Cancer & Celiac Disease
Lymphoma risk is increased — but it’s not cause for alarm
By Christine Boyd
In 2016, Mike, then 38, was diagnosed with celiac disease. The San Luis Obispo, California resident had been an avid baker and found it hard to believe his favorite pastime could be making him sick. But Mike gave up gluten “cold turkey” and tried to embrace the new lifestyle, including gluten-free baking. Two years later, though, his symptoms—abdominal pain and diarrhea—hadn’t improved much and doctors diagnosed refractory celiac disease.
About 10 percent of people diagnosed with celiac disease don’t get better on a gluten-free diet1. This is usually the result of hidden gluten still in the diet. Other causes can include lactose or fructose intolerance or digestive conditions including small intestinal bacterial overgrowth and decreased pancreatic digestive enzymes. Less than two percent of the time, the culprit is refractory celiac disease.2
Defined as persistent (and usually severe) symptoms, along with small intestinal inflammation that persists after one year on a strict gluten-free diet, refractory celiac disease typically affects older adults; children are almost never affected.3 Some people with refractory celiac disease never improve on the gluten-free diet, while others initially improve, but then stop.
The double diagnosis hit Mike hard. “Celiac disease changes your life but refractory celiac disease introduces a new level of uncertainty—and fear,” he says. “Would I develop cancer?”
There are two categories of refractory celiac disease, known as type 1 and type 2. People with type 1 are usually not as sick and there’s a feeling they’re hypersensitive to gluten and can’t restrict the diet sufficiently enough to achieve healing, explains gastroenterologist Daniel Leffler, MD, MS, Director of Clinical Research at the Celiac Center at Beth Israel Deaconess Medical Center in Boston, MA. Type 2, which is less common than type 1, is a dysplastic condition where the intestinal cells have already changed in an abnormal way and can’t heal by themselves, Leffler says. Type 2 carries a high risk for cancer; if followed for five years, about half with type 2 will develop cancer, says Leffler.
A Closer Look at Lymphoma
Much of the research on cancer in celiac disease has focused on lymphoma, especially non-Hodgkins lymphoma, one of three broad lymphoma subtypes. Lymphomas are immune cancers, meaning they arise from immune cells called lymphocytes. Experts think these cancers probably develop in celiac disease as a result of an overactive and faulty immune response; a hyperactive immune response might make lymphocytes grow and divide more often than normal, increasing the risk of them developing into lymphoma cells.
Increased rates of lymphoma, especially non-Hodgkins lymphoma, have been reported in a number of autoimmune diseases, including Sjogren’s, lupus and rheumatoid arthritis (RA), although some of this risk could result from the use of immune modifying medications.
Overall, lymphoma risk is two to three times increased in celiac disease, compared to the general population. However, lymphoma risk isn’t the same across all people with celiac disease. According to a 2013 study led by researchers at the Celiac Disease Center at Columbia University Medical Center, people with celiac disease who achieved good intestinal healing had about half the lymphoma risk than those with persistent intestinal damage (atrophy)4. Having total atrophy was worse than partial atrophy, increasing the risk nine times for a rare subtype of lymphoma called enteropathy associated T-cell lymphoma (EATL).
EATL is the most well known lymphoma associated with celiac disease; it almost never occurs in people without celiac disease, although EATL is sometimes diagnosed first and leads to a celiac diagnosis. Because EATL is so rare, even a nine-fold increased risk doesn’t materially increase what is referred to as the “absolute” risk. This means the vast majority of people with celiac disease won’t develop lymphoma. Furthermore, the Columbia study suggests treatment with the gluten-free diet helps reduce lymphoma risk. A follow up biopsy can confirm intestinal healing—and provide reassurance. (Note, a follow up biopsy is not always done in adults but celiac experts may recommend repeating the biopsy three to five years after commencing the gluten-free diet.)5
Celiac and Other Cancers
Small intestinal carcinoma is also closely linked with celiac disease. Studies show it’s two to four times increased in celiac disease, probably because of intestinal inflammation, which leads to chronic irritation and high tissue turnover, upping cancer risk.6,7 However, small intestinal carcinoma is also a very rare cancer. So despite the increased risk, most people with celiac disease will never develop it, especially if they follow a strict gluten-free diet.
Even in a large celiac center, we see these cancers very infrequently, says Leffler, adding that because these cancers are so rare, studying them, including identifying those patients most at risk, is challenging.
Other gastrointestinal cancers, including colon cancer, don’t appear to be increased in celiac disease8. The studies pretty consistently show no increased risk for colon cancer, which is what we expect since the colon isn’t directly involved in celiac disease, says Leffler.
Thyroid disease is more common in celiac disease but thyroid cancer doesn’t appear to be increased. Earlier studies suggested a potential link, but these studies focused on special populations. Larger, more recent studies have found no increased risk for thyroid or papillary cancer9.
Other common cancers, including lung and breast cancers, are not increased in celiac disease either10. In fact, some earlier studies suggested celiac disease could be protective against breast cancer, probably because women diagnosed with celiac disease had, on average, lower body weight than the general population (higher body fat is linked with increased breast cancer risk). However, as the population of people diagnosed with celiac disease becomes larger and more heterogeneous (with fewer underweight individuals), studies aren’t showing the same degree of protection against breast cancer. We may still see a reduced risk but it’s no longer statistically significant, says Leffler.
Can You Reduce Your Cancer Risk?
There are no published guidelines for cancer screening in celiac disease. For most people with celiac disease, the best preventative measures are to reduce inflammation by following a strict gluten-free diet and following their primary care doctor’s recommendations for cancer screenings, says Sonia Kupfer, MD, Director of the Gastrointestinal Cancer Risk and Prevention Clinic and Director of Clinical Genetic Research at the University of Chicago Celiac Disease Center. Depending on age, gender, family history and other risk factors, this can include blood tests, mammograms, gynecological or prostate exams, and colonoscopies.
If you’re not feeling well, or you have new signs or symptoms that are concerning you, it’s a good idea to get evaluated, says Leffler. If possible, seek out a celiac disease center or academic medical center for persistent or unresolved celiac symptoms.11
Mike is being treated at a top academic center for refractory celiac disease and doing everything he can to reduce his cancer risk. In refractory celiac disease, the key is to get the inflammation under control, says Kupfer. Inflammation can be reduced with the help of a number of medications, depending on the type of refractory celiac disease. New treatment options are being studied, including a novel therapy that blocks a specific immune target involved in refractory celiac disease, interleukin-15 (IL-15). (Learn more about investigational treatments for refractory celiac disease, as well as for celiac-related cancers at clinicaltrials.gov.)
The bottom line? With good control of celiac disease, the cancer risk is very small—not much different from those without celiac disease.
Medical writer Christine Boyd is formerly the health editor for Gluten Free & More magazine.
1-3 National Organization for Rare Disorders, Refractory Celiac Disease, rarediseases.org
4,8 Lebwohl BL et al. Muscoal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease, Ann Intern Med Aug 6 2013 159(3):169-175.
5 Celiac Disease Center at Columbia University Medical Center, Follow Up, celiacdiseasecenter.columbia.edu
6 Ludvigsson J et al. Low Risk of Gastrointestinal Cancer Among Patients With Celiac Disease, Inflammation, or Latent Celiac Disease, Clin Gastro and Hep 2012 10(1):30-36.
7 Ilus T et al. Incidence of Malignancies in Diagnosed Celiac Patients: A Population-based Estimate, Amer J Gastro, 2014, (109):1471-1477.
9 Ludvigsson et al. Risk of Thyroid Cancer in a Nationwide Cohort of Patients with Biopsy-Verified Celiac Disease, Thyroid, 2013 Aug; 23(8): 971–976
10 Han et al. Association Between Coeliac Disease and Risk of Any Malignancy and Gastrointestinal Malignancy, A Meta-Analysis. Medicine (Baltimore). 2015 Sep; 94(38): e1612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635766/
11 The Society for the Study of Celiac Disease is developing a recognition program for celiac disease centers.