Coeliac patients have a higher incidence of non-Hodgkin's lymphoma than that of the general population [7, 34-39], Malignancy develops in 8-13% of patients. EATL is slightly more frequent in males and has its peak in the sixth decade of life. An interesting recent finding shows that the incidence of lymphoma in CD diagnosed in elderly patients (over 60 years) was much higher (23%) than that in younger population (8%). Moreover, other autoimmune diseases, dermatitis herpetiformis and autoimmune thyroiditis, were common in this group of patients . The relationship between EATL and CD is underlined by the finding of the CD associated DQA1 0501, DQB1 0201 phenotype in EATL patients.
In most cases lymphoma and CD are found together or diagnosed at about the same time. The diagnosis of lymphoma arising in the context of CD is often difficult and delayed because the symptoms are nonspecific and indistinguishable from noncomplicated CD itself. A rise in serum IgA level can be found, but this could be also seen in uncomplicated CD. In some patients the symptoms are acute, involving for instance intestinal perforation or obstruction, bleeding from the tumor or an opportunistic infection. Tumors are usually located in the jejunum but may be found in the ileum, stomach and colon. At diagnosis, the lymphoma is usually widespread and the prognosis is therefore very poor .
The understanding of celiac-associated lymphomas has improved in recent years . It was shown that celiac-associated lymphomas were of single histogenetic type. Immunohistological and molecular studies then indicated that these tumors are of T-cell origin. It appears likely that enteropathy associated T-cell lymphoma derives from intraepithelial lymphocytes (IEL); monoclonal HML-1 antibody stains lymphoma cells (CD 103+ lymphocytes expressing integrin-a; E-fi 7 characteristic for mucosal associated lymphocytes). The lymphoma cells are usually pleomorphic and manifest a cytotoxic CD3+, CD4/CD8-phenotype [41, 42], A monomorphic small cell variant has been described in which the cells are CD3+, CD4-, CD8+ and CD56+. To assess the clonality of duodenal mucosal T cells in coeliac patients, the analysis of TCR rearrangements by multiplex polymer chain reaction (PCR) on DNA extracted from duodenal biopsies of patients with complicated and noncomplicated celiac disease was recently performed and published . None of the 15 patients studied had histological evidence of lymphoma. In this study performed by PCR analysis of Vy-Jy genes, it was found that a minority of patients had a monoclonal rearrangement and the majority of patients had a polyclonal (8 cases) or oligoclonal (3 cases) pattern. A monoclonal pattern was associated with complicated CD (ulcerative jejunitis and nonresponsive CD), whereas, polyclonal or oligoclonal patterns were associated with uncomplicated CD. Three patients with complicated CD evolved later to T-cell lymphoma with liver or bonemarrow invasion. Interestingly, identical clones were found in enteropathic duodenojejunum and peripheral blood in a patient with large cell lymphoma with bonemarrow invasion. The study suggested that some patients with adult onset of the disease may have a cryptic low-grade T-cell lymphoma and may be at a higher risk of developing a subsequent overt enteropathy-associated T-cell lymphoma. Moreover, the authors of this study suggested that in patients with complicated CD, molecular analysis of clonality may be used to provide earlier diagnosis of lymphoma by detecting a predominant T-cell clone before a tumor mass is evident [43,44].
The relationship of lymphoma and refractory sprue (i.e., disease mimicking coeliac sprue refractory to a gluten-free diet) seems to be clinically important. Recently, a multicenter study was presented demonstrat ing that ulcerative jejuno-ileitis, collagenous colitis and mesenteric lymph node cavitation are the most frequent associated features of refractory sprue. Abnormal phenotypic intestinal intraepithelial lymphocyte population expressing CD3 but not CD8, with a clonal TCR-y gene configuration was found in most patients with refractory sprue suggesting that most patients with refractory sprue may have a prelymphomatous condition .
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