Malignancy in Celiac Disease

Celiac.com 05/27/2023 - Malignancy must be a concern for all of us with celiac disease. The association between increased mortality in celiac disease due to malignant disease has been known since 1962(1) . Subsequent studies have confirmed various types of malignancies occurring in celiac patients with the most frequent being lymphomas, which account for 51-72% of celiac disease-associated malignancy(2, 3) . Both small bowel lymphomas and adenocarcinoma, the most frequent celiac disease-associated malignancies, typically arise in the jejunum but also are found in the duodenum and ileum(2) . Other sites of carcinoma found in greater than expected numbers have been the mouth, pharnyx, lung, breast, and testes2, 3. Celiac disease-associated cancer is found in both child and adult celiacs(2).

Enteropathy associated T-cell lymphoma (EATL) of the small bowel is the major lymphoma associated with celiac disease(2, 4). This type of non-Hodgkin lymphoma appears to be primarily associated with celiac disease and is known to increase in people with celiac disease who are 50-70 years of age(4) . There appears to be two forms of EATL, and one of them may originate during refractory celiac disease(2,4). Abnormalities in refractory celiac disease lymphocytes are similar to those of this form of EATL(3) . While the majority of patients with celiac disease have improved symptoms with a strict gluten-free diet, those with refractory celiac disease may be non-responsive because of complications due to the development of EATL(5).

The Importance of a Gluten-Free Diet

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The exact rate of malignancy in celiac disease is unknown since much of the silent or asymptomatic form of the disease remains undiagnosed(5) . Also, the celiac disease status of patients with established lymphoma may never be determined, or may be missed at examination(2, 5). However, European studies have shown an increased mortality rate due to malignancies in celiac disease as high as two to nearly four times that of the non-celiac disease population(2) . Most deaths occurred in the first 3-4 years after diagnosis.

Several studies have demonstrated the protective effect of a strict gluten-free diet against malignancy(2, 5) . There appears to be a clear correlation between increased cancer rates (comparing the celiac disease and non-celiac disease populations) and the amount of gluten ingestion. In one of the studies, the excess morbidity of patients on a strict gluten-free diet was only 1.2 compared to 10.7 in patients on a normal (gluten-containing) diet(5). After 5 years or more on a strict gluten-free diet, there appears to be no significant increase in the overall cancer risk compared to the non-celiac disease population. Furthermore, a strict gluten-free diet appears to specifically reduce EATL(6).

The Importance of Early Diagnosis

Conferring the protective effect of a gluten-free diet with early diagnosis is important in malignancies like lymphoma, which has a poor prognosis(5). The expected five-year survival of advanced small bowel lymphoma is 25-30%; that of intestinal T cell lymphoma is only about 25%7 . Furthermore, gastrointestinal lymphomas often are presented as high grade (i.e., more advanced) malignancy, and are often widespread(5,6).

Unfortunately some cases of celiac disease are not diagnosed until presentation of lymphoma. T-cell lymphomas most often arouse the suspicion of undiagnosed celiac disease, but B-cell lymphomas exist in celiac disease as well(8). However, the diagnosis of lymphoma can be difficult to ascertain due to non-specific symptoms or symptoms similar to celiac disease(5,7). Presenting features of gastrointestinal lymphoma are similar to that of uncomplicated celiac disease; "Unexplained deterioration, abdominal pain, weight loss, severe muscle weakness, lymphadenopathy (disorder of the lymph nodes), abdominal mass and pyrexia (fever) should arouse suspicion of lymphoma."(5). Some patients may also have intestinal obstruction, perforation, or bleeding. Furthermore, patients with small bowel tumors (including adenocarcinoma) may present with abdominal pain, anemia, bleeding, weight loss, or obstruction(2, 7). Therefore, Ruskone-Fourmestraux and Rambaud suggest that "the diagnosis of coeliac disease must be made as early as possible and the diet commenced, even in asymptomatic subjects, after detailed and complete patient information."(6). Once diagnosed, therapy for lymphoma or adenocarcinoma may include surgery (such as resection of a portion of the intestine), chemotherapy, and/or radiotherapy(5).

Regarding cancer, there is both good and bad news for those of us with celiac disease. While we have an increased risk of cancer, the risk is still very small for most celiacs. The symptoms of gastrointestinal cancers, and especially small bowel cancers, are similar to those of celiac disease itself. It appears, however, that with the exception of refractory celiac disease, a strict gluten-free diet over time may remove the increased chance of cancer due to celiac disease. Undeniably, our vigilant adherence and attitude toward the gluten-free lifestyle must be a mainstay and we must be up to the challenge.

References:

1. Gough KR, Read AE, Naish JM. 1962. Intestinal reticulosis as a complication of idiopathic steatorrhea. Gut 3: 232-39. 
2. Green PHR, and Jabri B. 2002. Celiac disease and other precursors to small-bowel malignancy. Gastroenterol Clin N Am 31:625-39.
3. Seraphin P, and Mobarhan S. 2002. Mortality in patients with celiac disease. Nutrition Rev 60: 116-8.
4. Catassi C, et al. 2002. Risk of non-Hodgkin lymphoma in celiac disease. JAMA 287:1413-9.
5. Holmes GKT. 2002. Coeliac disease and malignancy. Digest Liver Dis 34:229-37.
6. Ruskone-Fourmestraux A, and Rambaud JC. 2001. Gastrointestinal lymphoma: prevention and treatment of early lesions. Best Practice & Res Clin Gastroenterol 15:337-54.
7. Gill SS, Heuman DM, and Mihas AA. 2001. Small intestinal neoplasm. J Clin Gastroenterol 33: 267-82.
8. Freeman H, Lemoyne M, and Pare P. 2002. Coeliac disease. Best Pract & Res 16:37-49.