lymphoma and follicular lymphoma often produce multiple polyp-like extensions of the mucosa (lymphomatoid polyposis), a gross appearance that is not seen in EATL. DLBCL and Burkitt lymphoma often produce large masses that may grossly resemble EATL. Occassionally, the tumor cells of EATL are immunoblast-like and mimic the cells of DLBCL, but they do not express B cell markers such as CD20 and Pax-5 which are always expressed in DLBCL (like other B cell lymphomas). Therefore, it is readily distinguishable by their immunophenotypic characteristics.
Extranodal NK/T cell lymphoma is a lymphoma of natural killer (NK) or T cell lineage that most commonly presents with a facial mass. A small percentage of patients may present with gastrointestinal involvement. Because the morphology of the tumor cells is so variable, it is important to consider extranodal NK/T cell lymphoma in all cases of aggressive extranodal lymphoma associated with vascular invasion and necrosis. The key diagnostic features of NK/T cell lymphoma are the demonstration of NK/T cell markers (CD2, cytoplasmic CD3, CD56, and cytotoxic granule proteins) and Epstein-Barr virus (EBV), which is uniformly present. In contrast, EATL is not associated with EBV infection and infrequently expresses CD56.
Gamma-delta T cell lymphoma most commonly involves the liver and spleen (hepatosplenic gamma-delta T cell lymphoma), but less commonly involves other areas in the gastrointestinal tract. The diagnosis of gamma-delta T cell lymphoma is usually made based upon biopsy specimens demonstrating infiltrating atypical lymphocytes that express CD2, surface CD3, CD7, CD56, and CD16, and do not express CD4, CD5, CD8 or B-cell surface markers. The atypical lymphocytes express gamma/delta T cell receptors. Like gamma-delta T cell lymphoma, EATLs express pan-T antigens (surface CD3+) and do not express CD4, CD5, or CD8. In contrast to gamma-delta T cell lymphoma, EATLs typically express CD103. The T cell receptor beta gene is clonally rearranged. In addition, EATL (type I) seldom express CD56. These properties will be helpful to distinguish between them.
Patients with anaplastic large cell lymphoma (ALCL) typically present with painless lymphadenopathy. The tumor is composed of large blastic cells with horseshoe-shaped nuclei, prominent nucleoli, with or without a prominent golgi complex (seen as a paranuclear clearing, or hof) in a cohesive growth pattern. By immunohistochemistry, homogeneous and strong expression of CD30 in a membrane/golgi pattern can be observed. There is also expression of T-cell antigens or no lineage-specific antigens as in the case of the null cell type. However, a subpopulation of EATL may resemble ALCL histologically and partly express CD30. ALCL is not associated with celiac disease-type symptoms or the presence of the intraepithelial lymphocytic infiltrates in the adjacent “normal” mucosa.
In this case, peptic ulcer, poorly differentiated adenocarcinoma and B cell lymphoma were easily excluded because of the monoclonal tumor cells which expressed only T cell markers. Although tumor cells showed necrosis, positive immunostaining for CD3 and heavy inflammatory background, the negative result of EBV detection and absence of CD56+ NK/T cells excluded the possibility of extranodal NK/T cell lymphoma and Gamma-delta T cell lymphoma. ALCL was the most difficult one to be distinguished among the differential diagnosis. However, the intraepithelial lymphocytic infiltration and partly expression of CD30 were critical to rule out the diagnosis of ALCL. In addition, the pleomorphology and negative staining for CD56 and CD8 led to the diagnosis of EATL type I, but not type II. Taken these together, our final diagnosis was gastric EATL type I.
We herein reported a case of EATL arising in stomach which was an uncommon site for this disease. It worth noting that the severe necrosis and inflammatory background, which were also observed in other extranodal T-lymphomas
[5, 6, 11], may obscure the relatively small number of tumor cells. For the same reason, the patient in this study underwent biopsy twice under gastroscope, while the result was not satisfied because of too much necrosis. In this situation, it was dangerous to make the diagnosis of gastritis or ulcer without careful evaluation of the lymphoid component. The final diagnosis in this case also underlined this point. In addition, as same as other T-lymphomas occurred in uncommon sites
[12–16], the gastric EATL also exhibits the genetic disorder which will be helpful to distinguish from reactive process.