Background
Coeliac disease (CD) is a permanent autoimmune enteropathy triggered by the ingestion of gluten, the storage protein complex of wheat, rye and barley. Gluten causes, in genetically determined individuals carryng the HLA-DQ2/DQ8 haplotype, an inflammatory response of the small bowel mucosa, resulting in villous atrophy, infiltration of T-lymphocytes and hyperplasia of the cripts. The only known treatment for this disorder is the life – long withdrawn from the diet of the above mentioned cereals. CD occurs worldwide and its prevalence is estimated about 1/150 individuals [
1‐
3].
The association between CD and neoplasms has been long established [
4]. In the '60s, a population-based study has already reported a 100-fold increased risk of non-Hodgkin's lymphoma in patients affected by CD [
5]. More recently, this risk has been resized to 3-fold by an Italian study and 9-fold by a study from States [
6,
7].
It has been also noted that CD patients have a higher risk of developing a small bowel adenocarcinoma respect to the general population and this neoplasm is the second invasive malignancy for incidence in these patients [
7‐
10].
In contrast, several studies have shown a lower risk of breast cancer in patients affected by CD [
11‐
13].
An increased mortality due to cancer in patients with CD has been also described [
14,
15]. There are considerable, but not definitive, evidences that the strict compliance to gluten-free diet is protective against the development of malignancies [
16‐
18].
We carried out a perspective, population-based study on 1968 coeliac patients with the aim to evaluate the malignancy risk of developing a malignancy and to assess if the delayed diagnosis of coeliac disease and the consequent prolonged dietary exposure to gluten increase the risk of developing a neoplasm.
Discussion
This study demonstrates that coeliac patients have an increased risk of developing cancer in relation to the age of diagnosis of CD. In fact, the mean age at diagnosis of CD in the group of patients that developed sooner or later a cancer is higher than that of patients who did not develop a cancer. Some Authors have supposed that the diagnostic delay is a risk factor for developing a malignancy because of the prolonged period of dietary exposure to gluten [
15,
16]. This risk is more relevant for the intestine -specific cancers such as small bowel carcinoma and non Hodking's lymphoma.
No cases of oropharyngeal and esophageal squamous carcinoma have been found, although Askling et al reported a high risk in coeliac population [
12]. It is noteworthy that in the Swedish study, the patients were selected among those requiring hospitalization, so the severity of disease was a selection bias to be considered. In addition, there could be some genetic and environmental factors, such as the diet, exerting a protective effect towards tumors of the upper gastrointestinal tract among the Italian people. As matter of the fact, no excess of non hematological malignancies was found by a previous Italian population-based study [
15].
Small bowel carcinoma is a rare malignancy that usually arises trough an adenoma-carcinoma sequence [
21‐
23]. However, among our population, only a patient developed intestinal adenomas. These data did not support the theory that a premalignant lesion exists between villous atrophy and small intestine carcinoma, lending support to previous reports [
24]. While small intestine carcinoma is a male predominant malignancy, four out of the five patients affected by this cancer were female. Since CD is prevalent among women, this finding is a further confirm of the link between small bowel neoplasm and CD.
From a public health perspective, the overall risk of developing a cancer in coeliac population found in this study and the uncertain protective effect of gluten free diet do not support the opportunity of a serological screening for coeliac disease on general population in order to prevent a malignancy. But the high mean age at the diagnosis of CD for the group of patients that developed a cancer suggests that an accurate search for malignancies should be performed in patients diagnosed with CD as adult and in the elderly.
This study presents some potential limitation; first of all, the ascertainment bias. This can only be addressed by a prospective study with age- and gender- matched controls. Moreover, all the Clinical Centers involved are tertiary centers for the diagnosis and treatment of gastrointestinal diseases. Then, the accurate and frequent clinical controls the patients with CD use to undergo to, can lead to the diagnosis of a higher cases of malignancies. So, an excess of the risk for tumors is likely to be estimated, particularly that of gastrointestinal sites, since they can be detected during the endoscopy usually performed for the hystological diagnosis of CD [
25]. This work considered the incidence of malignancies before and/or simultaneously the diagnosis of CD only and not during the follow-up. Until the diagnosis of CD, the patients do not have more frequent clinical control than healthy population.
Collaborating Centers
Cattedra di Medicina Interna II, Univ. Cattolica, Roma, G.Gasbarrini, M.D., V. De Vitis, M.D.; Dipartimento di Pediatria, Univ. Federico II, Napoli, L. Greco, M.D., S. Auricchio, M.D.; Ospedale per gli infermi di Faenza – Azienda USL di Ravenna, D.Santini, M.D., F. Scaggiante M., M.D., Vincenzi M., Federici M.D.; Istituto Giannina Gaslini, Pediatria III, Genova, E. Castellano, M.D., A.Calvi, M.D.; Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Univ. Torino, Sategna-Guidetti, S. Grosso; Unità di Gastroenterologia, IRCCS Policlinico S. Matteo, Univ. Pavia, Campanella J., M.D., Corazza G.R., M.D.; Unita' Operativa di Nutrizione Clinica, Ospedale S. Eugenio, Roma, G. Sandri, M.D., G. Giorgetti, M.D.; Monica Amici, Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi, Bologna, U. Volta, M.D., L. De Franceschi, M.D.; Servizio di Gastroenterologia ed Endoscopia Digestiva, Ospedale USL 9, Treviso, S. Lo Perfido, M.D., ; Divisione di Gastroenterologia, IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Foggia, F. Perri, M.D., V. Festa M.D.,; Clinica di Gastroenterologia ed Epatologia, Univ. Perugia, M.A. Pelli, M.D., M.L. Cavalletti M.D.,; Unità Operativa di Gastroenterologia ed Endoscopia Digestiva, Ospedale di Circolo e Fondazione Macchi, Varese, S. Segato, M.D., M. Curzio M.D.,; Servizio di Gastroenterologia ed Endoscopia Digestiva, Dipartimento Oncologia, Ospedale S. Giovanni AS, Torino, M. Pennazio M.D.,, F.P. Rossini, M.D.; Cattedra di Gastroenterologia, Ist. di Clinica Medica II, Univ. La Sapienza, Roma, A. Picarelli M.D.; Divisione di Gastroenterologia, Ospedale Mauriziano Umberto I, Torino, A. Pera, M.D., E. Ercole M.D.; Unità Operativa di Gastroenterologia, Dip.to di Patofisiologia Clinica, Univ. Pol. "Careggi" Firenze, M.T. Passaleva; Clinica Pediatrica, Servizio di Gastroenterologia, Univ. La Sapienza, Roma, M. Barbato M.D.,; Istituto di Medicina Interna, Univ. Cagliari, P. Usai M.D.,, M.F. Dore M.D.,; Divisione di Gastroenterologia, Ospedale Regionale, Bolzano, F.Chilovi, M.D., L. Piazzi, M.D. L.Zancanella M.D., and Servizio di Gastroenterologia Pediatrica e Servizio di Gastroenterologia, Univ. Modena, V. Boarino, M.D., A. Ferrari M.D.,
Competing interests
The Author(s) declare that they have no competing interests.
Authors' contributions
MS designed the study, organized the database, interpreted the data, drafted the manuscript and performed the statistical analysis. UV designed the study, revised critically the manuscript and added important points to the discussion, collected the data, performed the statistical analysis. AMM and RdB organized the electronic database and collected the data. MdV conceived the study, coordinated the collaborating centers and helped the draft of the manuscript. Collaborating Centers enrolled the patients, collected and interpreted the data. All Authors approved the final draft of the manuscript.