The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease

Abstract

Celiac disease (CD) is an autoimmune disorder that can lead to serious health consequences, including cancer. The gluten-free diet (GFD) is the primary treatment for CD and has been shown to lead to clinical remission of the disease. However, the effect of the GFD on cancer development in CD patients is not well understood. This narrative review analyzed observational studies investigating the association between cancer development and adherence to the GFD in CD patients. The most common cancer identified was non-Hodgkin’s lymphoma, followed by others such as colon carcinoma and thyroid cancer. Late diagnosis, type of cancer, and type of CD were factors relevant to the protective role of the GFD. However, there is still no consensus in the scientific literature regarding the GFD’s role in cancer development in CD. While some studies suggest a protective role, others have not identified an association between the GFD and cancer. More research is needed to understand the relationship between the GFD and cancer development in CD patients. Nonetheless, the GFD is essential for the clinical, serological, and histological remission of CD and improved quality of life.

1. Introduction

Celiac disease (CD) is an autoimmune systemic disorder with multiple clinical manifestations triggered by the ingestion of gluten in genetically predisposed individuals [1]. The only available effective treatment so far consists of excluding gluten-protein fractions found in wheat, rye, barley, and hybrids like kamut and triticale—from the diet [2]. CD may occur at all ages and present a variety of signs and symptoms such as stunted growth/short stature, weight loss, abdominal pain, diarrhea/constipation, irritability, osteoporosis, iron-deficiency anemia, among others [3]. Moreover, CD has been associated with increased mortality due to long-term complications such as lymphoproliferative malignancy [4].

Cancer is defined as a chronic multifactorial disease characterized by the uncontrolled growth of cells, and it represents the second leading cause of death worldwide, with the expectation that the number of cases will increase significantly in the coming decades [5, 6]. One of the most serious possible complications of CD is the development of malignancies. In a retrospective population-based cohort in Sweden, Lebwohl et al. [4] evaluated the association between CD and mortality risk in 49.829 patients compared to control participants in the general population matched by age, sex, county and calendar period (n = 246.426). The authors found that CD patients displayed increased risk of death from cancer (2.7 vs. 2.2 per 1000 person-years; HR, 1.29 [95% CI, 1.22–1.36]).

The precise risk of malignancy in adult celiac patients is difficult to assess. However, studies indicate that untreated patients with severe histological intestinal damage are more susceptible to developing cancer [2]. In the retrospective cohort study by Ludvigsson et al. [7], the mortality in CD was examined according to small-intestinal histopathology. The authors identified the highest hazard ratio (HR) in the first year after biopsy with an HR of 3.78 for death due to malignancy (95% CI, 3.14–4.55). After 5 years of follow-up, death from malignancy was only moderately increased (HR, 1.17; 95% CI, 1.03–1.33), which might be explained by the longer duration of treatment at this point, as mucosal inflammation may persist up to a year after implementation of the gluten-free diet (GFD).

The benefits of the GFD on the health and clinical manifestations of CD patients are well established in the literature. A large proportion of these individuals respond completely to the GFD and have a normal life expectancy. However, variables such as late diagnosis, advanced age and low adherence to the GFD represent risk factors for the development of disease complications [8]. Although it may seem simple to remove gluten from the diet, CD treatment may be compromised due to lack of widespread availability of gluten-free products, their high cost, the risk of cross-contamination, the social burden caused by the restrictive nature of the diet, among other factors. Together, these variables may lead to low adherence to the GFD [9].

In a recent study, Marafini, Monteleone and Stolfi [10] suggested that since non-adherence or non-responsiveness to the GFD may lead to chronic inflammation of the small intestine, it is tempting to speculate that a gluten-containing diet in celiac patients could promote the activation of immune/inflammatory signals and ultimately favor the onset or progression of lymphomas and intestinal carcinomas.

Although CD is a common condition with potentially serious health consequences, including cancer, very few studies specifically address the GFD as a possible protective factor in the development of malignancies in celiac individuals. Therefore, this narrative review discusses the role of the GFD in the onset of malignancies in CD, prevalence and characteristics of the main types of cancer found in these patients and the importance of the diet to the treatment and prevention of complications.

2. Methods

The literature search was carried out in 2022 and updated in 2023 for articles that analyzed the role of the GFD in the development of malignancies in patients with CD. No time restrictions were applied for publication date. The following electronic databases were used: Scielo (Scientific Electronic Library Online), Lilacs (Latin American and Caribbean Centre on Health Sciences Information), Pubmed (US National Library of Medicine—National Institutes of Health), Google Scholar and the Brazilian Digital Library of Theses and Dissertations. The search was conducted by two researchers independently and without conflicts of interest.

The keywords used were “coeliac/celiac disease”, “cancer”, “malignancy”, “neoplasm”, “lymphoma”, “gluten-free diet”, “dietary adherence”, and corresponding terms in Portuguese and Spanish. The Boolean operators AND and OR were used to combine the descriptors.

Original articles (observational studies: cross-sectional, case control and cohort) that investigated a possible association between the occurrence of malignancies and adherence or not to a GFD in patients with CD were included in this review. The following exclusion criteria were applied: (i) reviews, letters, conference summaries, case reports and books; (ii) studies that did not evaluate the GFD in the context of cancer development and (iii) studies that did not follow the criteria recommended by the European Society for Paediatric Gastroenterology Hepatology and Nutrition for the diagnosis of CD (characteristic mucosal changes observed by intestinal biopsy and serological testing).

For the selection of articles, all the abstracts were read and the ones that met the inclusion criteria were chosen. Studies were analyzed according to the year of publication, origin country, aim, study design, sample characterization, main results and conclusions regarding the role of the GFD in the onset of cancer in patients with CD.

3. Results and discussion

After reading, analyzing and excluding studies that did not meet the established criteria, eight articles were selected to compose this review (Figure 1).

Figure 1.

Flow diagram of literature search and selection criteria.

The general characteristics and main data of the studies are described in Table 1.

Author/year	Study design	Country	Aim	Sample (n)	Main results	Conclusion
[11]	Prospective cohort	United States of America	To estimate the risk of malignancy in a cohort of patients with celiac disease compared to the general US population and to determine whether a gluten-free diet is protective.	381 patients from the New York Presbyterian Hospital (245 women and 136 men).	In CD patients, an increased risk of small bowel adenocarcinoma, esophageal cancer, melanoma and non-Hodgkin’s lymphoma was observed compared to the general population.	Despite the increased risk of cancer in celiac patients, this is observed before the diagnosis of CD and may be reduced with strict adherence to a GFD. The risk for non-Hodgkin’s lymphoma, however, appears to persist despite treatment with a GDF.
[12]	Prospective cohort	Italy	To estimate the risk of developing cancer in undiagnosed celiac patients and assess whether this risk correlates with the age of patients at the time of CD diagnosis.	1968 patients (1485 women and 483 men/mean age = 36.2 years) diagnosed with CD at collaborating centers of the Italian Registry of Celiac Disease Complications.	This study suggests that the GFD probably protects against the development of malignancies in CD patients, since the older the age at CD diagnosis, the greater the risk of cancer.	The GFD is probably protective against the development of malignancies in CD patients.
[13]	Prospective cohort	Italy	To assess whether strict adherence to a GFD reduces the risk of developing enteropathy-associated T-cell lymphoma.	1757 patients (443 men and 1314 women/mean age = 38.6 years) diagnosed with CD at collaborating centers of the Italian Registry of Celiac Disease Complications.	The risk of developing intestinal lymphoma in celiac patients who maintain gluten in the diet was significantly higher compared to the risk in patients who followed the diet properly.	These results show that a GFD is protective against the development of CD-associated T-cell lymphoma.
[14]	Retrospective cohort	Italy	To evaluate the incidence of malignant and non-malignant complications in a cohort of patients with CD on a GFD, and to assess whether the onset of complications is related to non-adherence to the diet.	549 patients (no further sample details).	A total of 3.3% of patients developed complications on a GFD (n = 18), with 7 of them being malignant and 11 non-malignant. Complications appear to be independent of optimal adherence to the GFD and seem to affect patients diagnosed with classic CD more than patients with subclinical CD.	In this study, no association was identified between adherence to a GFD and the onset of malignancies.
[15]	Case control	Sweden	To investigate the importance of CD features and adherence to a GFD for lymphoma risk.	59 lymphoma patients and 137 matched controls (n = 196) from a population cohort of 11,650 inpatients with CD. Out of the 196 participants, 81 were men and 115, women.	Low dietary adherence was not significantly associated with overall lymphoma risk (odds ratio 1.83, 95% confidence interval 0.78–4.31) or with lymphoma subtypes. There was, however, an indication of increased risk of B-cell lymphoma (odds ratio 4.74, confidence interval 0.89–25.3) or extra-intestinal lymphoma (odds ratio 3.00, confidence interval 0.73–12.3) in poor adherence to the diet.	Adherence to the GFD did not significantly alter lymphoma risk, but a moderate effect cannot be ruled out.
[16]	Prospective cohort	Italy	To carry out a prospective analysis of the risk of celiac patients developing thyroid carcinoma.	1757 patients (443 men and 1314 women/mean age = 38.6 years).	The number of dietary transgressions per month (frequency of consumption of gluten-containing foods) did not correlate with the development of thyroid carcinoma.	Strict adherence to a GFD does not seem to protect against the development of this malignancy.
[17]	Retrospective case control	Argentina	To determine the risk of colorectal neoplasia among patients with CD.	354 patients (118 cases and 236 controls). Patients with CD were considered cases and those without CD were considered controls. For each case, two controls were randomly selected and matched for age, gender, indication for colonoscopy and family history of first- and second-degree colorectal cancer.	The study did not indicate a greater risk of colorectal neoplasia in patients with CD, since the risk of polyps, adenomas and advanced neoplastic lesions was similar in both groups. In individuals with CD, poor adherence to the GFD was independently associated with the presence of adenomas (odds ratio 6.78, confidence interval 1.39–33.20 p = 0.01).	Low adherence to a GFD increases the risk of developing adenomas.
[18]	Retrospective cohort	Italy	To describe the risk of colon cancer in a group of celiac patients.	1757 patients (443 men and 1314 women).	During the study period, six patients developed colon carcinoma. The standardized incidence rate resulted in 0.29 (95% CI = 0.07–0.45). When the risk was stratified by gluten intake, the incidence rate dropped to 0.07 (95% CI = 0.009–0.27) for patients with strict adherence to the GFD.	The low risk of developing cancer in CD patients decreases during the first year after diagnosis and is even lower for celiac patients following a strict GFD.

Table 1.

Studies on the role of a gluten-free diet in the development of malignancies in celiac disease patients.

The articles included in this review were published between 2003 and 2014. One study was conducted in Argentina, one is from the United States, one from Sweden, and five are from Italy. Regarding the design of the studies, four were prospective cohorts, two retrospective cohorts, one case control and one retrospective case control. All screened articles were extracted from the PubMed database and written in English.

The American study by Green et al. [11] aimed to estimate the risk of malignancy in a cohort of patients with CD compared to the general population of the United States and to determine whether a GFD would be protective in this regard. Participants were treated between July 1981 and January 2000 at the New York Presbyterian Hospital, which has a reference center for CD. Adherence to the GFD was questioned at the initial contact and at subsequent visits by an investigator, with no further details on the content of the questions. The frequency of conscious/voluntary gluten ingestion in the previous month was evaluated.

Among a total of 381 patients, 64% were women (n = 245). During the study period, 3.4% of participants died (n = 13), eight of them due to cancer. A total of 11.3% (n = 43) were diagnosed with malignancy: nine after CD diagnosis, seven within a month of diagnosis and 27 before diagnosis. The most common neoplasm identified was non-Hodgkin’s lymphoma (NHL) (n = 9), followed by breast cancer (n = 5), melanoma (n = 5), small intestine (n = 3), colon (n = 3), esophagus (n = 3), lung (n = 3), chronic lymphocytic leukemia (n = 2), ovarian (n = 2) and cervical cancer (n = 2). The study results revealed an increased risk of malignancy in patients with CD compared to the general population of the United States. This finding is consistent with European studies that reported higher rates of cancer of the small intestine, esophagus and lymphoma among individuals with celiac disease [19].

It is important to emphasize that most of these cancer cases occurred before the diagnosis of CD, and a late diagnosis means longer exposure of the patient to dietary gluten. However, an increased risk of NHL was identified among participants despite their strict adherence to a GFD for about 5 years. Thus, the authors suggest that the increased risk for cancer in general occurs before the diagnosis of CD and that it may be reduced with compliance to the GFD. The risk of non-Hodgkin’s lymphoma, however, appears to persist despite adequate dietary treatment [11].

In 2007, Silano and colleagues published a study which may be compared to the work by Green et al. [11]. The objective was to evaluate whether the late diagnosis of CD and the consequent prolonged dietary exposure to gluten would increase the risk of developing neoplasia. The study population consisted of patients diagnosed with CD at the Italian Gastroenterology Centers between January 1982 and March 2005. A total of 1968 individuals were included, of whom 1485 were women (75.4%), with a mean age at CD diagnosis of 36.2 ± 13.8 years [12].

Among 1968 patients, 55 were diagnosed with cancer (2.09%) either before or simultaneously with the diagnosis of CD, compared to 42.1 expected cases, with a standardized morbidity ratio (SMR) of 1.3 (95% CI = 1.0–1.7). The most frequent malignant neoplasm was gastrointestinal non-Hodgkin lymphoma (n = 20), followed by colon carcinoma (n = 7), adenocarcinoma of the small intestine (n = 5), Hodgkin lymphoma (n = 4) and stomach and breast carcinomas (n = 3). Other tumor locations included liver, lung, ovary, thyroid cancer and myeloma (two cases each) and acute leukemia, melanoma and uterus (one case each). No patient developed two or more cancers [12].

The mean age at CD diagnosis for patients who developed cancer was 47.6 ± 10.2 years, which was significantly higher than the age at CD diagnosis for patients who did not develop malignancies (28.6 ± 18.2 years). Therefore, this study suggests that the GFD is a likely protector against the development of malignancies in CD patients, as the older the age at CD diagnosis, the longer the exposure time to gluten and the higher the risk of cancer [12].

Enteropathy-associated T-cell lymphoma (EATL) is a term proposed by [20] to describe the rare form of high-grade non-Hodgkin T-cell lymphoma of the upper small intestine associated with CD. Subsequently, in 1989, Holmes and colleagues pointed out that celiac patients have a high risk of developing malignancy, particularly lymphoma. That is corroborated by the findings of studies such as the one from Green et al. [11] and Silano and colleagues (2007), where the most common malignancy identified was non-Hodgkin lymphoma. In this context, Silano et al. [13] conducted another study with a different cohort to evaluate whether strict adherence to the GFD would reduce the risk of developing EATL [13].

The study sample consisted of 1757 patients diagnosed with CD between January 1982 and December 2006. Information about adherence to the GFD was obtained through interviews. Participants were classified into four groups according to the degree of gluten exposure reported in the interview. The first group comprised of patients who strictly followed the GFD; the second group was composed of patients who consumed up to four gluten-containing meals per month; the third group consumed five to ten gluten-containing meals per month; and the fourth group consumed more than 10 gluten-containing meals per month. Most patients (n = 1113) reported complete adherence to the GFD, belonging to the first group (63.4%); 16.9% were classified in the second group (n = 296); 9.8% in the third group (n = 172) and 9.9% in the fourth group (n = 173) [13].

A total of nine patients developed LTAE while the expected number, according to the RMP, was only 1.4. Among these individuals, only four followed a strict GFD after the diagnosis of CD. The authors mentioned that the risk of developing intestinal lymphoma is related to the presence of gluten in the diet, regardless of the number of gluten-containing meals:

“It is likely that the chronic stimulation of T-cells in celiac small-bowel mucosa, one of the mechanisms that are supposed to lead to the development of lymphoma, is induced even by a small amount of gluten, and therefore a few monthly dietary indiscretions are sufficient to induce the carcinogenic stimulation.”

This raises concerns about the possibility of patients withholding information during a consultation due to fear of admitting that they are not following the doctor’s or other healthcare professional’s advice. Omitting just one meal containing gluten per month, for example, may be harmful to the patient in a situation like this. In conclusion, the study pointed out that strict adherence to a GFD is protective against the development of gastrointestinal lymphoma. The authors highlight that individuals with CD should be adequately educated on the importance of complying with a GFD to prevent the appearance of this neoplasia [13].

In 2009, Tursi and colleagues investigated a different aspect from what had been evaluated in the previous studies mentioned above. The researchers explored the manifestation forms of CD (classic, subclinical and silent CD) while evaluating the incidence of malignant and non-malignant complications in a cohort of celiac patients on a GFD. The authors also assessed whether the occurrence of complications was related to non-adherence to the diet. The definitions used for the classification of CD were those of Green and Cellier [21], which state that classic CD is characterized by the presence of gluten-sensitive enteropathy with gastrointestinal symptoms (abdominal pain, diarrhea, weight loss and malabsorption syndrome). Subclinical CD refers to the presence of gluten-sensitive enteropathy with extraintestinal symptoms (iron-deficiency anemia, alopecia, recurrent abortion, among others) and the absence of gastrointestinal symptoms. The silent form of CD refers to the presence of gluten-sensitive enteropathy without any symptoms identified through screening of high-risk groups (first-degree relatives of celiac individuals, patients with insulin-dependent diabetes, down syndrome and thyroid disorders) [14].

The sample consisted of 549 Italian patients with CD, included between 1993 and 2006. Adherence to the GFD was evaluated according to an arbitrary quantitative scale based on the patient’s interview, considering whether there were: no food transgressions, less than one food transgression per month or more than one food transgression per month since the time of diagnosis. Regarding the form of CD manifestation, 251 patients (45.72%) presented the classic form of the disease, 262 (47.72%) the subclinical form and 36 (6.56%) the silent form. Regarding compliance to GFD, 381 patients (69.4%) were fully compliant, 112 patients (20.40%) reported less than one food transgression per month, and 56 patients (10.20%) reported at least one food transgression per month [14].

Eighteen patients developed complications while on a GFD, with 14 of them diagnosed with classical CD (77.7%) and four with subclinical CD (22.22%). None of the patients with silent CD presented complications. The most registered complications were neoplasms, observed in seven patients (38.89%). Unlike the findings of the previously mentioned studies, the most common malignancy was not EATL, but rather adenocarcinoma of the small intestine with three cases (n = 3), followed by EATL with two cases (n = 2) and colon carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma, both with one case each (n = 1). Among individuals with malignancies, six had classical CD, and only one had subclinical CD [14].

Regarding the GFD in patients who developed some type of cancer, results showed that three were compliant with the dietary treatment of CD, while four were not. The authors suggest that adherence to the diet does not seem to be a strong risk factor in the development of complications in celiac patients. Instead, the form of CD manifestation at the time of diagnosis appears to be more important in determining complications, such as in the case of classical CD, where the risk of severe endoscopic and histological damage is higher than in the subclinical and silent forms [14].

In Sweden, Olén et al. [15] also investigated CD characteristics and GFD compliance in regards to the risk of lymphoma. In this case-control study, 59 individuals with CD and lymphoma were identified as cases, and 137 controls which had only a CD diagnosis were matched from a population cohort of 11,650 patients. The degree of adherence to the GFD was evaluated through recorded information (by the patient’s nutritionist or physician from CD diagnosis until the end of follow-up) available in the medical records. The degree of GFD compliance was defined as: (i) good compliance (strict adherence to the GFD); (ii) low compliance (occasional exceptions or when the patient did not comply to the GFD) and (iii) compliance unknown (medical records did not contain or had scarce information about the patient’s diet) [15].

About 59% of the patients were female (n = 115), and the median age at CD diagnosis was 61 years. There was only one case of Hodgkin lymphoma, while 58 cases of non-Hodgkin lymphoma (NHL). Among the NHL cases, 57% were T-cell type (n = 33), 28% were B-cell type (n = 16), and 15% were unspecified NHL (n = 9). Regarding the location of both Hodgkin lymphoma and NHL, 51% (n = 30) were intestinal, and 42% (n = 27) were extraintestinal. Concerning the degree of compliance with the GFD, 34 (58%) patients in the case group had good compliance, 16 (27%) had poor compliance, and 9 (15%) had compliance unknown. Among the control group patients, 92 (67%) had good compliance, 27 (20%) had poor compliance, and 18 (13%) had compliance unknown [15].

No statistically significant risk of lymphoma in general was found in patients with poor compliance with the GFD. However, individuals with a history of weight loss at the time of CD diagnosis had an increased risk of lymphoma years after this diagnosis. The authors suggest that this may indicate that patients with more severe CD and more pronounced inflammation resulting in weight loss have a higher risk of developing lymphoma [15].

In 2011, Volta, Vicentini and Silano [16] conducted a prospective analysis of the risk of papillary thyroid carcinoma in celiac patients. The study sample included all individuals with CD diagnosed at the Collaborating Centers of the Italian Registry of Celiac Disease between January 1982 and December 2006. A validated form was completed for each patient including demographic data, possible occurrence of thyroid disease and adherence to the GFD. Dietary exposure to gluten was expressed in numerical values from 1 to 4 as follows: “1” for patients who did not consume meals containing gluten, “2” for patients who consumed up to 4 meals containing gluten per month, “3” for patients who consumed 5 to 10 meals containing gluten per month, and “4” for patients who consumed more than 10 meals containing gluten per month [16].

Among the 1757 participants, most were women (n = 1314, 74.7%). The mean age at CD diagnosis was 38.6 ± 12.6 years. A total of six patients were diagnosed with the papillary form of thyroid carcinoma, five of whom were women [16]. The fact that most celiac patients who develop papillary thyroid cancer are female reinforces that both CD and thyroid cancer are more frequent among women [21]. When analyzing the results of this study, it is important to consider that the age at CD diagnosis in patients who developed thyroid carcinoma did not differ statistically from the age of those who did not develop this type of cancer. Moreover, only one patient with carcinoma exhibited poor adherence to the GFD, while the other five had excellent compliance. These findings suggest that early diagnosis of CD and strict adherence to GFD may not confer a protective effect against the development of thyroid malignancy, contrary to what was reported in other studies [16].

In the multicenter retrospective case-control study conducted in four community hospitals in Buenos Aires, Pereyra et al. [17] aimed to determine the risk of colorectal neoplasia among celiac patients by quantifying the prevalence of colorectal polyps, adenomas and advanced neoplastic lesions (ANL) in comparison with healthy patients. Individuals with CD were considered cases, and those without CD were controls. The time since diagnosis and adherence to the GFD were evaluated. To evaluate diet compliance, Biagi’s validated questionnaire [22] was used, which is based on four simple questions and provides a final score on five levels (0-IV) that are clinically grouped into three levels: (0) or (I) are individuals who do not follow the GFD; (II) are those who follow the GFD, but with significant errors that require correction; and those with a score of (III) and (VI) follow a strict GFD [17].

During the analyzed period, 118 celiac patients who underwent prior colonoscopy were identified and included in the study as cases, and 236 patients without CD were included as controls. The reason for the colonoscopy was the individual’s need to undergo it, which could have been for colorectal cancer (CRC) screening, which is a critical detail in the study. The average age of cases was 56 years. Regarding the GFD compliance of patients with CD, 65% (n = 76) followed a strict GFD (scores III or IV), 20% (n = 23) did not follow a strict GFD (scores 0 or I), and 15% (n = 17) followed a GFD, but with errors that require correction (score II). Concerning the time of CD diagnosis, 41% of patients had been diagnosed for 5 to 10 years (n = 48), 32% had the diagnosis for less than 5 years (n = 37), and 27% had more than 10 years of diagnosis (n = 31). The presence of polyps, adenomas and ANLs in patients with CD was 24 (20%), 18 (15%) and 3 (2.5%), respectively [17].

In this study, the prevalence of colorectal polyps, adenomas and ANLs in celiac patients was not significantly different from that in patients without CD. However, results showed that patients with CD who did not follow a strict GFD had an increased risk for adenomas. Since most patients CD adhered strictly to the GFD, it is uncertain whether the absence of risk for colorectal neoplasia would persist in a larger sample with a higher prevalence of non-adherence to the diet. In conclusion, the authors did not find a higher risk of CRC in patients with CD; however, non-adherence to a strict GFD was an independent predictor for the presence of adenomas [17].

Finally, the Italian study by Volta et al. [18] aimed to describe the risk of colon carcinoma in a group of celiac patients. The study population consisted of patients diagnosed with CD at the Collaborating Centers of the Italian Register for Celiac Disease Complication between January 1982 and December 2006. A total of 1757 patients were included in the study, of whom 74.8% were female (n = 1314), with a mean age of 38.6 years. Information on compliance with the GFD was obtained through interviews, and the sample was divided into four groups according to the monthly frequency of gluten-containing meals. A total of 1113 patients reported adherence to the GFD (63.4%), 296 consumed gluten-containing meals one to four times a month (16.9%), 172 consumed up to 10 gluten-containing meals a month (9.8%), and 173 followed an unrestricted diet (9.9%).

Six patients (four women and two men) developed colon carcinoma during the follow-up period. Among those, four followed the GFD strictly and two did not. The SMR (observed cases = 6; expected cases = 28.9) overall for colon carcinoma was 0.29 (95% CI = 0.07–0.45). The cases for this type of carcinoma observed within 1 year from the diagnosis of CD were incident cases. Therefore, excluding these cases from the analysis to avoid ascertainment bias, the SMR drops to 0.13 (95% CI = 0.03–0.35) [18].

By stratifying the risk according to gluten intake, the SMR decreases even further to 0.07 (95% CI = 0.009–0.27) for CD patients who adhere strictly to the GFD. Furthermore, it is important to mention that all four patients who developed colon carcinoma, despite good adherence to the GFD, were diagnosed with CD at a much older age than the sample in this study (62.8 ± 8.2 vs. 38.6 ± 12.6; p < 0.05), which indicates that they maintained a gluten-containing diet for a longer time. In conclusion, the authors suggest that CD patients have a lower risk of developing colon carcinoma compared to the general population. This risk decreases during the first year after CD diagnosis, and it is even lower for treated patients who strictly follow the GFD [18].

4. Conclusion

There is still no consensus in the scientific literature regarding the role of the GFD in the development of malignancies in celiac patients. Some studies suggest that the diet plays a protective role, while others have not found an association between diet and cancer. The most common type of cancer identified in the studies was non-Hodgkin lymphoma, specifically enteropathy-associated T-cell lymphoma, followed by others such as Hodgkin’s lymphoma, colon carcinoma, adenocarcinoma of the small intestine and thyroid cancer.

Late CD diagnosis, cancer type and classification of CD form were relevant to the outcomes related to the protective or non-protective role of the GFD. However, it is important to emphasize that the GFD is essential for the clinical, serological and histological recovery of CD patients, also affecting their quality of life, regardless of its effect on the development of neoplasms or not.

This review contributes in pointing out the scarcity of studies that investigated the relation between the GFD and the onset of malignancies in CD and highlights the need to expand research on this topic. In the future, when new articles on the subject are published, the development of a systematic review may provide support for healthcare professionals’ recommendations in the prevention of complications associated with CD.