Celiac Disease followed by Lymphoma
Celiac disease is associated with an increased risk of lymphoma3, 4. Some studies estimate that the risk of lymphoma in patients with celiac disease may be as high as five times that of the general population.4. Theories behind the link between lymphoma and celiac disease include increased survival of intraepithelial lymphocytes secondary to IL-15 expression by enterocytes.4 Lymphoma development can occur in 60-80% of patients with refractory celiac disease (RCD).4 RCD represents a small portion of celiac disease patients (1-2%) and is defined as 6–12 months of continued enteropathy despite gluten free diet or return of symptoms after remission with gluten free diet.5 However, in our patient, lymphoma and chemotherapy occurred prior to the development of celiac disease.
Another report describes the association of histologically proven celiac disease with lymphoma and other malignancies. In that study 133 of the 259 malignancies studied were lymphomas, further suggesting the link between lymphoma and celiac disease.6 However, there is no mention of chemotherapy in these patients prior to their diagnosis of celiac disease, although 3 patients who survived more than 5 years after being diagnosed with lymphoma did receive chemotherapy.6
Lymphoma followed by Celiac Disease
We found one case describing a patient with lymphoma who developed celiac disease manifestations post-chemotherapy.7 This patient was initially treated with BEMOP-CA (bleomycin, etoposide, vincristine, methotrexate, prednisolone/cyclophosphamide, doxorubicin), followed by 3 cycles DHAP (cisplatin, cytosine arabinoside and dexamethasone) one year later due to recurrent lymphadenopathy and B symptoms. The patient was treated with combination chemotherapy LACE (lomustine, cytarabine, cyclophosphamide, etoposide) after which the patient developed 6 weeks of diarrhea and was eventually found to be seropositive for IgG and IgA antigliadin antibodies without anti-endomysial antibodies, confirming a diagnosis of celiac disease.7
A retrospective chart review of patients at the Mayo Clinic examined the prevalence of diarrheal symptoms in cancer patients after treatment with chemotherapy and found that some cases of celiac diseases were unmasked due to chemotherapy. In this study, 15 of 27 patients were identified as having both celiac disease and some form of cancer including lymphoma prior to initiation of chemotherapy. 12 of 27 patients were diagnosed with celiac disease after chemotherapy but it was not clear how many of these patients had lymphoma.8 Those with known celiac disease who were compliant with a gluten free diet prior to chemotherapy tolerated 5-fluorouracil without severe diarrhea. A majority of those with subsequently diagnosed CD on the same regimen experienced severe diarrhea more than 7 stools a day. Despite the small sample size of subjects, this paper suggests that chemotherapy possibly unmasked or caused celiac disease.
Both our patient and the patient in the previously described case report received chemotherapy regimens whose agents’ primary mechanisms involved direct cytotoxic injury. Our patient also received rituximab, a monoclonal antibody targeting CD-20. CD-20 is a receptor found on the vast majority of B-lymphocytes and rituximab facilitates increased complement-mediated and antibody-dependent cell-mediated cytotoxicity. This binding leads to an immune response which in turn reduces the B-cell population. Due to the high number of gut-associated lymphoid tissue (GALT) it is possible that rituximab and other B-cell-targeting chemotherapy agents cause imbalance of secretion and absorption in the small intestine leading to the pathology seen in celiac disease.
While the role of intestinal B-cells is unclear in inflammatory bowel disease, in one patient with IBD treated with rituximab 6 months after chemotherapy, immunophenotyping of B-lymphocytes showed complete ablation of CD-20+ B-cells in circulation and in other tissues but not the colon.9
Although there has not been a well-established association between lymphoma and celiac disease, there are rare cases in which celiac disease has its onset well after chemotherapy, as seen with our patient. It may be prudent to evaluate patients with lymphoma for celiac disease should they present with delayed refractory diarrhea after chemotherapy.