1. Introduction
Celiac disease (CeD) is an immune-mediated disease precipitated by the ingestion of gluten in genetically predisposed individuals [1]. Considering that many patients remain undiagnosed for many years before being correctly diagnosed and receiving an appropriate treatment, the exact prevalence of CeD is unknown [2]. According to recently published data, the worldwide serological and histological prevalence rates of CeD are 1.4% and 0.7%, respectively [3]. The prevalence is higher in females compared to males and in children compared to adults. The clinical spectrum of CeD is highly variable, from asymptomatic to severe malabsorptive form [2]. A strict lifelong gluten-free diet (GFD) is the only proven, globally accepted treatment for CeD; however, since it can negatively impact on quality of life, the compliance is often difficult to maintain [4,5].
The great majority of patients respond to a GFD and present an excellent disease prognosis; however, less than 1% of patients develop a series of serious complications that severely affect their survival [6]. Some preneoplastic conditions, such as refractory CeD type 1 and type 2 (RCD-I and RCD-II) and ulcerative jejunoileitis (UJI), as well as several types of malignancies, may complicate the disease course. Among them, non-Hodgkin lymphomas (NHL), including the characteristic enteropathy-associated T-cell lymphoma (EATL) and the small bowel carcinoma (SBC), have been typically associated with CeD [1,7]. In CeD patients, mortality from all causes seems to be 2-fold higher compared to the general population [8,9,10,11,12], and a relevant contribution to this increased death risk is associated with malignant diseases [8,9,10,13]; thus, we aimed to comprehensively review the available evidence regarding the association between CeD and cancer risk. We will focus in particular on lymphomas (among them EATL) and SBC, which are the characteristic malignancies complicating CeD.
2. Methods
A literature search from the bibliographic databases of Embase, PubMed, Scopus, and Web of Science was performed using the following keywords: (“Celiac Disease” OR “Coeliac Disease”) AND (“Cancer” OR “Neoplasm” OR “Tumor” OR “Lymphoma” OR “EATL” OR “Adenocarcinoma”). Initially, 6379 papers written in English and published between January 1980 and June 2021 were identified. In order to assess the appropriateness for the study’s aim, titles and abstracts of the papers were evaluated by the authors and 385 articles (171 case reports) relating to malignancy in CeD were finally selected and read in full. Paper references were checked to ensure that all potentially relevant articles were retrieved and examined in detail (Figure 1). The articles were categorized by topic and summarized according to their content.
3. Celiac Disease and the Overall Risk of Malignancies
The interest in evaluating whether CeD patients have an increased risk of developing malignancies dates back several decades [14,15,16,17,18,19,20,21], and a large number of studies investigating this association have been published so far. Early studies suggested the existence of greater risk, in particular for lymphoma [14,15,16,17,18,19,20,21], while others claimed no differences in comparison to the general population [22]. An increased risk for all cancers (standardized incidence ratio (SIR) = 1.3, 95% CI 1.2–1.5) was reported in a large Swedish population-based cohort study [23]. Interestingly, a decline in the relative risk with the increase in the length of follow-up was observed, with SIR being only slightly and non-significantly elevated (1.1, 95% CI 0.9–1.4) after 10 or more years. These results were confirmed by several other subsequent investigations, although the magnitude of the increased risk was demonstrated to be modest [24,25,26,27,28]. Card et al. [24] found an SIR of 2.0 (95% CI 1.24–3.06) in the peridiagnostic period (<2 years after CeD diagnosis), although this value decreased and became non-significant in the postdiagnostic period (SIR = 1.02, 95% CI 0.70–1.45). The same results were found by West et al. [25]; after excluding the first year after diagnosis of CeD, the overall risk of malignancies was comparable to that of the general population (adjusted hazard ratio (HR) = 1.1, 95% CI 0.87–1.39). Very recently, a large Swedish study involving 47,241 CeD patients confirmed these previous results, demonstrating a very small increase in cancer risk (HR = 1.11, 95% CI 1.07–1.15) compared to controls [28]. This latter study in particular found elevated risk of developing a malignancy only in patients diagnosed after the age of 40 years, and this association was higher in the first year after CeD diagnosis (HR = 2.47, 95% CI 2.22–2.74) but disappeared when the first year of follow-up was excluded (HR = 1.01, 95% CI 0.97–1.05) [28]. According to Grainge et al., the increased risk of developing a malignancy persists up to 15 years after diagnosis and then returns to a similar level to that of non-celiac patients (SIR = 0.92, 95% CI 0.61–1.33, after 15 years of follow-up) [27]. In contrast, other studies showed no differences at all in the risk of developing cancer at all sites between CeD patients and the general population [11,29,30,31,32]. Opposite results were obtained for metanalysis. Han et al. demonstrated an increased risk of malignancies in CeD (odds ratio (OR) = 1.25, 95% CI 1.09–1.44) [33], while Tio et al. claimed no differences compared to the general population (OR = 1.07, 95% CI 0.89–1.29) [12].
Robust data demonstrate that CeD patients have an increased modest long-term risk of mortality from all causes [8,9,10,11,12,13,34]. Corrao et al. [8] showed a 2-fold increase in mortality in their entire CeD patient cohort (standardize mortality ratio (SMR) = 2.0, 95% CI 1.5–2.7); in addition, they demonstrated that SMRs increased significantly in patients with diagnostic delay, in those with severe symptoms at presentation, and in those not adherent to GFD [8]. In a recent population-based cohort Swedish study, including 49,829 patients diagnosed between 1969 and 2017, a small but statistically significant increased mortality risk was demonstrated in CeD patients as compared to the general population [35]. This increased risk of mortality seems to be limited to patients with an overt CeD and not those subjects with positive serology only (unrecognized CeD) [36,37,38]. A relevant proportion of this increased risk of mortality, as reported above, is attributable to the development of malignant diseases [8,9,10,13,34,35]. The SMR for cancers in CeD patients has been shown to vary from 1.61 (95% CI 1.19–2.13) [10] to 2.6 (95% CI 1.7–3.9) [8]. Other studies, while finding no differences in overall cancer-related death, reported significant excess risk of dying from malignant lymphoproliferative diseases in CeD patients [34,39,40].
Despite the conflicting and inconclusive results about the association between CeD and overall cancer risk, the association with some specific malignancies (lymphomas and SBC) is well established.
4. Celiac Disease and Lymphomas
Studies evaluating the risk of lymphoproliferative malignancies in CeD patients are depicted in Table 1. Early investigations reported a 100-fold elevation of risk of lymphoma among patients with CeD [41,42], although more recent data have estimated the excess risk of lymphoma to be more modest. Indeed, in these studies, only patients from referral centers and also those with malignancy already present at the time of CeD diagnosis were included. More recent population-based studies, which were not affected by these biases, confirmed the higher risk of developing lymphomas compared to the general population, although standardized incidence ratios of about 3–12 for all NHLs [10,11,23,24,25,26,27,29,31] and 16–40 specifically for gut lymphomas [24,43] have been reported. In a large cohort study conducted in Sweden involving 11,019 patients, the SIR for NHL in CeD patients was reported to be 6.3 (95% CI 4.2–12.5) [23]. Almost equal figures were published by Smedby et al. [44], who confirmed the elevation of NHL risk in CeD (SIR = 6.6, 95% CI 5.0–8.6). Elfstrom and colleagues performed an interesting study involving an impressive number of patients (28,989 with histologically proven CeD (Marsh 3), 13,140 patients with duodenal inflammation (Marsh 1–2), and 3711 patients with positive serology) [45]. While the risk of lymphoproliferative malignancies was increased in CeD patients and in those with inflammation (HR = 2.82, 95% CI 2.36–3.37, and 1.81, 95% CI 1.42–2.31, respectively), in subjects with only positive serology, a risk profile similar to that of the general population (HR = 0.97, 95% CI 0.44–2.14) was reported [45]. Another recent study performed in Sweden confirmed that the risk of lymphoproliferative cancers was higher in CeD patients compared to controls, both considering (HR = 2.20, 95% CI 1.94–2.49) and excluding (HR = 1.75, 95% CI 1.52–2.01) the first year of follow-up after the diagnosis of enteropathy [28]. This association was also confirmed in cohorts of patients with NHL [43,46,47,48,49]. In particular, Gao et al. [46] studied 37,869 NHL patients, finding a risk of CeD more than five times higher (OR = 5.35, 95% CI 3.56–8.06) than that for controls.
The prognosis for CeD patients is severely affected in cases of lymphoma development. Indeed, almost all published studies are concordant in attributing an increased mortality risk from lymphoproliferative diseases in these patients [8,9,10,11,13,37,39,40]. Although the early study by Corrao et al. [8] reported an SMR of 69.3 (95% CI 40.7–112.6) for NHL, subsequent studies scaled back the disease-specific mortality risk. Indeed, an SMR of 11.4 (95% CI 7.8–16.0) was observed in a large (n = 10,032) Swedish cohort of hospitalized CeD patients [9], while a rate of 5.07 (95% CI 2.55–10.06) was observed in a population-based cohort study from Finland conducted in biopsy-proven CeD patients [10]. In a competing risk analysis, compared to the general population, CeD patients showed a 0.15% excess risk of dying from NHL up to 10 years postdiagnosis [39].
4.1. Enteropathy-Associated T-Cell Lymphoma
Almost a century has passed since the first description in 1937 of the association between small intestinal malignant lymphoma and steatorrhea in 6 patients by Fairley and Mackie [57]. While initially intestinal malabsorption was considered secondary to the presence of lymphoma, a link with CeD was suggested for the first time in the 1960s by Gough et al., who described five cases of small bowel lymphoma in patients with long-standing enteropathy [14]. The term “enteropathy-associated T-cell lymphoma” (EATL) was introduced by O’Farrelly et al. in 1986 and is still widely used to describe the rare form of aggressive T-cell non-Hodgkin lymphoma (NHL) of the small intestine, which characteristically complicates CeD [58].
With an annual incidence of 0.16–1.00 per million people in Western countries, EATL is a rare tumor, accounting for only 5% of all gastrointestinal lymphomas [59,60,61]; however, in parallel to the rising incidence of CeD over the last 40 years [62,63], the incidence of EATL is also progressively increasing [59].
In the vast majority of cases, EATL develops from a complication known as refractory CeD (RCD), which is clinically defined as persistent or recurrent symptoms and signs of malabsorption with villous atrophy, despite a strict GFD for at least 12 months [64,65]. Depending on the absence or presence of aberrant intraepithelial lymphocytes (IELs; lacking surface CD3 and generally CD8 but expressing intracellular CD3), RCD can be classified into two types: RCD type I (RCD-I), which mimes a CeD at diagnosis, and RCD II, which is characterized by the presence of a percentage of aberrant IELs, with monoclonality of TCR in the majority of cases, which is above 20% using flow cytometry and 50% using immunohistochemical analysis [64,65]. Considering that 60–80% of patients with RCD-II will develop intestinal lymphoma within 5 years, this entity can be considered as a prelymphoma (pre-EATL; low-grade lymphoma) [65,66,67,68]. RCD has a very low incidence (0.04–1.5%) [69] but RCD-II represents 15–75% of cases among all patients with RCD according to different studies [66,67,68]. Ulcerative jejunoileitis (UJI) can also complicate CeD, with the development of multiple ulcerations in the intestinal wall evolving in strictures [70,71]. UJI resembles RCD-II in immunological features and both can subsequently progress into EATL through the accumulation in the intestinal epithelium of aberrant (cytoplasmic CD3 9CD3ε0+, CD103+, CD8−, CD4−, TCR-αβ−) and clonal (restricted rearrangements of TCR-γ chain) IELs that are abnormally expanded by the antiapoptotic action of IL-15 [72,73,74]. As far as we know, it is unclear whether RCD-I and RCD-II are different phases of the same process or two different conditions; however, these two entities are unrelated probably, since progression of RCD-I to RCD-II has rarely been described [68] and EALT in patients with RCD-I is an exceptional event [66,75].
Interestingly, it has been hypothesized that viral infections may play a role in the development of CeD complications [76]. Even though Perfetti et al. demonstrated that Epstein–Barr virus (EBV) can be found in 70.5% of biopsies from patients with RCD-I and RCD-II versus 16.6% of controls with uncomplicated CeD [77], data regarding a possible role of this virus in the evolution to EATL are limited and discordant [78,79,80].
According to the World Health Organization Classification of tumors of hematopoietic and lymphoid tissues, EATL can be divided into types 1 and 2 [81,82,83]. EATL type 1 is characterized by non-monomorphic cytomorphology (pleomorphic, anaplastic, immunoblastic), CD56 negativity, and common gains of 1q and 5q regions. It is strongly associated with CeD and HLA-DQ2 genotype. In contrast, EATL type 2, recently named monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) [84], shows a monomorphic small- to medium-sized tumor cell morphology, frequent CD56 expression and MYC oncogene locus gain, and rare gains of 1q and 5q regions. EATL type 2 is less frequently associated with CeD and HLA-DQ2 genotype [85,86], even if some cases are reported in the literature [87]. EATL type 1 is typically found in Western countries, especially in Northern Europe, where CeD is more prevalent. In Asian populations in contrast, where CeD is rare, intestinal T-cell lymphomas are predominantly if not exclusively type 2 EATL [83,88].
4.1.1. Clinical Presentation
Based on clinical presentation, CeD-associated EATL (EATL type 1) can be classified as primary or secondary. Secondary EATL develops in patients with a known history of CeD, whereas CeD diagnosis is achieved at the time of lymphoma development in patients with primary EATL. Considering the low specificity of symptoms and the low index of clinical suspicion in patients without CeD, the diagnosis of primary EATL is much harder to achieve and typically delayed [89].
The median age at diagnosis of EATL is 60 years, with a comparable proportion of males and females affected [75,83,90]. In patients with secondary EATL, the classical presentation mimics an exacerbation of CeD symptoms, such as abdominal pain, diarrhea, and unexplained weight loss (despite the persistent adherence to GFD) [91]. The concomitant presence of systemic or B symptoms (fever and night sweating; loss of >10% of body weight is present in almost all the patients due to malabsorption) should raise suspicions for this complication, and once the diagnosis is established, they are signs of clinical progression [83,89]. Despite their very low specificity, hypoalbuminemia, anemia, and increased lactate dehydrogenase (LDH) on laboratory tests may also help raise the level of suspicion [91]. Malnutrition is very common, in particular when EATL develops after a long-standing RCD [89,92].
Considering that EATL may be frequently complicated by intestinal perforation, obstruction, and hemorrhage [89,90,93], many of these tumors are diagnosed during emergency laparotomy [75]. At the macroscopic examination, EATL appears as a massive tumor infiltration, which may be transparietal, with thickened plaques, ulcers, or strictures of the intestinal wall [91,94]. The small intestine, and in particular the jejunum, is the most frequent localization of EATL, although this tumor may also arise in the stomach, large bowel, or rectum [83,90,93]. Multiple locations at diagnosis have been frequently reported (50–100%) [90,93,94], and extraintestinal sites may also be involved [83,90,93]. There are some reports of an association between EATL and peripheral eosinophilia [95], mesenteric lymph node cavitation [96], and splenic atrophy [97], which is associated with an increased risk of severe infections and sepsis [98].
4.1.2. Staging and Prognostic Systems
Regarding all lymphomas and EATL, staging procedures are recommended, such as bone marrow examination, abdomen and chest computed tomography (CT), and ultrasound examination of the neck, in order to manage patients appropriately from a therapeutic point of view. In patients with EATL, classic lymphoma staging systems have been demonstrated to be inadequate in prognostic stratification and treatment guidance [99,100]. The accuracy of the well-validated International Prognostic Index (IPI), composed of age, LDH levels, Ann Arbor stage, number of extranodal sites, and Eastern Cooperative Oncology Group performance status (ECOG-PS) [99], turned out to be low for extranodal T-cell lymphomas, including EATL [83,99,101,102,103]. This is mainly because 3 out of 5 components of the IPI (age, number of extranodal sites, and tumor stage) are irrelevant for EATL prognosis. The ability for prognostic discrimination of the Lugano system [100], the staging method commonly used for intestinal lymphomas, is uncertain among EATL patients. The Prognostic Index for Peripheral T-cell Lymphoma (PIT), assessed by age, ECOG-PS, LDH levels, and bone marrow involvement [104], seems to have higher accuracy in predicting survival of EATL patients [83]. Indeed, among the four parameters considered for the prognostic stratification in the PIT model, only bone marrow involvement may be irrelevant for survival prediction of EATL patients, since it is present only in a few subjects [83,105]. More recently, a new clinical prognostic model integrating IPI variables with B-symptoms (fever or night sweats) was developed specifically for EATL patients (EATL Prognostic Index [EPI]) [105]. Three risk groups are identified by the EPI score: patients with B-symptoms (high-risk group: median overall survival [OS] 2 months); patients with an IPI score ≥2 and no B-symptoms (intermediate risk group: median OS of 7 months); patients with an IPI score of 0 or 1 and no B-symptoms (low-risk group: median OS 34 months) [105]. The addition of B-symptoms as a parameter in EPI model resulted in improved recognition of the patients with an extremely poor prognosis needing more aggressive therapies; although very promising, it lacks an independent external validation process. Among the limitations of all these scores is the fact that they have been developed from patient series, which were either very heterogeneous or very small, and in an era preceding the use of intensified chemotherapy or autologous hematopoietic stem cell transplantation (except for EPI study, in which 10 patients were treated with allogenic or autologous stem cell transplantation); thus, these models may be useless in selecting modern therapies.
4.1.3. Imaging and Endoscopy
In cases of suspicion, the presence of an overt lymphoma can be ruled out with several diagnostic tools, including upper and lower endoscopy, chest and abdomen CT scans with enteroclysis, magnetic resonance (MR) enterography, PET scans, wireless capsule enteroscopy, and single- and double-balloon enteroscopy (SBE and DBE). In some cases, laparotomy, intraoperative enteroscopy, and full-thickness biopsies can also be necessary to achieve diagnosis. Nevertheless, the exact diagnostic algorithm in EATL is still unclear [106], mainly because there are no studies directly comparing the accuracy of the different diagnostic modalities [107]. In CT scans, which have higher accuracy compared to small bowel enema, EATL appears as a thickened small bowel loop with possible signs of mucosal ulceration. In addition, CT scans can be preferred allowing an extraintestinal visualization. Indeed, beyond the detection of small bowel thickening, it was proposed that mesenteric lymph node cavitation, intussusception, and small-sized spleen (<120 cm3) should raise suspicion for RCD-II or EATL [108]. Although in a prospective cohort of 8 EATL and 30 RCD-II patients 18F-FDG PET demonstrated high sensitivity, with sites affected by the lymphoma (subsequently confirmed histologically) observed in all patients [109], active peristalsis and bowel inflammation may impact its specificity [110]. In the detection of EATL confined to the epithelial layer of the bowel or in the case of multifocality, as well as in assessing the response to treatment, MR enterography has been revealed to be particularly useful [111]. One study showed a sensitivity of 0.88 (95% CI: 0.47, 0.99) and specificity of 0.97 (95% CI: 0.87, 0.99), with an overall high diagnostic accuracy [112].
Diagnostic accuracy can be further improved by endoscopic techniques [113]. Wireless capsule endoscopy enables the exploration of the entire small bowel, assessing the extent of neoplastic involvement and the presence of ulcerations. It is a well-tolerated procedure but it does not allow one to obtain tissue samples and it is contraindicated in cases of suspected strictures [114]; however, it should be the first-line approach to detect complications and to identify patients deserving enteroscopy [115]. DBE, or alternatively SBE, is fundamental in reaching a definite diagnosis of EATL, being the only procedure allowing the collection of biopsy specimens [116].
4.1.4. Pathology
The cornerstone in the diagnosis of EATL remains the histological examination of tumor specimens. EATL type 1 is composed of CD3+, CD4−, CD8−, CD7+, CD5−, and CD56− cells, with a phenotype similar to the majority of normal intestinal intraepithelial T-cell receptor (TCR) α/β+ T lymphocytes [86]. In addition, most of these neoplastic cells express CD30. EATL type 1 originates from cytotoxic IELs (CD8+ αβ intraepithelial T lymphocyte), as demonstrated by the cytotoxic phenotype of tumor cells, which are perforin+, granzyme B+, and TIA-1+ [117,118]. The phenotype mostly consists of medium- to large-sized tumor cells with round or angulated vesicular nuclei, prominent nucleoli, a pale-staining cytoplasm, and an increased mitotic index, which is often associated with moderate to abundant infiltration of eosinophils, histiocytes, and small lymphocytes [94]. The surrounding mucosa shows histologic features of active CeD, such as increased IELs infiltration, crypt hyperplasia, and villous atrophy. EATL type 2, in contrast, is characterized by a monomorphic infiltration of small- to medium-sized T-lymphocytes CD3+, CD4−, CD8+, CD56+, and TCR α/β+ [85,86], and is typically not associated with CeD, suggesting a different pathogenetic mechanism compared to type 1.
It has been speculated that the clonal T-cell population found in the intestinal mucosa of RCD patients could be the precursor of overt EATL [64,119,120]. Indeed, Daum et al. [119] demonstrated that a clonal TCR-γ gene rearrangement could be found in 3/8 duodenal biopsies of patients with EATL, in 2/2 patients with UJI, in 2/3 patients with RCD evolving to EATL, and in 1/6 patient with RCD, whereas clonal rearrangements were present in all resected EATL. Although similar results were obtained by Verbeek et al. [121], these authors also demonstrated that flow cytometric determination of aberrant IELs could predict EATL development in RCD patients more accurately than T-cell clonality analysis with polymerase chain reaction (PCR). The presence of TCR-γ clonal amplification in the duodenal biopsies of RCD-II and UJI patients, as well as in the subsequent tumor specimens [64,119], and the high predictive value of the quantification of aberrant T-cells for the identification of those RCD patients at risk of evolving in EATL [121], support the concept that these two conditions should be considered as “cryptic lymphomas” and should prompt an extensive diagnostic workup to exclude the presence of malignancy; however, the presence of clonal TCR-γ gene rearrangements is not infrequent, even in cases lacking features of RCD-II [122,123]. Hussein et al. demonstrated that TCR-γ clonal amplification was present not only in 67% of RCD-II, but also in 17% of patients with RCD-I and in 6% of CeD patients under GFD [122]. Similar results were obtained by Celli et al. [123], who showed clonal T-cell populations in different groups of patients with intestinal lymphocytosis (RCD-I, RCD-II, CeD and Helicobacter pylori-associated lymphocytosis); therefore, for appropriate diagnosis and classification of RCD, the results of TCR-γ gene rearrangement analyses should be interpreted cautiously, and immunophenotypic, histological and clinical data should also be considered.
Immunohistochemistry and flow cytometry allow the identification of the abnormal phenotype of IELs in RCD and EATL, which distinguish these two conditions from uncomplicated CeD. Abnormal IELs lose the surface markers CD3, CD4, and CD8, while the expression of intracytoplasmic CD3 (CD3ε) is preserved (in >50% of lymphocytes at immunohistochemistry and >20–25% at flow cytometry) [65,66,124]. According to Verbeek et al., flow cytometric analysis seems to be preferrable to immunohistochemistry in the discrimination of RCD-I and RCD-II using the proposed cut-off of 20% of aberrant IELs [121]. Nevertheless, considering that flow cytometry is available only in tertiary referral centers, commonly both CD3/CD8 immunohistochemistry (simple and accurate in paraffin embedded duodenal tissue at low cost [124]) and TCR clonal rearrangement by PCR are used for the evaluation of patients meeting criteria for complicated CeD [125]. Furthermore, the presence of concurrent persistent monoclonality and aberrant immunophenotype (especially if ≥80% CD3ε+ CD8− IELs) is a strong predictor of EATL development, and the continual monitoring of these alterations may be more accurate than snapshot analysis for the evaluation of lymphomagenesis risk [126].
4.1.5. Genetics
Homozygosity for HLA-DQ2 (HLA-DB1*02) and allelic variants of the MYO9B gene region have been found to be strongly associated with the development of EATL [127,128]. EATL types 1 and 2 are distinct in their genetic alterations. While increases in chromosomes 1q and 5q occur frequently in EATL type 1 and rarely in EATL type 2, the opposite is true for increases in MYC oncogene locus—both types of lymphomas share a high prevalence of 9q gains and 16q losses [86,129,130]; however, these genetic alterations are still not routinely detected for diagnosis, prognostic estimation, and treatment selection.
Very recently, mutational events that drive the progression through lymphoma in CeD patients have been identified in a study involving 50 RCD-II and 19 EATL patients [131]. Gain-of-function mutations in the JAK1-STAT3 pathway, together with mutations in negative regulators of NF-kB (TNFAIP3 and TNIP3), were found to be frequently involved in the emergence of malignant lymphocytes.
4.1.6. Treatment
A standard therapeutic approach in patients with EATL is still lacking. Prospective controlled or randomized clinical trials are difficult to perform because of the low incidence of this malignancy, the wide spectrum of its clinical presentation, its complex diagnosis, and malnutrition or poor performance status, which prevent the possibility of active therapies. Considering the difficulties involved in treatment, these patients have a very poor prognosis, with a 5-year survival rate lower than 20% [66,67,68,75,83,89,93,105,125,132]. A large retrospective study involving 37 patients with EATL revealed that the type of CeD (RCD-I vs. RCD-II), serum albumin levels, completion of at least one cycle of chemotherapy, and surprisingly surgical tumor resection were predictors of overall survival (OS) [75].
The primary role of surgery in the management of EATL is local debulking and resection of tumor masses with a high risk of complication (perforation or bleeding) during chemotherapy and radiotherapy [91]. Moreover, considering that frequently a complication is the revealing event of lymphoma, emergency surgery also has an important diagnostic role [89,90,93]. A major concern when patients are treated surgically is the possible delayed start of chemotherapy; however, data from reports on single cases or small series seems to suggest a better prognosis and a minor risk of perforation in patients with complete resection compared to those with residual disease [90,91,93,133,134]. Interestingly, reductive surgery has also been revealed to be an independent predictor of better prognosis [75].
The most widely used treatment for EATL in clinical practice is standard-dose chemotherapy, although with disappointing results in terms of prognosis (estimated median OS of around 7.5 months), regardless of the stage of the lymphoma at onset [75,89,90,93,135,136,137]. Chemotherapy cannot even be started in more than half of the patients because of their compromised performance status, mainly due to pre-existing unresponsive CeD (with consequent malnutrition), lymphoma dissemination, and in most cases advanced age [91]. Moreover, of those in whom chemotherapy can be started, a further 50% are not able to complete the scheme because of complications, disease relapse, or iatrogenic toxicity [89]. The overall response rate of patients who are able to complete the chemotherapy course is in the range of 40% to 60%, with a slightly higher percentage of responses recorded for early compared to advanced stages [83,89,90,93]. No more than 40% of patients achieve a complete response, with a mean duration of remission in those patients of nearly 6 months [83,89,90,93,136,137]. Only a study from Germany, prospectively evaluating 23 patients with intestinal lymphoma, was able to demonstrate a mean progression-free survival of 28 months (range, 17–39 months) in patients achieving complete remission after chemotherapy and a 2-year survival rate of 28% (95% CI 13–43%) [90]. The cumulative 2-year survival was clearly higher, although not statistically significantly different, in early-stage compared to advanced-stage patients (38% (95% CI 17–59%) vs. 14% (95% CI 0–32%); p = 0.13) [90].
Although CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the most widely used chemotherapy regimen, it provides a 5-year OS of only 9–20% [89,93,135,136,137]. In the large study by Delabie et al. [83], a median OS of 10 months (5-year OS 20%) was reported using a combination chemotherapy containing anthracycline (mainly CHOP; 27/52 patients). Many other therapeutic schemes have been tested, such as BACP (bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone) [135], ProMACE-MOPP (prednisone, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, and procarbazine) [135], VAMP (vincristine, doxorubicin, high-dose methotrexate, and prednisolone) [89], PEACE-BOM (prednisolone, etoposide, doxorubicin, cyclophosphamide–bleomycin, vincristine, and methotrexate) [89], and CHOEP (CHOP plus etoposide) [136]. In all of these regimens, 2–4 cornerstone drugs, with proven efficacy in lymphoproliferative disease, are present; however, the results are similarly disappointing, with heavier toxicities if the dose intensity is increased (BACOP) or other drugs are included (ProMACE-MOPP, PEACE-BOM, and CHOEP) [91].
The poor survival outcomes achievable with conventional chemotherapy have paved the way for the evaluation of other treatments, such as high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Unfortunately, this therapeutic option is not available for the majority of patients, who are characterized by poor general conditions, unresponsiveness to debulking therapy, iatrogenic toxicity, or early relapse [91]. Available data regarding ASCT as a treatment for EATL patients are summarized in Table 2.
As far as other novel treatment options are considered, very limited data are currently available. Alemtuzumab, a monoclonal antibody targeting CD52, has been investigated as an adjunctive drug to the CHOP regimen in peripheral T-cell lymphoma [138,139,140]; however, only case reports of EATL patients treated with anti-CD52 have been reported, with conflicting results [141,142,143]. Cladribine (2-CDA), a synthetic purine nucleoside with cytotoxic effects, has been proven to be promising. Furthermore, 2-CDA has been tested more extensively in RCD-II, in which it was demonstrated to improve symptoms and histology, prolong OS, and reduce the probability of EATL development [144,145]. No information is available for overt EATL, except for patients with unresponsive lymphoma treated with 2-CDA in the series by Raderer et al. [133]. Romidepsin, a histone deacetylase inhibitor, was administered as a single agent in a phase II trial on different types of T-cell lymphoma [146]. The single patient with EATL included in this study achieved a complete response, stable 8 months after treatment. Another promising target is represented by IL-15, which has a central role in IEL’s antiapoptotic signaling [74]. A fully humanized IL-15-specific antibody (AMG714) targeting this crucial step of lymphomagenesis has been developed and studies on its activity are ongoing. Finally, brentuximab vedotin, which targets CD30, might be promising when added to conventional chemotherapy and has been suggested as an upfront treatment in EATL [75,147,148].
Table 2Studies investigating treatment with high-dose chemotherapy followed by stem cell transplantation.
| Study | Year | Design | No. EATL | No. ASCT | Debulking Chemotherapy | Conditioning Treatment | Response and Survival |
|---|---|---|---|---|---|---|---|
| Gale et al. [89] | 2000 | Retrospective | 31 | 2 | PEACE-BOM | BEAM | 1 CR; disease-free 64 months after diagnosis |
| Blystad et al. [149] | 2001 | Retrospective | 2 (total 40 NHL) | 2 | CHOP, MACOP-B | BEAM (or BEAM-like) + TBI | NR |
| Okuda et al. [150] | 2002 | Retrospective | 1 | 1 | CHOP, ESHAP | MCVC | Relapse after 8 months, death 17 months after ASCT |
| Chonabayashi et al. [151] | 2007 | Retrospective | 1 | 1 | EPOCH-ICE | MPH-FARA + TBI | Alive at 11 months |
| Jantunen et al. [152] | 2003 | Retrospective | 5 | 5 | CHOP | BEAM (or BEAM-like) | OS: 2 months. 2 pts died from TRC; 2 progressed early (0 and 1 month); 1 relapsed and died at 14 months |
| Rongey et al. [153] | 2006 | Retrospective | 1 | 1 | CHOP | BEAM | Alive and in remission at 18 months |
| Bishton et al. [101] | 2007 | Retrospective | 6 | 6 | IVE + HDMTX | BEAM | 5 CR |
| Al-Toma et al. [154] | 2007 | Retrospective | 4 | 4 | CHOP | BEAM or MPH-FARA | 1 in ongoing CR after 32 months |
| Nava et al. [155] | 2007 | Retrospective | 1 | 1 | CHOEP | BEAM | No evidence of residual disease 70 days after ASCT |
| Reimer et al. [156] | 2009 | Prospective | 5 (total 83 NHL) | 5 | CHOP + DACMEMP (or PAEM) | TBI + HDCTX | NR |
| Sieniawski et al. [137] | 2010 | Prospective | 54 | 14 | CHOP—IVE/MTX | TBI + HDMPH or BEAM | Remission rate: 69% |
| Prochazka et al. [157] | 2011 | Retrospective | 2 (total 29 NHL) | 2 | PACEB-IVAM-HAM | BEAM | 1 CR; survival not reported |
| Nijeboer et al. [158] | 2015 | Retrospective | 61 | 8 † | Different regimens | MPH-FARA or CTX-FARA | Complete response: 39% |
† 7 underwent autologous stem cell transplantation and 1 allogeneic stem cell transplantation. Abbreviations: PEACE-BOM, prednisolone, etoposide, doxorubicin, cyclophosphamide–bleomycin, vincristine, and methotrexate; BEAM, carmustine, etoposide, cytarabine, and melphalan; EPOCH-ICE, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin–ifosfamide, etoposide, and carboplatin; MPH-FARA, melphalan + fludarabine; TBI, total body irradiation; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; MACOP-B, methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin; NR, not reported; ESHAP, etoposide, methylprednisolone, cytarabine, and cisplatin; MCVC, ranimustine, carboplatin, etoposide, and cyclophosphamide; IVE, ifosfamide, etoposide, and epirubicin; HDMTX, high-dose methotrexate; TRC, transplant-related complications; CHOEP, cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide; PACEB, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, and prednisone; IVAM, ifosfamide, etoposide, cytosine arabinoside, and methotrexate; HAM, cytarabine and mitoxantrone; HDCTX, high-dose cyclophosphamide; DACMEMP, dexamethasone, carmustine, melphalan, etoposide, and cytarabine; PAEM, etoposide, methylprednisolone, cytarabine, and cisplatin; HDMPH, high-dose melphalan; CTX-FARA, fludarabine, cyclophosphamide.
4.2. Other Lymphomas
Several reports demonstrated that CeD patients are at increased risk of developing a wide range of lymphoproliferative diseases, including non-intestinal T-cell lymphomas or B-cell lymphomas. From a public health perspective, considering that EATL is a rare malignancy, this association is more interesting. Indeed, the majority of lymphomas developing in these patients are of the non-EATL type [43,44,48].
In the case–control study by Catassi et al., the risk of NHL as a whole was increased in CeD, although only 1 out of 6 cases of lymphoma was an EATL, while the risk was particularly increased for NHL of T-cell origin and of gastrointestinal localization [43]. Green et al. [29] evaluated a cohort of 381 CeD patients, finding a significantly increased risk of NHL (SMR = 9.1, 95% CI 4.7–13). Among the 9 patients with NHL, three had B-cell lymphomas, four had T-cell lymphomas, and two had large-cell lymphomas that were incompletely classified; five lymphomas were localized in the gastrointestinal tract, three involved lymph nodes, and one involved the skin (mycosis fungoides). EATL was present in only one patient. A subsequent population-based prospective study confirmed that several lymphoma types may develop in CeD patients [44]. In this report, EATL comprised only one-third of NHL and only half of the T-cell lymphomas (SIR for B-cell NHL overall = 2.2, 95% CI 1.3–3.6), while an increased risk of B and T cell lymphomas outside the gastrointestinal tract was also demonstrated (SIR = 3.6, 95% CI 2.3–5.2) [44]. The high risk of B- and T-cell NHL in CeD patients has also been confirmed in more recent data and metanalyses [12,159]; however, not all of the studies are concordant. Recently, van Gils et al., while reporting an increased risk of T-cell NHL in their case–control study (RR = 35.8, 95% CI 27.1–47.4), did not confirm the increased risk for B-cell NHL (RR = 1.4, 95% CI 0.9–2.3) [49].
Considering the relevance of B lymphocytes in the pathogenesis of CeD, the relation between B-cell NHL and CeD, although not completely understood, is not surprising [160]. In particular, the association with CeD with diffuse large B-cell lymphoma has been repetitively reported [47,54,161]. It seems that the link between CeD and lymphoma development is to be found in the chronic inflammation that characterizes these patients. In fact, patients with villous atrophy have a statistically significant higher risk of lymphoproliferative diseases compared to patients with crypt hyperplasia and an increase in intraepithelial lymphocytes [45]. In addition, patients in whom intestinal inflammation does not decrease after GFD (persistent villous atrophy after 6 months of GFD) are at increased risk of lymphoproliferative malignancies compared to those with mucosal healing [55]. Beyond NHL, Hodgkin lymphoma (HL) risk has also been reported as being 2- to 5-fold higher in CeD patients compared to the general population [12,23,31,45].
The risk of developing lymphomas varies according to the small intestinal histopathology [45]. In patients with CeD (Marsh 3), not only was an increased risk of T-cell NHL (HR = 48, 95% CI 15.8–145) confirmed, but associations with and B-cell NHL (HR = 1.9, 95% CI 1.32–2.73) and Hodgkin lymphoma (HR = 2.73, 95% CI 1.26–5.93) were also demonstrated. On the contrary, in patients with Marsh 1 and 2 histology, an association with B-cell NHL (HR = 2.05, 95% CI 1.32–3.18) but not with T-cell NHL (1.36, 95% CI 0.16–11.8) was found [45].
In general, patients with T-cell lymphomas have a poorer prognosis compared to those with B-cell lymphomas [90,159,162]. In a cohort of 63 patients diagnosed with both CeD and lymphoma (gastrointestinal tract in 37% of cases, lymph nodes in 33% of cases, extranodal in 29% of cases), the shortest median survival was demonstrated in patients with T-cell lymphomas other than EATL (10.9 months), while the survival of B-cell lymphoma patients was longer [162]. Similarly, another study found that the mean survival for patients with EATL or non-EATL T-cell NHL was shorter (mean survival periods of 3.2 ± 0.9 years and 2.8 ± 1.2 years, respectively) compared with patients with B-cell NHL or chronic lymphocytic leukemia (mean survival 15.5 ± 2.3 years and 18.9 ± 1.1 years, respectively, p = 0.03) [159]. This differential prognosis was also confirmed in a cohort including only intestinal lymphomas [90]: the two-year cumulative survival in patients with B-cell NHL was 94% (95% CI 82–100%) compared to 28% (95% CI 13–43%) in patients with T-cell NHL; cumulative survival rates after two years were similar in EATL and T-cell (non-EATL) patients (28% (95% CI 11.2–44.8%) vs. 29% (95% CI 0–62.5%)) [90].
In contrast, in patients with lymphoproliferative malignancies, the coexistence of CeD does not influence survival. Despite these patients showing an increased risk of death compared to patients with only lymphoproliferative malignancies (adjusted HR = 1.23; 95% CI 1.02–1.48), this greater mortality is only seen in the first year after malignancy diagnosis (adjusted HR = 1.76) and is due to the predominance of T-cell NHL in CeD individuals [163].
5. Celiac Disease and Small Bowel Carcinoma
Small bowel carcinoma (SBC) is a remarkably rare neoplasm, which although occurring sporadically in the majority of cases, CeD is recognized as a predisposing condition for this illness [164]. SBC arising with CeD (CeD-SBC) represents a peculiar entity, with several differences in clinical, histopathological, and molecular features compared to sporadic or complicating Crohn’s disease tumor (CrD-SBC).
5.1. Epidemiology
SBC are rare malignancies, which although accounting for less than 5% of gastrointestinal cancers, represent around 40% of small bowel neoplasms [165]. The estimated incidence of SBC varies between 3250 and 5300 new cases/year [164,166,167].
The studies investigating the risk of SBC in CeD patients are depicted in Table 3. The first investigations reported a very high relative risk of SBC (19 observed vs. 0.23 expected cases; RR = 82.6) [17], which subsequently has been reduced [23,24,26,29,56,168,169]. A recent Swedish study involving more than 48,000 patients with CeD demonstrated a low absolute risk of SBC, which was significantly increased compared to people without the disease (HR = 3.05, 95% CI 1.86–4.99) [169]. It is thought that SBC develops through the adenoma–carcinoma sequence [170]. Supporting this hypothesis, Emilsson et al. in their study, beyond demonstrating an increased risk of SBC in CeD patients, found a 5.73-fold increased risk of small bowel adenoma (95% CI 3.70–8.88) [169].
The median age at diagnosis of SBC in CeD individuals has been estimated to range from 53 to 62 years, which is lower than that of patients with sporadic SBC (56–72 years) [52,171,172,173,174]. The incidence of SBC cases is double in African Americans (10.2–14.1 per 1,000,000) compared to Caucasians (4.5–7.2 per 1,000,000) [175,176]. The only study investigating ethnic differences in SBC development with CeD reported this tumor only in Caucasians [52].
Table 3Studies evaluating the risk of small bowel carcinoma (SBC) in patients with CeD.
| Authors | Year | Country | Design | Size of the CeD Cohort | No. of SBC | Results |
|---|---|---|---|---|---|---|
| Swinson et al. [17] | 1983 | United Kingdom | Retrospective | 235 | 19 | Included only CeD patients with a diagnosed malignancy. |
| Cottone et al. [50] | 1999 | Italy | Retrospective | 216 | 1 duodenal adenocarcinoma | NR |
| Askling et al. [23] | 2002 | Sweden | Retrospective | Inpatient diagnosed with: CeD 11,019; DH 1354; both diagnoses 226 | 8 cases in CeD cohort (6 adenocarcinomas, 1 mixed carcinoid-adenocarcinoma and 1 unclassified); no cases in DH cohort; 1 case in CeD + DH cohort | Increased risk in CeD cohort: SIR = 10 (95% CI 4.4–20) |
| Green et al. [29] | 2003 | USA | Prospective | 381 | 3 | Cancer diagnosed before or simultaneously CeD |
| Card et al. [24] | 2004 | United Kingdom | Prospective | 865 | 1 | Increased risk in the peridiagnostic period (≤2 years after diagnosis of CeD): |
| West et al. [25] | 2004 | United Kingdom | Retrospective | 4732 (23,620 controls) | 29 † | Increased risk of gastrointestinal cancers: |
| Silano et al. [26] | 2007 | Italy | Prospective | 1968 | 5 | Cancer diagnosis preceded diagnosis of CeD. |
| Anderson et al. [30] | 2007 | United Kingdom | Retrospective | 2079 (490 EMA+; 1133 AGA+; 456 AGA+ and EMA-) | 3 | Despite the increased SIR, no significant association: |
| Lohi et al. [32] | 2009 | Finland | Retrospective | 6849 (202 tTG positive; 73 EMA positive) | 121 † | 115 cases in tTG-negative, 6 cases in tTG-positive, 0 cases in EMA-positive. |
| Grainge et al. [27] | 2012 | United Kingdom | Retrospective | 435 | 1 | Expected cases: 0.09; SIR = 11.1 (95% CI 0.28–61.6) |
| Elfstrom et al. [168] | 2012 | Sweden | Prospective | 28,882 Marsh score 3 |
25 in Marsh 3 |
After 1 year of follow-up after CeD diagnosis: |
| Ilus et al. [56] | 2014 | Finland | Retrospective | 32,439 | 27 | Increased risk of SBC |
| van Gils et al. [49] | 2018 | Netherlands | Retrospective case–control | 261/301,337 cases |
136 with CeD |
Increased risk of SBC: RR = 11.9 (95% CI 8.2–17.2) |
| Caio et al. [177] | 2019 | Italy | Retrospective | 770 | 5 | NR |
| Emilsson et al. [169] | 2020 | Sweden | Retrospective | 48,119 CeD patients and 239,249 controls | 74 | Beginning 1 year after diagnosis of CeD, 29 CeD patients (0.06%) and 45 controls (0.02%) developed SBC. |
† Gastrointestinal cancers, not otherwise specified. Abbreviations: AGA, anti-gliadin antibody; aHR, adjusted hazard ratio; CeD, celiac disease; DH, dermatitis herpetiformis; EMA, endomysial antibody; HR, hazard ratio; NR, not reported; RR, relative risk; SBC, small bowel carcinoma; SIR, standardized incidence rate; SMR, standardized morbidity ratio; tTG, tissue transglutaminase.
5.2. Histopathology, Molecular Biology and Pathogenesis
From a histopathological point of view, SBC as a whole are predominantly (52–60%) adenocarcinomas (i.e., of glandular type histology) [178]. This is true also in CeD, where 54% of SBC show a glandular histotype and 15% of cases are instead medullary-type cancers [178]. The majority of CeD-SBC, similarly to sporadic SBC, express intestinal phenotype markers such as the caudal-related homeobox transcription factor (CDX)2, the goblet cell marker mucin (MUC)2, cytokeratin (CK)20, or the small bowel brush border marker CD10 [178].
A high density of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs) has been demonstrated in CeD-SBC, while lower levels of TILs have been found in sporadic SBC or Crohn’s-disease-associated SBC (CrD-SBC) [171]. This finding suggests a greater host immune response against tumors in CeD-SBC compared to other forms of small bowel tumors, and may contribute to explaining the better prognosis of these patients [52,172,177]. In addition, MSI also induced the antitumor response, which has been claimed as explaining the better survival of CeD-SBC. Indeed MSI, which is a consequence of defective DNA mismatch repair, is found at a higher prevalence rate in CeD-SBC (65–73%) compared to CrD-SBC (0–16%) and sporadic SBC (9–35%) [171,172,173,179,180,181,182,183]. Recently, two main subtypes of CeD-SBC have been described, the first with MSI and high TILs, and the second showing prominent TGF-β activation [184].
Some genetic alterations have been reported in sporadic SBC. In particular, TP53 (58%), KRAS (53.6%), APC (26.8%), SMAD4 (17.4%), and PIK3CA (16%) are commonly mutated [185,186]. TP53 alterations are crucial in small bowel carcinogenesis, as demonstrated by TP53 gene product overexpression in about half of the cases of both CeD-SBC and CrD-SBC [171,179,187]. KRAS mutations, an early event in the adenoma–carcinoma sequence of colorectal cancer, have been found in 31% of CeD-SBC and 12–43% of CrD-SBC [171,179,183,187,188]. While nonsense APC mutations have not been reported, in CeD-SBC promoter hypermethylation is frequently present (in 73% of cases) [173]. The aberrant nuclear expression of β-catenin observed in most CeD-SBC and sporadic SBC cases suggests an involvement of the Wnt/β-catenin pathway [178,189,190]. In addition, several potentially druggable genetic alterations, such as HER2 mutations or amplification, have been identified in the majority of SBC [171,185,191].
Since non-familial SBC is a very rare tumor, its pathogenesis is largely unknown. Differing from CrD-SBC and sporadic SBC [178,187,192,193], dysplastic lesions have very rarely been found in CeD-SBC [170,174,178]. Moreover, no dysplasia distant from SBC has been identified in CeD patients [170,178,179,180,183,187]. An inflammation–hyperplasia–dysplasia–carcinoma sequence has been hypothesized to explain the pathogenesis of CeD-SBC [164], although additional studies are necessary to confirm this model of carcinogenesis.
5.3. Clinical Presentation and Diagnosis
The duration of CeD prior to SBC diagnosis varies between 1.4 and 17 years [52,171,173,174]. Nevertheless, few cases of SBC diagnosed coincidentally with the underlying enteropathy have been reported [171,173,174].
SBC in CeD is localized preferentially in the jejunum and duodenum. The clinical manifestations of SBC at onset are extremely variable. Frequently, bleeding is present, either occult with anemia and positive fecal occult blood test or overt with melena or hematemesis. Abdominal pain and unexplained weight loss are common. Similarly to EATL, SBC is also frequently complicated, with intestinal obstruction, intussusception, and perforation (in case of locally advanced lesions); consequently, diagnosis occurs during emergency surgery [194]. In patients with an established diagnosis of CeD, all of these symptoms apart from isolated anemia should raise suspicion for SBC and should lead to the initiation of the diagnostic workup. These symptoms are shared with other neoplastic complications of CeD, but some characteristics may be peculiar. EATL should be ruled out firstly when the above-reported symptoms are present, along with diarrhea and fever [91]; UJI has to be considered in the presence of diarrhea and intestinal obstruction [2].
Once SBC is suspected, all CeD patients should undergo an upper gastrointestinal endoscopy that allows the lesion to be found and sampled if located proximally to the ligament of Treitz. Nevertheless, since the majority of SBC cases are located in the jejunum, additional diagnostic tests, such as DBE/SBE, CT, and MRI enterography, are usually needed [195,196]. Additionally, small bowel capsule endoscopy has been reported to be useful in the diagnosis of SBC [196], although some concerns have to be considered in its use, including the impossibility to take biopsies for histologic diagnosis and the risks of capsule retention and of missing the tumor, particularly in cases at proximal sites [164].
5.4. Prognosis and Treatment
SBC exhibits a worse prognosis compared to colon adenocarcinoma, which is frequently compared due to its rarity [197]. In a retrospective study involving 217 patients with SBC, the authors demonstrated a median OS of 20 months (95% CI 16–24) and a 5-year OS of 26% [198]. Very similar results (median OS of 20.1 months and 5-year OS rate of 26%) were subsequently reported among 491 SBC, which were mostly sporadic [199]. The asymptomatic nature of the tumor until the late disease is among the primary reasons for this bad outcome, with tumors already metastatic at diagnosis in several cases. Recently, Aparicio et al. [200] reported the survival of a large cohort of patients with SBC (n = 347, 6 of them with CD), differentiating the outcome according to the tumor stage; in patients with locally resected cancer the 5-year OS was 65.9%, while those with metastatic SBC the median OS was 12.7 months (2.2 months in patients receiving BSC only and 14.6 months for patients treated with palliative chemotherapy). In addition to the tumor stage at diagnosis, poor differentiation, positive margins, duodenal localization, male gender, black ethnicity, and older age are also associated with worse outcomes [166,199,200,201].
In addition, the OS of SBC significantly differs according to the predisposing chronic immune-mediated intestinal disorder. The predisposing condition is a stage-independent prognostic factor in patients undergoing surgery [171], with CeD-SBC having a significantly longer survival compared to CrD-SBC (5-year survival rate 64.2–83% vs. 26–38%) and sporadic SBC patients [171,172,177,179,183,200,202,203,204].
Some favorable histological and molecular factors may contribute to explaining the better prognosis of CeD-SBC. Glandular and medullary tumors, the predominant histotype of CeD-SBC, are associated with longer OS [178,204,205]. CeD-SBC is typically associated with high TIL density and MSI-high status [171,172,173], and both factors have been associated with better outcomes [171,178,204,205]. A recent study demonstrated an increased proportion of PD-L1-positive cases in both CeD-SBC and CrD-SBC as compared to sporadic SBC [204]. PD-L1+ tumors showed higher TILs and PD-1+ immune cell density, were more frequently MSI-high cases, and exhibited better outcomes compared to PD-L1-negative cases.
Currently, treatment recommendations in CeD-SBC patients are borrowed from sporadic SBC [206]. Surgical resection with lymphadenectomy is the only recommended curative treatment for SBC without distant metastases and is necessary for long-term survival [194]. While it could be sufficient at stage I, resection should be followed by adjuvant chemotherapy (e.g., FOLFOX, LV5FU2 or fluoropyrimidine) at stage II or III [206]. At stage IV, the only recommended treatment is systemic chemotherapy [206]. Tumor molecular analysis may provide the rationale for the use of targeted therapies. For instance, in several case reports of metastatic SBC, the presence of KRAS wild-type has been demonstrated to predict responsiveness to antiepidermal growth factor receptor monoclonal antibodies (cetuximab and panitumumab) alone or combined with chemotherapy [207,208]. In contrast, nine patients with metastatic SBC KRAS wild-type showed no response to panitumumab in a phase 2 clinical trial (7 showing progression and 2 showing stable disease) [209]. Although rare in CeD-SBC, HER-2 amplification has been investigated as a potential therapeutic target [191,210]. In addition, immunotherapy, and in particular PD-1/PD-L1 blockade, could be considered in advanced SBC with MSI (i.e., CeD-SBC [204]), as mismatch repair deficiency has been demonstrated to predict response to anti-PD-1 antibodies [211].
6. Celiac Disease and Other Malignancies
Whether CeD patients are at higher risk of developing malignancies other than lymphomas and SBC is still under debate. A large body of evidence regarding the epidemiological link between CeD and a wide spectrum of malignancies has been produced (Table 4).
Studies investigating the association between CeD and the risk of developing gastrointestinal (GI) cancers reported conflicting results [11,24,25,27,28,168]. West et al. [25] found an increased risk of any GI cancer compared to the general population, both in the year after diagnosis of CeD (adjusted HR = 3.31, 95% CI 1.40–7.83) and beyond this period, although in the latter cases the magnitude of risk was lower (adjusted HR = 1.65, 95% CI 0.99–2.76). Similarly, in the Lebwohl et al. study, in which a very large number of CeD patients were included, the risk of GI cancer was increased as compared to the general population (HR = 1.34, 95% CI 1.24–1.45), although it became non-significant excluding the first year of follow-up (HR = 1.05, 95% CI 0.96–1.15) [28]. Indeed, the risk of GI cancers seems to decrease over time [24,168]. A large Swedish cohort study demonstrated that in the first year after duodenal biopsy, CeD patients showed a 5.95-fold increase in the probability of being diagnosed with GI cancer, whereas this risk progressively decreased and become non-significant thereafter [168]. Some of the early risks may be due to confounders, as symptoms of GI cancer might cause investigations leading to a diagnosis of CeD. The progressively decreasing risk was demonstrated not only for GI cancer as a whole, but also for specific types of tumors (esophagus, small intestine, colon and rectum, liver, pancreas) [168]. In particular, while the association with colon cancer was particularly high in the first year (HR = 7.94, 95% CI 5.21–12.1), thereafter this risk decreased and returned to a comparable level to that of the general population [168]. Evidence on the risk of colon cancer in patients with CeD is extensive, albeit not conclusive. Two large population-based cohort studies demonstrated an increased risk of colon cancer but did not provide information regarding the length of follow-up [23,56]. On the contrary, a case–control study performed in the United States found no association with premalignant lesions (colonic adenomas) [212], while several other papers also reported no association [11,26,27,28,29,31,213]. Finally, a multicenter Italian study reported that CeD patients have a significantly lower risk of developing colon carcinoma as compared to the general population (SIR = 0.29, 95% CI 0.07–0.45) [214]. With respect to other GI cancers, conflicting results about the risk in CeD patients have been reported for esophagus [23,27,29,31,49,56,168,213], stomach [11,23,26,28,31,56,168], pancreas [23,28,31,56,168,213], and liver [23,28,56,168] cancers (Table 4). In the meta-analysis performed by Han et al. [33], CeD was associated with a 60% increase in GI cancer risk (pooled OR = 1.60, 95% CI 1.39–1.84), and among single types of tumors, an increased risk was found only for esophageal cancer (pooled OR = 3.72, 95% CI 1.90–7.28).
In their study, Askling et al. reported a significantly decreased risk of breast cancer in women with CeD [23]. This finding was confirmed in many other population-based studies [25,26,31,215], including the one by Ilus et al., encompassing more than 20,000 Finnish CeD females [56]. Very recently, this negative association was also demonstrated in a large Swedish population-based study among 29,381 CeD females (HR = 0.83, 95% CI 0.74–0.92) [28]. The reasons for this repetitively reported protective effect of CeD toward breast cancer are not completely clear, although lower BMI and consequently lower estrogen exposure may play a role [216,217]. Moreover, it has been noted that starvation during adolescence and a low growth rate in childhood, both features that can occur in CeD, protect against breast cancer [218,219,220]. Moreover, female patients with CeD showed a significantly decreased risk of endometrial cancer (HR = 0.60; 95% CI 0.41–0.86), while no association was found with ovary tumors (HR = 0.89, 95% CI 0.59–1.34) [215]. Regarding the risk of prostate cancer, one of the most frequent tumors in males, the literature is concordant—CeD patients have a similar risk as the general population [23,25,31,56,221].
Additionally, the associations between CeD and thyroid cancers have been investigated, with conflicting results. In 2006, Kent et al. found a significantly increased risk of thyroid papillary carcinoma in a US cohort of 606 CeD patients, with a very high SIR (22.52, 95% CI 14.90–34.04) [222]. These results were later confirmed in an Italian multicenter cohort study, although the risk was lower and not statistically significant (SIR = 2.55, 95% CI 0.83–5.55) [223]. Other authors came to opposite conclusions. Askling et al. found only 1 case of thyroid cancer among 11.019 CeD patients (SIR = 0.6, 95% CI 0.0–3.3) [23], while 7 cases out of 29,074 CeD patients were detected by Ludvigsson et al. (HR = 0.6, 95% CI 0.3–1.3) [224].
It is likely that there is no significant association between the presence of CeD and melanoma development. While a study reported a 5-fold increase in the risk of melanoma [29], two large population-based study reported no association [23,225]. In particular, a study performed on 29,000 Swedish subjects demonstrated a risk profile similar to that of the general population [225].
Table 4Studies investigating the risk of developing several types of malignances in CeD patients.
| Study | Year | Country | Study Design | CeD Cases—n | Cancer Cases—n | Main Findings |
|---|---|---|---|---|---|---|
| Colon and rectum cancer | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 26 | Compared to the general population: |
| Green et al. [29] | 2003 | USA | Hospital-based prospective cohort study | 381 | 3 | No increased risk of colon cancer: SIR = 0.8 (95% CI 0.1–7.2) |
| Viljamaa et al. [11] | 2006 | Finland | Population-based prospective cohort study | 781 | 4 | No increased risk of colon and rectum cancer: SIR = 1.1 (95% CI 0.3–2.8) |
| Silano et al. [26] | 2007 | Italy | Hospital-based prospective cohort study | 1968 | 7 | No increased risk of colon cancer: SIR = 1.1 (95% CI 0.68–1.56) |
| Goldacre et al. [31] | 2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 11 colon cancers |
No increased risk (excluding cases occurred within the first year after CeD diagnosis): |
| Lebwohl et al. [212] | 2010 | USA | Retrospective cohort study | 180 | 23 | No significant increased risk of colorectal adenomas: OR = 0.75 (95% CI 0.41–1.34) |
| Landgren et al. [213] | 2011 | USA | Hospital-based retrospective cohort study | NR | 11 colon cancers |
No increased risk: |
| Grainge et al. [27] | 2012 | United Kingdom | Population-based retrospective cohort study | 435 | 6 | No increased risk of colorectal cancer: SIR = 1.17 (95% CI0.43–2.54) |
| Elfstrom et al. [168] | 2012 | Sweden | Population-based retrospective cohort study | 28,989 | First year of follow-up: |
First year of follow-up: |
| Pereyra et al. [226] | 2013 | Argentina | Multicenter retrospective case–control study | 118 | 24 polyps |
No increased risk compared to controls. |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 133 colon cancers |
Increased risk of colon cancer: SIR = 1.35 (95% CI 1.13–1.58) |
| Volta et al. [214] | 2014 | Italy | Multicenter retrospective cohort study | 1757 | 6 | Decreased risk of colon carcinoma compared to the general population: SIR = 0.29 (95% CI 0.07–0.45) |
| Lebwohl et al. [28] | 2021 | Sweden | Population-based cohort study | 47,241 | 448 | No increased risk of colorectal cancer: HR = 1.06 (95% CI 0.96–1.18) |
| Esophagus | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 6 | Increased risk of esophageal cancer: SIR = 4.2 (95% CI 1.6–9.2) |
| Green et al. [29] | 2003 | USA | Hospital-based prospective cohort study | 381 | 3 | Significantly increased risk of esophageal cancer: SIR = 12 (95% CI 6.5–21) |
| Goldacre et al. [31] | 2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 5 | No increased risk (excluding cases occurred within the first year after CeD diagnosis): adjusted Rate Ratio = 2.58 (95% CI 0.84–6.07) |
| Landgren et al. [213] | 2011 | USA | Hospital-based retrospective cohort study | NR | 11 | Significantly increased risk: adjusted RR = 1.86 (95% CI 1.03–3.36) |
| Grainge et al. [27] | 2012 | United Kingdom | Population-based retrospective cohort study | 435 | 3 | No increased risk: SIR = 2.86 (95% CI 0.59–8.37) |
| Elfstrom et al. [168] | 2012 | Sweden | Population-based retrospective cohort study | 28,989 | First year of follow-up: 4 |
First year of follow-up: HR = 6.17 (95% CI 1.52–25.0) |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 22 | No increased risk: SIR = 1.47 (95% CI 0.92–2.23) |
| van Gils et al. [49] | 2018 | Netherlands | Population-based case–control study | 28 CeD patients with esophageal cancer | 28,070 patients with esophageal cancer and without CeD | No increased risk of esophageal adenocarcinoma: |
| Stomach | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 6 | No increased risk: SIR = 0.9 (95% CI 0.3–2.0) |
| Viljamaa et al. [11] | 2006 | Finland | Population-based prospective cohort study | 781 | 2 | No increased risk: SIR = 1.2 (95% CI 0.2–4.5) |
| Silano et al. [26] | 2007 | Italy | Hospital-based prospective cohort study | 1968 | 3 | Slightly increased risk: SIR = 3.0 (95% CI 1.3–4.9) |
| Goldacre et al. [31] | 2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 8 | No increased risk (excluding cases occurred within the first year after CeD diagnosis): adjusted Rate Ratio = 1.83 (95% CI 0.79–3.62) |
| Elfstrom et al. [168] | 2012 | Sweden | Population-based retrospective cohort study | 28,989 | First year of follow-up: 7 |
First year of follow-up: HR = 1.67 (95% CI 0.66–4.22) |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 37 | No increased risk: SIR = 0.90 (95% CI 0.63–1.23) |
| Lebwohl et al. [28] | 2021 | Sweden | Population-based cohort study | 47,241 | 65 | No increased risk: HR = 1.21 (95% CI 0.91–1.61) |
| Pancreas | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 9 | No statistically significant increase in risk: SIR = 1.0 (95% CI 0.9–3.6) |
| Goldacre et al. [31] | 2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 2 | No increased risk (excluding cases occurred within the first year after CeD diagnosis): adjusted Rate Ratio = 0.57 (95% CI 0.07–2.05) |
| Landgren et al. [213] | 2011 | USA | Hospital-based retrospective cohort study | NR | 13 | Significantly increased risk: aRR = 2.27 (95% CI 1.22–4.23) |
| Elfstrom et al. [168] | 2012 | Sweden | Population-based retrospective cohort study | 28,989 | First year of follow-up: 26 |
First year of follow-up: HR = 10.7 (95% CI 5.77–19.7) |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 45 | Significantly decreased risk: SIR = 0.73 (95% CI 0.53–0.97). The risk was decreased particularly in females (SIR = 0.59, 95% CI 0.36–0.89) |
| Lebwohl et al. [28] | 2021 | Sweden | Population-based cohort study | 47,241 | 152 | Significantly increased risk: HR = 2.30 (95% CI 1.87–2.82). |
| Liver | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 11 | Increased risk: SIR = 2.7 (95% CI 1.3–4.7) |
| Elfstrom et al. [168] | 2012 | Sweden | Population-based retrospective cohort study | 28,989 | First year of follow-up: 15 |
First year of follow-up: HR = 6.05 (95% CI 2.96–12.4) |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 24 | No increased risk: SIR = 0.98 (0.63–1.45) |
| Lebwohl et al. [28] | 2021 | Sweden | Population-based cohort study | 47,241 | 115 | Significantly increased risk: HR = 1.80 (95% CI 1.44–2.25). |
| Breast | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 7 | Significantly decreased risk: SIR = 0.3 (95% CI 0.1–0.5) |
| Green et al. [29] | 2003 | USA | Hospital-based prospective cohort study | 381 | 5 | No increased risk: SIR = 1.2 (95% CI 0.2–7.2) |
| Card et al. [24] | 2004 | United Kingdom | Population-based prospective cohort study | 4732 | 5 | No increased risk: |
| West et al. [25] | 2004 | United Kingdom | Population-based cohort study | 4732 | 8 | Significantly decreased risk: adjusted HR = 0.31 (95% CI 0.15–0.63). |
| Viljamaa et al. [11] | 2006 | Finland | Population-based prospective cohort study | 781 | 9 | No significant increased risk: SIR = 0.9 (95% CI 0.4–1.7) |
| Silano et al. [26] | 2007 | Italy | Hospital-based prospective cohort study | 1968 | 3 | Significantly decreased risk: SIR = 0.2 (95% CI 0.04–0.62) |
| Goldacre et al. [31] | 2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 6 | Borderline decreased risk: SIR = 0.48 (95% CI 0.17–1.04) |
| Lohi et al. [32] | 2009 | Finland | Population-based retrospective cohort study | 73 (EMA + subjects) | 1 | No increased risk: RR = 0.71 (95% CI 0.10–5.07) |
| Grainge et al. [27] | 2012 | United Kingdom | Population-based retrospective cohort study | 435 | 5 | No significant increased risk: SIR = 0.71 (95% CI 0.23–1.66) |
| Ludvigsson et al. [215] | 2012 | Sweden | Population-based retrospective cohort study | 17,852 | 151 | Decreased risk: HR = 0.85 (95% CI 0.72–1.01) |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 239 | Significantly decreased risk: SIR = 0.70 (95% CI 0.62–0.79) |
| Lebwohl et al. [28] | 2021 | Sweden | Population-based cohort study | 47,241 | 383 | Significantly decreased risk: HR = 0.83 (95% CI 0.74–0.92). |
| Endometrium and Ovary | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 7 | No decreased risk of ovary cancer: SIR = 1.3 (95% CI 0.5–2.7) |
| Ludvigsson et al. [215] | 2012 | Sweden | Population-based retrospective cohort study | 17,852 | 31 endometrium cancers |
Significant decreased risk of endometrial cancer: HR = 0.60 (95% CI 0.41–0.86) |
| Prostate | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 14 | No significantly increased risk: SIR = 0.7 (95% CI 0.4–1.2) |
| West et al. [25] | 2004 | United Kingdom | Population-based cohort study | 4732 | 6 | No significantly increased risk: aHR = 1.05 (95% CI 0.42–2.57) |
| Goldacre et al. [31] | 2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 4 | No significantly increased risk: adjusted ratio = 0.67 (95% CI 0.18–1.73) |
| Ludvigsson et al. [221] | 2012 | Sweden | Population-based retrospective cohort study | 10,995 | 185 | No increased risk: HR = 0.92 (95% CI 0.79–1.08) |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 248 | No significantly increased risk: SIR = 0.97 (95% CI 0.85–1.09) |
| Thyroid | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 1 | No increased risk: SIR = 0.6 (95% CI 0.0–3.3) |
| Kent et al. [222] | 2006 | USA | Monocentric retrospective cohort | 606 | 3 | Significantly increased risk of thyroid papillary cancer: SIR = 22.52 (95% CI 14.90–34.04) |
| Volta et al. [223] | 2011 | Italy | Multicenter retrospective cohort study | 1757 | 6 | Increased risk of thyroid papillary cancer, although not statistically significant: SIR = 2.55 (95% CI 0.93–5.55) |
| Ludvigsson et al. [224] | 2013 | Sweden | Population-based retrospective cohort study | 29,074 | 7 | No increased risk of all thyroid cancers: HR = 0.6 (95% CI 0.3–1.3). |
| Lung | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 12 | No increased risk: SIR = 1.0 (95% CI 0.5–1.7) |
| Green et al. [29] | 2003 | USA | Hospital-based prospective cohort study | 381 | 3 | No increased risk: SIR = 0.8 (95% CI 0.1–7.2) |
| Card et al. [24] | 2004 | United Kingdom | Population-based prospective cohort study | 4732 | 8 | No increased risk: |
| West et al. [25] | 2004 | United Kingdom | Population-based cohort study | 4732 | 57 | Borderline significant decreased risk: aHR = 0.37 (95% CI 0.13–1.02) |
| Viljamaa et al. [11] | 2006 | Finland | Population-based prospective cohort study | 781 | 2 | No increased risk: SIR = 0.6 (95% CI 0.1–2.1) |
| Goldacre et al. [31] | 2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 13 | No increased risk: adjusted Rate Ratio = 1.07 (95% CI 0.57–1.83) |
| Grainge et al. [27] | 2012 | United Kingdom | Population-based retrospective cohort study | 435 | 6 | No increased risk: SIR = 0.78 (95% CI 0.29–1.69) |
| Ilus et al. [56] | 2014 | Finland | Population-based prospective cohort study | 32,439 | 86 | Significantly decreased risk: SIR = 0.60 (95% CI 0.48–0.74). This result was confirmed both in males and females |
| Lebwohl et al. [28] | 2021 | Sweden | Population-based cohort study | 47,241 | 196 | Statistically significant decreased risk when the first-year of follow-up is excluded: HR = 0.84 (95% CI 0.71–0.99) |
| Melanoma | ||||||
| Askling et al. [23] | 2002 | Sweden | Population-based prospective cohort study | 11,019 | 4 | No increased risk: SIR = 0.6 (95% CI 0.2–1.7) |
| Green et al. [29] | 2003 | USA | Hospital-based prospective cohort study | 381 | 5 | Significantly increased risk: SIR = 5.0 (95% CI 2.1–12.0) |
| Lebwohl et al. [225] | 2014 | Sweden | Population-based retrospective cohort study | 29,028 | 78 | No increased risk: aHR = 0.94 (95% CI 0.73–1.20) |
Abbreviations: aHR, adjusted hazard ratio; CeD, celiac disease; CI, confidence interval; HR, hazard ratio; NR, not reported; OR, odds ratio; RR, relative risk; SIR, standardized incidence ratio.
7. The Protective Effect of a Gluten-Free Diet
Strict adherence to GFD is of paramount importance in reducing the risk of developing CeD complications, and its protective effect was proven more than 30 years ago [21]. Holmes et al. showed that for CeD patients who have taken a GFD for 5 years or more, the risk of developing cancer for all sites is comparable to that of the general population [21]. This is further demonstrated by the significantly increased mortality risk in non-adherent patients (SMR = 6.0, 95% CI 4.0–8.8) [8]. In recent decades, many studies have addressed this issue, confirming the importance of compliance to a GFD in order to decrease the risk of malignancies [9,11,22,170,227,228]. Compared to controls, the risk of developing lymphoproliferative malignancies is higher in patients with villous atrophy (Marsh score 3) than in those with intestinal inflammation without villous atrophy (Marsh scores 1 and 2) [168]. These data, together with the evidence that patients with persistent villous atrophy after the GFD have an increased risk of hematologic and lymphoproliferative malignancies compared to those with mucosal healing [28,55], further reinforce the importance of dietary adherence in diminishing the risk of life-threatening complications.
GFD seems to also be useful in reducing the risk of SBC and GI cancers. Elfstrom et al. [168] demonstrated that the risk of SBC in CeD patients decreases, although does not disappear, after the first year of follow-up, likely because the adoption of a GFD reduces intestinal inflammation and mucosal damage [229]. The risk of SBC according to the follow-up biopsy in CeD was evaluated in the study by Emilsson et al. [169], who confirmed a strong but non-significant reduction in risk with mucosal healing (HR = 0.18, 95% 0.02–1.61).
The effect of a GFD in preventing or reducing the risk of developing malignancies has not been universally proven. Poor compliance to a GFD was not significantly associated with an increased risk of malignant lymphoma in individuals with CeD diagnosed in adulthood in the study by Olen et al. [228]. Specifically, the risk of T-cell lymphoma (OR = 1.01, 95% CI 0.32–3.15) or intestinal lymphomas (OR = 0.66, 95% CI 0.17–2.56) was not increased in non-compliant patients, while an association with B-cell lymphoma (OR = 4.74, 95% CI 0.89–25.3) and extraintestinal lymphoma (OR = 3.00, 95% CI 0.73–12.29) was demonstrated although did not achieve statistical significance [228]. Other authors, based on the reduced malignancy risk in asymptomatic CeD patients diagnosed because of familiarity as compared to patients diagnosed because of symptoms, claimed that there is no convincing evidence that GFD further reduces the risk of malignant complications in asymptomatic subjects [46]. Nevertheless, on the basis of the majority of the available data and awaiting more conclusive studies, a rigorous and life-long GFD should be maintained in all patients with CeD, regardless of the presence of symptoms.
8. Conclusions
It is difficult to draw firm conclusions regarding the association between CeD and the risk of developing neoplasms, mainly due to the largely variable clinical presentation, since these patients can be either asymptomatic or severely symptomatic.
In contrast to the increase in awareness of the pathogenesis of CeD that occurred in the last decade, as well as the reduction of the diagnostic delay, we still have poor knowledge of the risk factors that may contribute to the development of CD-associated neoplasms. Based on the available literature, we can report that CeD patients have a modestly increased risk of developing lymphomas, in particular the characteristic EATL, as well as SBC, as compared to the general population. Several studies have investigated the association of CeD with other cancer types, although so far there is a lack of conclusive evidence to suggest a higher prevalence of other malignancies in CeD patients. On the contrary, the presence of CeD seems to be protective against the development of some tumors, such as breast cancer in women, although the reason why is not completely clear. The majority of data come from adult CeD patients, while very limited data are available on malignancies in children, with conflicting results shown [13,23,27,168]. The study by Solaymani-Dodaran et al. reported increased mortality due to cancer in children with CeD [13], while diagnostic delay was found as a risk factor for increased cancer incidence and increased mortality [8,26]. A subsequent paper from the same research group confirmed that in childhood-diagnosed CeD patients, an increased mortality risk from external causes and lymphoproliferative malignancies persisted after a long follow-up [34].
Overall, the risk of developing EATL and SBC is very small in humans. Despite this, these tumors are burdened by a very poor prognosis, and strategies aimed at reducing their incidence should be followed. Until now, no surveillance programs have been introduced in CeD patients and probably will not be implemented in the future, since the relative rarity of these tumors means that active surveillance is not cost-effective; therefore, even if the effect of a strict GFD in preventing the development of cancer in CeD is still debated, it is the only available preventive strategy able to reduce the risk of these very aggressive forms of cancer. It seems reasonable that chronic inflammation maintained by continuous exposure to dietary gluten leads to persistent activation of immune and inflammatory signals, ultimately favoring the onset or progression of neoplastic foci.
In conclusion, unlike the important steps forward that have been made regarding the knowledge of the pathogenetic mechanisms of CeD in the last few years, as well as in the reduction of diagnostic delay, we still know little about the risk factors and mechanisms that contribute to the development of neoplasms in these patients. Further experimental data and large multicenter cohort studies, conducted not only in Western countries, are needed to ensure better comprehension of the association between malignancies and CeD. In addition, although large phase 3 clinical trials are hard to perform since EATL and SBC are rare, innovative clinical trial designs and multicenter collaborations are crucial to improve the management of patients with these infrequent but devastating tumors.
Conceptualization, F.Z.; methodology, F.P. (Filippo Pelizzaro); investigation, F.P. (Filippo Pelizzaro) and I.M.; writing—original draft preparation, F.P. (Francesco Piazza) and F.Z.; writing—review and editing, F.P. (Filippo Pelizzaro), I.M., M.F., F.P. (Francesco Piazza), B.B., A.D., E.V.S., F.F. and F.Z.; supervision, F.Z. and F.F. All authors have read and agreed to the published version of the manuscript.
This research received no external funding.
The authors declare no conflict of interest.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Studies investigating the association between CeD and the risk of lymphoma and lymphoma-associated mortality.
| Study | Year | Country | Study Design | CeD Cases—n | Lymphoma Cases—n | Main Findings |
|---|---|---|---|---|---|---|
| Holmes et al. [ |
1989 | United Kingdom | Monocentric retrospective cohort study | 210 | 9 | Increased risk of NHL: SIR = 42.7 (95% CI 19.6–81.4) |
| Cottone et al. [ |
1999 | Italy | Hospital-based retrospective cohort | 228 | 6 | Incidence of NHL was 3/100 against an expected incidence of 0.8 (p < 0.01) |
| Green et al. [ |
2001 | USA | Nationwide cross-sectional survey | 1612 | 3 | Relative risk for the development of lymphoma of 300 (60–876) |
| Corrao et al. [ |
2001 | Italy | Multicenter prospective cohort study | 1072 | 16 (death from NHL) | Increased risk of death from NHL: SMR = 69.3 (95% CI 40.7–112.6) |
| Askling et al. [ |
2002 | Sweden | Population-based prospective cohort study | 11,019 | 44 | Increased risk of: |
| Catassi et al. [ |
2002 | Italy | Multicenter case–control study | 6 | 653 | CeD was associated with: |
| Peters et al. [ |
2003 | Sweden | Population-based retrospective cohort study | 10,032 | 22 | Excess of mortality for NHL: SMR = 11.4 (95% CI 7.8–16.0) |
| Green et al. [ |
2003 | USA | Hospital-based prospective cohort study | 381 | 9 | Increased risk of NHL: standardized morbidity ratio = 9.1 (95% CI 4.7–13). |
| Howdle et al. [ |
2003 | United Kingdom | Clinical registry-based cohort | 37 | 86 | 37/86 with lymphoma |
| Card et al. [ |
2004 | United Kingdom | Population-based prospective cohort study | 869 | 12 | Peridiagnostic period: |
| West et al. [ |
2004 | United Kingdom | Population-based cohort study | 4732 | 23 | Increased risk of lymphoproliferative disease: aHR = 4.3 (95% CI 2.4–7.7) |
| Farré et al. [ |
2004 | Spain | Multicenter case–control study | 5 | 298 | No risk of lymphoma detected in silent or recognized CeD patients: OR = 0.62 (95% CI 0.10–3.79) |
| Smedby et al. [ |
2005 | Sweden | Population-based prospective cohort study | 11,650 | 56 | Increased risk of: |
| Viljamaa et al. [ |
2006 | Finland | Population-based prospective cohort study | 781 | 5 (4 EATL, 1 DLBCL) | Risk of NHL significantly increased: SIR = 3.2 (95% CI 1.0–7.5). |
| Smedby et al. [ |
2006 | Denmark and Sweden | Population-based case–control study | 28 | 3055 | Increased risk of: |
| Mearin et al. [ |
2006 | 10 European countries | Prospective, multicenter, case–control study | 66 | 1446 | Increased OR for NHL: 2.6 (95% CI 1.4–4.9) |
| Silano et al. [ |
2007 | Italy | Population-based prospective cohort study | 1968 | 20 | Significant increase in NHL risk: SIR = 4.7 (95% CI 2.9–7.3) |
| Anderson et al. [ |
2007 | United Kingdom | Population-based retrospective cohort study | 490 (EMA+) | 2 | No significant increased risk of NHL despite a raised SIR [7.47 (95% CI 0.00–17.83)] |
| Goldacre et al. [ |
2008 | United Kingdom | Hospital-based retrospective cohort | 1997 | 11 | Increased risk of NHL: adjusted Rate Ratio = 3.28 (95% CI 1.49–6.28). |
| Lohi et al. [ |
2009 | Finland | Population-based retrospective cohort study | 73 (EMA + subjects) | 2 | Increased mortality risk for lymphoma: RR = 9.51 (2.20–41.22) |
| Gao et al. [ |
2009 | Sweden | Population-based case–control study | 54 in NHL patients |
37,869 NHL |
Increased risk of: |
| Anderson et al. [ |
2009 | USA | Population-based case–control study | 25 | 33,721 | Borderline increased risk of NHL overall: OR = 1.5 (95% CI 0.9–2.5) |
| Lohi et al. [ |
2009 | Finland | Population-based retrospective cohort study | 73 (EMA + patients) | 2 | Increased risk of lymphoproliferative diseases: RR = 5.94 (95% CI 1.41–25.04) |
| Grainge et al. [ |
2011 | United Kingdom | Population-based prospective cohort study | 1092 | 6 | Increased risk of death from NHL: SMR = 7.06 (95% CI 2.59–15.4) |
| Elfstrom et al. [ |
2011 | Sweden | Population-based retrospective cohort study | 28,989 CD (Marsh 3) |
289 | Increased risk of lymphoproliferative malignancy in: |
| Grainge et al. [ |
2012 | United Kingdom | Population-based retrospective cohort study | 435 | 14 | Increased risk of NHL: SIR = 12.0 (95% CI 6.55–20.1). |
| Lebwohl et al. [ |
2013 | Sweden | Population-based cohort study | 7625 | 53 | Increased risk of NHL: SIR = 2.81 (95% CI 2.10–3.67). |
| Ilus et al. [ |
2014 | Finland | Population-based prospective cohort study | 32,439 | 132 | Increased risk of NHL: SIR = 1.94 (95% CI 1.62–2.29) |
| Abdul Sultan et al. [ |
2015 | United Kingdom | Population-based retrospective cohort study | 10,825 | 26 | Mortality rate per 10,000 person years: |
| van Gils et al. [ |
2018 | Netherlands | Population-based, case–control study | 261 in lymphomas and GI carcinomas |
301,337 (lymphomas and GI carcinomas) |
Increased risk of T-cell lymphoma: RR = 35.8 (95% CI 27.1–47.4) |
| Quarpong et al. [ |
2019 | United Kingdom | Population-based retrospective cohort study | 602 | 16 | SMR for lymphatic and hematopoietic malignancies: |
| Koskinen et al. [ |
2020 | Finland | Population-based cohort study | 12,803 | 44 | Increased risk of dying from lymphoproliferative diseases: HR = 2.36 (95% CI 1.65–3.39). |
| Lebwohl et al. [ |
2021 | Sweden | Population-based cohort study | 47,241 | 445 hematologic cancers |
Increased risk of: |
Abbreviations: CeD, celiac disease; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; EATL, enteropathy-associated T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; HR, hazard ratio; SMR, standardized mortality ratio; RR, relative risk; aHR, adjusted hazard ratio; OR, odds ratio.
References
1. Ludvigsson, J.F.; Bai, J.C.; Biagi, F.; Card, T.R.; Ciacci, C.; Ciclitira, P.J.; Green, P.H.R.; Hadjivassiliou, M.; Holdoway, A.; van Heel, D.A. et al. Diagnosis and management of adult coeliac disease: Guidelines from the British Society of Gastroenterology. Gut; 2014; 63, pp. 1210-1228. [DOI: https://dx.doi.org/10.1136/gutjnl-2013-306578]
2. Di Sabatino, A.; Corazza, G.R. Coeliac disease. Lancet; 2009; 373, pp. 1480-1493. [DOI: https://dx.doi.org/10.1016/S0140-6736(09)60254-3]
3. Singh, P.; Arora, A.; Strand, T.A.; Leffler, D.A.; Catassi, C.; Green, P.H.; Kelly, C.P.; Ahuja, V.; Makharia, G.K. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin. Gastroenterol. Hepatol.; 2018; 16, pp. 823-836.e2. [DOI: https://dx.doi.org/10.1016/j.cgh.2017.06.037] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29551598]
4. Zingone, F.; Swift, G.L.; Card, T.R.; Sanders, D.S.; Ludvigsson, J.F.; Bai, J.C. Psychological morbidity of celiac disease: A review of the literature. United Eur. Gastroenterol. J.; 2015; 3, pp. 136-145. [DOI: https://dx.doi.org/10.1177/2050640614560786] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25922673]
5. Marsilio, I.; Canova, C.; D’Odorico, A.; Ghisa, M.; Zingone, L.; Lorenzon, G.; Savarino, E.V.; Zingone, F. Quality-of-Life Evaluation in Coeliac Patients on a Gluten-Free Diet. Nutrients; 2020; 12, 2981. [DOI: https://dx.doi.org/10.3390/nu12102981] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33003417]
6. Biagi, F.; Gobbi, P.; Marchese, A.; Borsotti, E.; Zingone, F.; Ciacci, C.; Volta, U.; Caio, G.; Carroccio, A.; Ambrosiano, G. et al. Low incidence but poor prognosis of complicated coeliac disease: A retrospective multicentre study. Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver; 2014; 46, pp. 227-230. [DOI: https://dx.doi.org/10.1016/j.dld.2013.10.010] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24268568]
7. Al-Toma, A.; Volta, U.; Auricchio, R.; Castillejo, G.; Sanders, D.S.; Cellier, C.; Mulder, C.J.; Lundin, K.E.A. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur. Gastroenterol. J.; 2019; 7, pp. 583-613. [DOI: https://dx.doi.org/10.1177/2050640619844125]
8. Corrao, G.; Corazza, G.R.; Bagnardi, V.; Brusco, G.; Ciacci, C.; Cottone, M.; Sategna Guidetti, C.; Usai, P.; Cesari, P.; Pelli, M.A. et al. Mortality in patients with coeliac disease and their relatives: A cohort study. Lancet; 2001; 358, pp. 356-361. [DOI: https://dx.doi.org/10.1016/S0140-6736(01)05554-4]
9. Peters, U.; Askling, J.; Gridley, G.; Ekbom, A.; Linet, M. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch. Intern. Med.; 2003; 163, pp. 1566-1572. [DOI: https://dx.doi.org/10.1001/archinte.163.13.1566]
10. Grainge, M.J.; West, J.; Card, T.R.; Holmes, G.K.T. Causes of death in people with celiac disease spanning the pre- and post-serology era: A population-based cohort study from derby, uk. Am. J. Gastroenterol.; 2011; 106, pp. 933-939. [DOI: https://dx.doi.org/10.1038/ajg.2010.506]
11. Viljamaa, M.; Kaukinen, K.; Pukkala, E.; Hervonen, K.; Reunala, T.; Collin, P. Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: 30-year population-based study. Dig. Liver Dis.; 2006; 38, pp. 374-380. [DOI: https://dx.doi.org/10.1016/j.dld.2006.03.002]
12. Tio, M.; Cox, M.R.; Eslick, G.D. Meta-analysis: Coeliac disease and the risk of all-cause mortality, any malignancy and lymphoid malignancy. Aliment. Pharmacol. Ther.; 2012; 35, pp. 540-551. [DOI: https://dx.doi.org/10.1111/j.1365-2036.2011.04972.x]
13. Solaymani-Dodaran, M.; West, J.; Logan, R.F.A. Long-term mortality in people with celiac disease diagnosed in childhood compared with adulthood: A population-based cohort study. Am. J. Gastroenterol.; 2007; 102, pp. 864-870. [DOI: https://dx.doi.org/10.1111/j.1572-0241.2007.01111.x]
14. Gough, K.R.; Read, A.; Naish, J. Intestinal reticulosis as a complication of idiopathic steatorrhoea. Gut; 1962; 3, pp. 232-239. [DOI: https://dx.doi.org/10.1136/gut.3.3.232]
15. Austad, W.I.; Cornes, J.S.; Gough, K.R.; McCarthy, C.F.; Read, A.E. Steatorrhea and malignant lymphoma. The relationship of malignant tumors of lymphoid tissue and celiac disease. Am. J. Dig. Dis.; 1967; 12, pp. 475-490. [DOI: https://dx.doi.org/10.1007/BF02233180]
16. Harris, O.D.; Cooke, W.T.; Thompson, H.; Waterhouse, J.A. Malignancy in adult coeliac disease and idiopathic steatorrhoea. Am. J. Med.; 1967; 42, pp. 899-912. [DOI: https://dx.doi.org/10.1016/0002-9343(67)90071-X]
17. Swinson, C.M.; Coles, E.C.; Slavin, G.; Booth, C.C. Coeliac disease and malignancy. Lancet; 1983; 321, pp. 111-115. [DOI: https://dx.doi.org/10.1016/S0140-6736(83)91754-3]
18. Cooper, B.T.; Holmes, G.K.; Ferguson, R.; Cooke, W.T. Celiac disease and malignancy. Medicine; 1980; 59, pp. 249-261. [DOI: https://dx.doi.org/10.1097/00005792-198007000-00002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7392945]
19. Selby, W.S.; Gallagher, N.D. Malignancy in a 19-year experience of adult celiac disease. Dig. Dis. Sci.; 1979; 24, pp. 684-688. [DOI: https://dx.doi.org/10.1007/BF01314465]
20. Nielsen, O.H.; Jacobsen, O.; Pedersen, E.R.; Rasmussen, S.N.; Petri, M.; Laulund, S.; Jarnum, S. Non-tropical sprue. Malignant diseases and mortality rate. Scand. J. Gastroenterol.; 1985; 20, pp. 13-18. [DOI: https://dx.doi.org/10.3109/00365528509089626] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/3992161]
21. Holmes, G.K.; Prior, P.; Lane, M.R.; Pope, D.; Allan, R.N. Malignancy in coeliac disease--effect of a gluten free diet. Gut; 1989; 30, pp. 333-338. [DOI: https://dx.doi.org/10.1136/gut.30.3.333]
22. Collin, P.; Reunala, T.; Pukkala, E.; Laippala, P.; Keyriläinen, O.; Pasternack, A. Coeliac disease—Associated disorders and survival. Gut; 1994; 35, pp. 1215-1218. [DOI: https://dx.doi.org/10.1136/gut.35.9.1215]
23. Askling, J.; Linet, M.; Gridley, G.; Halstensen, T.S.; Ekström, K.; Ekbom, A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology; 2002; 123, pp. 1428-1435. [DOI: https://dx.doi.org/10.1053/gast.2002.36585]
24. Card, T.R.; West, J.; Holmes, G.K.T. Risk of malignancy in diagnosed coeliac disease: A 24-year prospective, population-based, cohort study. Aliment. Pharmacol. Ther.; 2004; 20, pp. 769-775. [DOI: https://dx.doi.org/10.1111/j.1365-2036.2004.02177.x]
25. West, J.; Logan, R.F.A.; Smith, C.J.; Hubbard, R.B.; Card, T.R. Malignancy and mortality in people with coeliac disease: Population based cohort study. Br. Med. J.; 2004; 329, pp. 716-718. [DOI: https://dx.doi.org/10.1136/bmj.38169.486701.7C] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15269095]
26. Silano, M.; Volta, U.; Mecchia, A.; Dessì, M.; Di Benedetto, R.; De Vincenzi, M.; Gasbarrini, G.; De Vitis, D.; Greco, L.; Auricchio, S. et al. Delayed diagnosis of coeliac disease increases cancer risk. BMC Gastroenterol.; 2007; 7, 8. [DOI: https://dx.doi.org/10.1186/1471-230X-7-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17349035]
27. Grainge, M.J.; West, J.; Solaymani-Dodaran, M.; Card, T.R.; Logan, R.F.A. The long-term risk of malignancy following a diagnosis of coeliac disease or dermatitis herpetiformis: A cohort study. Aliment. Pharmacol. Ther.; 2012; 35, pp. 730-739. [DOI: https://dx.doi.org/10.1111/j.1365-2036.2012.04998.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22288441]
28. Lebwohl, B.; Green, P.H.R.; Emilsson, L.; Mårild, K.; Söderling, J.; Roelstraete, B.; Ludvigsson, J.F. Cancer Risk in 47,241 Individuals With Celiac Disease: A Nationwide Cohort Study. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc.; 2021; in press [DOI: https://dx.doi.org/10.1016/j.cgh.2021.05.034]
29. Green, P.H.R.; Fleischauer, A.T.; Bhagat, G.; Goyal, R.; Jabri, B.; Neugut, A.I. Risk of malignancy in patients with celiac disease. Am. J. Med.; 2003; 115, pp. 191-195. [DOI: https://dx.doi.org/10.1016/S0002-9343(03)00302-4]
30. Anderson, L.A.; McMillan, S.A.; Watson, R.G.P.; Monaghan, P.; Gavin, A.T.; Fox, C.; Murray, L.J. Malignancy and mortality in a population-based cohort of patients with coeliac disease or “gluten sensitivity”. World J. Gastroenterol.; 2007; 13, pp. 146-151. [DOI: https://dx.doi.org/10.3748/wjg.v13.i1.146]
31. Goldacre, M.J.; Wotton, C.J.; Yeates, D.; Seagroatt, V.; Jewell, D. Cancer in patients with ulcerative colitis, Crohn’s disease and coeliac disease: Record linkage study. Eur. J. Gastroenterol. Hepatol.; 2008; 20, pp. 297-304. [DOI: https://dx.doi.org/10.1097/MEG.0b013e3282f2a5e2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18334873]
32. Lohi, S.; Mäki, M.; Montonen, J.; Knekt, P.; Pukkala, E.; Reunanen, A.; Kaukinen, K. Malignancies in cases with screening-identified evidence of coeliac disease: A long-term population-based cohort study. Gut; 2009; 58, pp. 643-647. [DOI: https://dx.doi.org/10.1136/gut.2007.140970] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18852259]
33. Han, Y.; Chen, W.; Li, P.; Ye, J. Association Between Coeliac Disease and Risk of Any Malignancy and Gastrointestinal Malignancy: A Meta-Analysis. Medicine; 2015; 94, e1612. [DOI: https://dx.doi.org/10.1097/MD.0000000000001612] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26402826]
34. Quarpong, W.; Card, T.R.; West, J.; Solaymani-Dodaran, M.; Logan, R.F.; Grainge, M.J. Mortality in people with coeliac disease: Long-term follow-up from a Scottish cohort. United Eur. Gastroenterol. J.; 2019; 7, pp. 377-387. [DOI: https://dx.doi.org/10.1177/2050640618814662]
35. Lebwohl, B.; Green, P.H.R.; Söderling, J.; Roelstraete, B.; Ludvigsson, J.F. Association Between Celiac Disease and Mortality Risk in a Swedish Population. JAMA; 2020; 323, pp. 1277-1285. [DOI: https://dx.doi.org/10.1001/jama.2020.1943] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32259229]
36. Canavan, C.; Logan, R.F.; Khaw, K.T.; West, J. No difference in mortality in undetected coeliac disease compared with the general population: A UK cohort study. Aliment. Pharmacol. Ther.; 2011; 34, pp. 1012-1019. [DOI: https://dx.doi.org/10.1111/j.1365-2036.2011.04811.x]
37. Lohi, S.; Mäki, M.; Rissanen, H.; Knekt, P.; Reunanen, A.; Kaukinen, K. Prognosis of unrecognized coeliac disease as regards mortality: A population-based cohort study. Ann. Med.; 2009; 41, pp. 508-515. [DOI: https://dx.doi.org/10.1080/07853890903036199]
38. Godfrey, J.D.; Brantner, T.L.; Brinjikji, W.; Christensen, K.N.; Brogan, D.L.; Van Dyke, C.T.; Lahr, B.D.; Larson, J.J.; Rubio-Tapia, A.; Melton, L.J., III et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology; 2010; 139, pp. 763-769. [DOI: https://dx.doi.org/10.1053/j.gastro.2010.05.041]
39. Abdul Sultan, A.; Crooks, C.J.; Card, T.; Tata, L.J.; Fleming, K.M.; West, J. Causes of death in people with coeliac disease in England compared with the general population: A competing risk analysis. Gut; 2015; 64, pp. 1220-1226. [DOI: https://dx.doi.org/10.1136/gutjnl-2014-308285]
40. Koskinen, I.; Virta, L.J.; Huhtala, H.; Ilus, T.; Kaukinen, K.; Collin, P. Overall and Cause-Specific Mortality in Adult Celiac Disease and Dermatitis Herpetiformis Diagnosed in the 21st Century. Am. J. Gastroenterol.; 2020; 115, pp. 1117-1124. [DOI: https://dx.doi.org/10.14309/ajg.0000000000000665]
41. Leonard, J.N.; Tucker, W.F.G.; Fry, J.S.; Coulter, C.A.; Boylston, A.W.; McMinn, R.M.; Haffenden, G.P.; Swain, A.F. Increased incidence of malignancy in dermatitis herpetiformis. Br. Med. J.; 1983; 286, pp. 16-18. [DOI: https://dx.doi.org/10.1136/bmj.286.6358.16] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6401441]
42. Fasano, A.; Catassi, C. Current approaches to diagnosis and treatment of celiac disease: An evolving spectrum. Gastroenterology; 2001; 120, pp. 636-651. [DOI: https://dx.doi.org/10.1053/gast.2001.22123] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11179241]
43. Catassi, C.; Fabiani, E.; Corrao, G.; Barbato, M.; De Renzo, A.; Carella, A.M.; Gabrielli, A.; Leoni, P.; Carroccio, A.; Baldassarre, M. et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA; 2002; 287, pp. 1413-1419. [DOI: https://dx.doi.org/10.1001/jama.287.11.1413]
44. Smedby, K.E.; Åkerman, M.; Hildebrand, H.; Glimelius, B.; Ekbom, A.; Askling, J. Malignant lymphomas in coeliac disease: Evidance of increased risks for lymphoma types other than enteropathy-type T cell lymphoma. Gut; 2005; 54, pp. 54-59. [DOI: https://dx.doi.org/10.1136/gut.2003.032094]
45. Elfström, P.; Granath, F.; Ekström Smedby, K.; Montgomery, S.M.; Askling, J.; Ekbom, A.; Ludvigsson, J.F. Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J. Natl. Cancer Inst.; 2011; 103, pp. 436-444. [DOI: https://dx.doi.org/10.1093/jnci/djq564]
46. Gao, Y.; Kristinsson, S.Y.; Goldin, L.R.; Björkholm, M.; Caporaso, N.E.; Landgren, O. Increased risk for non-Hodgkin lymphoma in individuals with celiac disease and a potential familial association. Gastroenterology; 2009; 136, pp. 91-98. [DOI: https://dx.doi.org/10.1053/j.gastro.2008.09.031]
47. Smedby, K.E.; Hjalgrim, H.; Askling, J.; Chang, E.T.; Gregersen, H.; Porwit-MacDonald, A.; Sundström, C.; Akerman, M.; Melbye, M.; Glimelius, B. et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J. Natl. Cancer Inst.; 2006; 98, pp. 51-60. [DOI: https://dx.doi.org/10.1093/jnci/djj004]
48. Luisa Mearin, M.; Catassi, C.; Brousse, N.; Brand, R.; Collin, P.; Fabiani, E.; Schweizer, J.J.; Abuzakouk, M.; Szajewska, H.; Hallert, C. et al. European multi-centre study on coeliac disease and non-Hodgkin lymphoma. Eur. J. Gastroenterol. Hepatol.; 2006; 18, pp. 187-194. [DOI: https://dx.doi.org/10.1097/00042737-200602000-00012]
49. van Gils, T.; Nijeboer, P.; Overbeek, L.I.; Hauptmann, M.; Castelijn, D.A.; Bouma, G.; Mulder, C.J.; van Leeuwen, F.E.; de Jong, D. Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up: Celiac disease, lymphoma and GI carcinoma. United Eur. Gastroenterol. J.; 2018; 6, pp. 1485-1495. [DOI: https://dx.doi.org/10.1177/2050640618800540]
50. Cottone, M.; Termini, A.; Oliva, L.; Magliocco, A.; Marrone, C.; Orlando, A.; Pinzone, F.; Di Mitri, R.; Rosselli, M.; Rizzo, A. et al. Mortality and causes of death in celiac disease in a Mediterranean area. Dig. Dis. Sci.; 1999; 44, pp. 2538-2541. [DOI: https://dx.doi.org/10.1023/A:1026655609906] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10630509]
51. Green, P.H.R.; Stavropoulos, S.N.; Panagi, S.G.; Goldstein, S.L.; McMahon, D.J.; Absan, H.; Neugut, A.I. Characteristics of adult celiac disease in the USA: Results of a national survey. Am. J. Gastroenterol.; 2001; 96, pp. 126-131. [DOI: https://dx.doi.org/10.1111/j.1572-0241.2001.03462.x]
52. Howdle, P.D.; Jalal, P.K.; Holmes, G.K.T.; Houlston, R.S. Primary small-bowel malignancy in the UK and its association with coeliac disease. QJM-Mon. J. Assoc. Phys.; 2003; 96, pp. 345-353. [DOI: https://dx.doi.org/10.1093/qjmed/hcg058]
53. Farré, C.; Domingo-Domenech, E.; Font, R.; Marques, T.; Fernandez de Sevilla, A.; Alvaro, T.; Villanueva, M.G.; Romagosa, V.; de Sanjose, S. Celiac disease and lymphoma risk: A multicentric case--control study in Spain. Dig. Dis. Sci.; 2004; 49, pp. 408-412. [DOI: https://dx.doi.org/10.1023/B:DDAS.0000020494.79480.30]
54. Anderson, L.A.; Gadalla, S.; Morton, L.M.; Landgren, O.; Pfeiffer, R.; Warren, J.L.; Berndt, S.I.; Ricker, W.; Parsons, R.; Engels, E.A. Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies. Int. J. Cancer; 2009; 125, pp. 398-405. [DOI: https://dx.doi.org/10.1002/ijc.24287] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19365835]
55. Lebwohl, B.; Granath, F.; Ekbom, A.; Smedby, K.E.; Murray, J.A.; Neugut, A.I.; Green, P.H.R.; Ludvigsson, J.F. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: A population-based cohort study. Ann. Intern. Med.; 2013; 159, pp. 169-175. [DOI: https://dx.doi.org/10.7326/0003-4819-159-3-201308060-00006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23922062]
56. Ilus, T.; Kaukinen, K.; Virta, L.J.; Pukkala, E.; Collin, P. Incidence of malignancies in diagnosed celiac patients: A population-based estimate. Am. J. Gastroenterol.; 2014; 109, pp. 1471-1477. [DOI: https://dx.doi.org/10.1038/ajg.2014.194] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25047399]
57. Fairley, N.H.; Mackie, F.P. The clinical and biochemical syndrome in lymph-adenoma and allied diseases involving the mesenteric lymph glands. Br. Med. J.; 1937; 1, pp. 375-381. [DOI: https://dx.doi.org/10.1136/bmj.1.3972.375]
58. O’Farrelly, C.; Feighery, C.; O’Briain, D.S.; Stevens, F.; Connolly, C.E.; McCarthy, C.; Weir, D.G. Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T cell lymphoma. Br. Med. J. (Clin. Res. Ed.); 1986; 293, pp. 908-910. [DOI: https://dx.doi.org/10.1136/bmj.293.6552.908]
59. Sharaiha, R.Z.; Lebwohl, B.; Reimers, L.; Bhagat, G.; Green, P.H.; Neugut, A.I. Increasing incidence of enteropathy-associated T-cell lymphoma in the United States, 1973–2008. Cancer; 2012; 118, pp. 3786-3792. [DOI: https://dx.doi.org/10.1002/cncr.26700]
60. Verbeek, W.H.M.; Van De Water, J.M.W.; Al-Toma, A.; Oudejans, J.J.; Mulder, C.J.J.; Coupé, V.M.H. Incidence of enteropathy - Associated T-cell lymphoma: A nation-wide study of a population-based registry in the Netherlands. Scand. J. Gastroenterol.; 2008; 43, pp. 1322-1328. [DOI: https://dx.doi.org/10.1080/00365520802240222]
61. Catassi, C.; Bearzi, I.; Holmes, G.K.T. Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology; 2005; 128, pp. S79-S86. [DOI: https://dx.doi.org/10.1053/j.gastro.2005.02.027] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15825131]
62. Catassi, C.; Kryszak, D.; Bhatti, B.; Sturgeon, C.; Helzlsouer, K.; Clipp, S.L.; Gelfond, D.; Puppa, E.; Sferruzza, A.; Fasano, A. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann. Med.; 2010; 42, pp. 530-538. [DOI: https://dx.doi.org/10.3109/07853890.2010.514285]
63. Rubio-Tapia, A.; Kyle, R.A.; Kaplan, E.L.; Johnson, D.R.; Page, W.; Erdtmann, F.; Brantner, T.L.; Kim, W.R.; Phelps, T.K.; Lahr, B.D. et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology; 2009; 137, pp. 88-93. [DOI: https://dx.doi.org/10.1053/j.gastro.2009.03.059] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19362553]
64. Cellier, C.; Delabesse, E.; Helmer, C.; Patey, N.; Matuchansky, C.; Jabri, B.; MacIntyre, E.; Cerf-Bensussan, N.; Brousse, N. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet; 2000; 356, pp. 203-208. [DOI: https://dx.doi.org/10.1016/S0140-6736(00)02481-8]
65. Rubio-Tapia, A.; Murray, J.A. Classification and management of refractory coeliac disease. Gut; 2010; 59, pp. 547-557. [DOI: https://dx.doi.org/10.1136/gut.2009.195131]
66. Malamut, G.; Afchain, P.; Verkarre, V.; Lecomte, T.; Amiot, A.; Damotte, D.; Bouhnik, Y.; Colombel, J.F.; Delchier, J.C.; Allez, M. et al. Presentation and Long-Term Follow-up of Refractory Celiac Disease: Comparison of Type I With Type II. Gastroenterology; 2009; 136, pp. 81-90. [DOI: https://dx.doi.org/10.1053/j.gastro.2008.09.069]
67. Al-toma, A.; Verbeek, W.H.M.; Hadithi, M.; Von Blomberg, B.M.E.; Mulder, C.J.J. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: Retrospective evaluation of single-centre experience. Gut; 2007; 56, pp. 1373-1378. [DOI: https://dx.doi.org/10.1136/gut.2006.114512] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17470479]
68. Daum, S.; Ipczynski, R.; Schumann, M.; Wahnschaffe, U.; Zeitz, M.; Ullrich, R. High rates of complications and substantial mortality in both types of refractory sprue. Eur. J. Gastroenterol. Hepatol.; 2009; 21, pp. 66-70. [DOI: https://dx.doi.org/10.1097/MEG.0b013e328307c20c]
69. van Wanrooij, R.L.J.; Bouma, G.; Bontkes, H.J.; Neefjes-Borst, A.; van Grieken, N.C.; von Blomberg, B.M.E.; Mulder, C.J.J. Outcome of Referrals for Non-Responsive Celiac Disease in a Tertiary Center: Low Incidence of Refractory Celiac Disease in the Netherlands. Clin. Transl. Gastroenterol.; 2017; 8, e218. [DOI: https://dx.doi.org/10.1038/ctg.2016.70]
70. Biagi, F.; Poggioli, G.; Mazzoni, G.; Corazza, G.R. Intestinal strictures. Lancet; 1998; 352, 876. [DOI: https://dx.doi.org/10.1016/S0140-6736(98)06170-4]
71. Biagi, F.; Lorenzini, P.; Corazza, G.R. Literature review on the clinical relationship between ulcerative jejunoileitis, coeliac disease, and enteropathy-associated T-cell. Scand. J. Gastroenterol.; 2000; 35, pp. 785-790. [DOI: https://dx.doi.org/10.1080/003655200750023129]
72. Mention, J.J.; Ahmed, M.B.; Bègue, B.; Barbe, U.; Verkarre, V.; Asnafi, V.; Colombel, J.F.; Cugnenc, P.H.; Ruemmele, F.M.; McIntyre, E. et al. Interleukin 15: A key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology; 2003; 125, pp. 730-745. [DOI: https://dx.doi.org/10.1016/S0016-5085(03)01047-3]
73. Di Sabatino, A.; Ciccocioppo, R.; Cupelli, F.; Cinque, B.; Millimaggi, D.; Clarkson, M.M.; Paulli, M.; Cifone, M.G.; Corazza, G.R. Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut; 2006; 55, pp. 469-477. [DOI: https://dx.doi.org/10.1136/gut.2005.068684]
74. Malamut, G.; El Machhour, R.; Montcuquet, N.; Martin-Lannerée, S.; Dusanter-Fourt, I.; Verkarre, V.; Mention, J.J.; Rahmi, G.; Kiyono, H.; Butz, E.A. et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J. Clin. Investig.; 2010; 120, pp. 2131-2143. [DOI: https://dx.doi.org/10.1172/JCI41344]
75. Malamut, G.; Chandesris, O.; Verkarre, V.; Meresse, B.; Callens, C.; Macintyre, E.; Bouhnik, Y.; Gornet, J.M.; Allez, M.; Jian, R. et al. Enteropathy associated T cell lymphoma in celiac disease: A large retrospective study. Dig. Liver Dis.; 2013; 45, pp. 377-384. [DOI: https://dx.doi.org/10.1016/j.dld.2012.12.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23313469]
76. Meresse, B.; Ripoche, J.; Heyman, M.; Cerf-Bensussan, N. Celiac disease: From oral tolerance to intestinal inflammation, autoimmunity and lymphomagenesis. Mucosal Immunol.; 2009; 2, pp. 8-23. [DOI: https://dx.doi.org/10.1038/mi.2008.75]
77. Perfetti, V.; Baldanti, F.; Lenti, M.V.; Vanoli, A.; Biagi, F.; Gatti, M.; Riboni, R.; Dallera, E.; Paulli, M.; Pedrazzoli, P. et al. Detection of Active Epstein-Barr Virus Infection in Duodenal Mucosa of Patients With Refractory Celiac Disease. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc.; 2016; 14, pp. 1216-1220. [DOI: https://dx.doi.org/10.1016/j.cgh.2016.03.022] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27033429]
78. de Bruin, P.C.; Jiwa, N.M.; Oudejans, J.J.; Radaszkiewicz, T.; Meijer, C.J. Epstein-Barr virus in primary gastrointestinal T cell lymphomas. Association with gluten-sensitive enteropathy, pathological features, and immunophenotype. Am. J. Pathol.; 1995; 146, pp. 861-867.
79. Ilyas, M.; Niedobitek, G.; Agathanggelou, A.; Barry, R.E.; Read, A.E.; Tierney, R.; Young, L.S.; Rooney, N. Non-Hodgkin’s lymphoma, coeliac disease, and Epstein-Barr virus: A study of 13 cases of enteropathy-associated T- and B-cell lymphoma. J. Pathol.; 1995; 177, pp. 115-122. [DOI: https://dx.doi.org/10.1002/path.1711770203] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7490676]
80. Walsh, S.V.; Egan, L.J.; Connolly, C.E.; Stevens, F.M.; Egan, E.L.; McCarthy, C.F. Enteropathy-associated T-cell lymphoma in the West of Ireland: Low-frequency of Epstein-Barr virus in these tumors. Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc; 1995; 8, pp. 753-757.
81. Swerdlow, S.; Campo, E.; Harris, N.; Jaffe, E.; Pileri, S.; Stein, H.; Thiele, J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues; International Agency for Research on Cancer: Lyon, France, 2008; ISBN 9789283244943
82. Campo, E.; Swerdlow, S.H.; Harris, N.L.; Pileri, S.; Stein, H.; Jaffe, E.S. The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood; 2011; 117, pp. 5019-5032. [DOI: https://dx.doi.org/10.1182/blood-2011-01-293050] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21300984]
83. Delabie, J.; Holte, H.; Vose, J.M.; Ullrich, F.; Jaffe, E.S.; Savage, K.J.; Connors, J.M.; Rimsza, L.; Harris, N.L.; Müller-Hermelink, K. et al. Enteropathy-associated T-cell lymphoma: Clinical and histological findings from the international peripheral T-Cell lymphoma project. Blood; 2011; 118, pp. 148-155. [DOI: https://dx.doi.org/10.1182/blood-2011-02-335216] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21566094]
84. Fei, F.; Reddy, V.; Patel, C.R.; Dhall, D.; Lee, G.; Meng-Jun, X.; Al Diffalha, S. Monomorphic Epitheliotropic Intestinal T-cell Lymphoma: A Study of Four Cases and Review of Literature. Ann. Clin. Lab. Sci.; 2020; 50, pp. 806-812. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33334797]
85. Chott, A.; Haedicke, W.; Mosberger, I.; Fodinger, M.; Winkler, K.; Mannhalter, C.; Muller-Hermelink, H.K. Most CD56+ intestinal lymphomas are CD8+CD5- T-cell lymphomas of monomorphic small to medium size histology. Am. J. Pathol.; 1998; 153, pp. 1483-1490. [DOI: https://dx.doi.org/10.1016/S0002-9440(10)65736-7]
86. deLeeuw, R.J.; Zettl, A.; Klinker, E.; Haralambieva, E.; Trottier, M.; Chari, R.; Ge, Y.; Gascoyne, R.D.; Chott, A.; Müller-Hermelink, H.K. et al. Whole-Genome Analysis and HLA Genotyping of Enteropathy-Type T-Cell Lymphoma Reveals 2 Distinct Lymphoma Subtypes. Gastroenterology; 2007; 132, pp. 1902-1911. [DOI: https://dx.doi.org/10.1053/j.gastro.2007.03.036]
87. Lenti, M.V.; Biagi, F.; Lucioni, M.; Di Sabatino, A.; Paulli, M.; Corazza, G.R. Two cases of monomorphic epitheliotropic intestinal T-cell lymphoma associated with coeliac disease. Scand. J. Gastroenterol.; 2019; 54, pp. 965-968. [DOI: https://dx.doi.org/10.1080/00365521.2019.1647455]
88. Tse, E.; Gill, H.; Loong, F.; Kim, S.J.; Ng, S.B.; Tang, T.; Ko, Y.H.; Chng, W.J.; Lim, S.T.; Kim, W.S. et al. Type II enteropathy-associated T-cell lymphoma: A multicenter analysis from the Asia Lymphoma Study Group. Am. J. Hematol.; 2012; 87, pp. 663-668. [DOI: https://dx.doi.org/10.1002/ajh.23213]
89. Gale, J.; Simmonds, P.D.; Mead, G.M.; Sweetenham, J.W.; Wright, D.H. Enteropathy-type intestinal T-cell lymphoma: Clinical features and treatment of 31 patients in a single center. J. Clin. Oncol.; 2000; 18, pp. 795-803. [DOI: https://dx.doi.org/10.1200/JCO.2000.18.4.795]
90. Daum, S.; Ullrich, R.; Heise, W.; Dederke, B.; Foss, H.D.; Stein, H.; Thiel, E.; Zeitz, M.; Riecken, E.O. Intestinal non-Hodgkin’s lymphoma: A multicenter prospective clinical study from the German Study Group on intestinal non-Hodgkin’s lymphoma. J. Clin. Oncol.; 2003; 21, pp. 2740-2746. [DOI: https://dx.doi.org/10.1200/JCO.2003.06.026]
91. Di Sabatino, A.; Biagi, F.; Gobbi, P.G.; Corazza, G.R. How I treat enteropathy-associated T-cell lymphoma. Blood; 2012; 119, pp. 2458-2468. [DOI: https://dx.doi.org/10.1182/blood-2011-10-385559]
92. Wierdsma, N.J.; Nijeboer, P.; de van der Schueren, M.A.E.; Berkenpas, M.; van Bodegraven, A.A.; Mulder, C.J.J. Refractory celiac disease and EATL patients show severe malnutrition and malabsorption at diagnosis. Clin. Nutr.; 2016; 35, pp. 685-691. [DOI: https://dx.doi.org/10.1016/j.clnu.2015.04.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25979847]
93. Novakovic, B.J.; Novakovic, S.; Frkovic-Grazio, S. A single-center report on clinical features and treatment response in patients with intestinal T cell non-Hodgkin’s lymphomas. Oncol. Rep.; 2006; 16, pp. 191-195. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16786145]
94. Domizio, P.; Owen, R.A.; Shepherd, N.A.; Talbot, I.C.; Norton, A.J. Primary lymphoma of the small intestine: A clinicopathological study of 119 cases. Am. J. Surg. Pathol.; 1993; 17, pp. 429-442. [DOI: https://dx.doi.org/10.1097/00000478-199305000-00001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8470758]
95. Hovenga, S.; de Graaf, H.; Joosten, P.; van den Berg, G.A.; Storm, H.; Langerak, A.W.; Kluin, P.M.; Kibbelaar, R.E. Enteropathy-associated T-cell lymphoma presenting with eosinophilia. Neth. J. Med.; 2003; 61, pp. 25-27. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12688567]
96. McBride, O.M.B.; Skipworth, R.J.E.; Leitch, D.; Yalamarthi, S. Cavitating mesenteric lymph node syndrome in association with coeliac disease and enteropathy associated T-cell lymphoma: A case report and review of the literature. Case Rep. Med.; 2010; 2010, pp. 1-4. [DOI: https://dx.doi.org/10.1155/2010/478269]
97. Di Sabatino, A.; Rosado, M.M.; Cazzola, P.; Riboni, R.; Biagi, F.; Carsetti, R.; Corazza, G.R. Splenic hypofunction and the spectrum of autoimmune and malignant complications in celiac disease. Clin. Gastroenterol. Hepatol.; 2006; 4, pp. 179-186. [DOI: https://dx.doi.org/10.1016/S1542-3565(05)00982-1]
98. Di Sabatino, A.; Carsetti, R.; Corazza, G.R. Post-splenectomy and hyposplenic states. Lancet; 2011; 378, pp. 86-97. [DOI: https://dx.doi.org/10.1016/S0140-6736(10)61493-6]
99. International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A Predictive Model for Aggressive Non-Hodgkin’s Lymphoma. N. Engl. J. Med.; 1993; 329, pp. 987-994. [DOI: https://dx.doi.org/10.1056/NEJM199309303291402] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8141877]
100. Rohatiner, A.; D’Amore, F.; Coiffier, B.; Crowther, D.; Gospodarowicz, M.; Isaacson, P.; Lister, T.A.; Norton, A.; Salem, P.; Shipp, M. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann. Oncol.; 1994; 5, pp. 397-400. [DOI: https://dx.doi.org/10.1093/oxfordjournals.annonc.a058869] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8075046]
101. Bishton, M.J.; Haynes, A.P. Combination chemotherapy followed by autologous stem cell transplant for enteropathy-associated T cell lymphoma. Br. J. Haematol.; 2007; 136, pp. 111-113. [DOI: https://dx.doi.org/10.1111/j.1365-2141.2006.06371.x]
102. Vose, J.M.; Neumann, M.; Harris, M.E. International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes international T-cell lymphoma project. J. Clin. Oncol.; 2008; 26, pp. 4124-4130. [DOI: https://dx.doi.org/10.1200/JCO.2008.16.4558]
103. Savage, K.J.; Chhanabhai, M.; Gascoyne, R.D.; Connors, J.M. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann. Oncol.; 2004; 15, pp. 1467-1475. [DOI: https://dx.doi.org/10.1093/annonc/mdh392] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15367405]
104. Gallamini, A.; Stelitano, C.; Calvi, R.; Bellei, M.; Mattei, D.; Vitolo, U.; Morabito, F.; Martelli, M.; Brusamolino, E.; Iannitto, E. et al. Peripheral T-cell lymphoma unspecified (PTCL-U): A new prognostic model from a retrospective multicentric clinical study. Blood; 2004; 103, pp. 2474-2479. [DOI: https://dx.doi.org/10.1182/blood-2003-09-3080] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14645001]
105. De Baaij, L.R.; Berkhof, J.; Van De Water, J.M.W.; Sieniawski, M.K.; Radersma, M.; Verbeek, W.H.M.; Visser, O.J.; Oudejans, J.J.; Meijer, C.J.L.M.; Mulder, C.J.J. et al. A new and validated clinical prognostic model (EPI) for enteropathy-associated T-cell lymphoma. Clin. Cancer Res.; 2015; 21, pp. 3013-3019. [DOI: https://dx.doi.org/10.1158/1078-0432.CCR-14-2195] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25779949]
106. Leighton, J.A. The role of endoscopic imaging of the small bowel in clinical practice. Am. J. Gastroenterol.; 2011; 106, pp. 27-36. [DOI: https://dx.doi.org/10.1038/ajg.2010.410]
107. Al-Toma, A.; Verbeek, W.H.M.; Mulder, C.J.J. The management of complicated celiac disease. Dig. Dis.; 2007; 25, pp. 230-236. [DOI: https://dx.doi.org/10.1159/000103891] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17827946]
108. Mallant, M.; Hadithi, M.; Al-Toma, A.B.; Kater, M.; Jacobs, M.; Manoliu, R.; Mulder, C.; van Waesberghe, J.H.T.M. Abdominal computed tomography in refractory coeliac disease and enteropathy associated T-cell lymphoma. World J. Gastroenterol.; 2007; 13, pp. 1696-1700. [DOI: https://dx.doi.org/10.3748/wjg.v13.i11.1696] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17461472]
109. Hadithi, M.; Mallant, M.; Oudejans, J.; van Waesberghe, J.-H.T.M.; Mulder, C.J.; Comans, E.F.I. 18F-FDG PET versus CT for the detection of enteropathy-associated T-cell lymphoma in refractory celiac disease. J. Nucl. Med.; 2006; 47, pp. 1622-1627. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17015897]
110. Hoffmann, M.; Vogelsang, H.; Kletter, K.; Zettinig, G.; Chott, A.; Raderer, M. 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) for assessment of enteropathy-type T cell lymphoma. Gut; 2003; 52, pp. 347-351. [DOI: https://dx.doi.org/10.1136/gut.52.3.347]
111. Laird, J.; Leach, M.; Ballantyne, S. The value of small bowel magnetic resonance imaging in the management of enteropathy associated T-cell lymphoma. Br. J. Haematol.; 2008; 142, pp. 136-137. [DOI: https://dx.doi.org/10.1111/j.1365-2141.2008.07019.x]
112. Van Weyenberg, S.J.B.; Meijerink, M.R.; Jacobs, M.A.J.M.; Van Kuijk, C.; Mulder, C.J.; Van Waesberghe, J.H.T.M. MR enteroclysis in refractory celiac disease: Proposal and validation of a severity scoring system. Radiology; 2011; 259, pp. 151-161. [DOI: https://dx.doi.org/10.1148/radiol.11101808] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21330559]
113. Elli, L.; Casazza, G.; Locatelli, M.; Branchi, F.; Ferretti, F.; Conte, D.; Fraquelli, M. Use of enteroscopy for the detection of malignant and premalignant lesions of the small bowel in complicated celiac disease: A meta-analysis. Gastrointest. Endosc.; 2017; 86, pp. 264-273.e1. [DOI: https://dx.doi.org/10.1016/j.gie.2017.04.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28433612]
114. Daum, S.; Wanschaffe, U.; Glasenapp, R.; Borchert, M.; Ullrich, R.; Zeitz, M.; Faiss, S. Capsule endoscopy in refractory celiac disease. Endoscopy; 2007; 39, pp. 455-458. [DOI: https://dx.doi.org/10.1055/s-2007-966239] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17516353]
115. Ferretti, F.; Branchi, F.; Orlando, S.; Roncoroni, L.; Barigelletti, G.; Fabiano, S.; Vecchi, M.; Penagini, R.; Doneda, L.; Elli, L. Effectiveness of Capsule Endoscopy and Double-Balloon Enteroscopy in Suspected Complicated Celiac Disease. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc.; 2020; in press [DOI: https://dx.doi.org/10.1016/j.cgh.2020.11.010]
116. Hadithi, M.; Al-Toma, A.; Oudejans, J.; Van Bodegraven, A.A.; Mulder, C.J.; Jacobs, M. The value of double-balloon enteroscopy in patients with refractory celiac disease. Am. J. Gastroenterol.; 2007; 102, pp. 987-996. [DOI: https://dx.doi.org/10.1111/j.1572-0241.2007.01122.x]
117. Daum, S.; Foss, H.-D.; Anagnostopoulos, I.; Dederke, B.; Demel, G.; Araujo, I.; Riecken, E.-O.; Stein, H. Expression of cytotoxic molecules in intestinal T-cell lymphomas. J. Pathol.; 1997; 182, pp. 311-317. [DOI: https://dx.doi.org/10.1002/(SICI)1096-9896(199707)182:3<311::AID-PATH888>3.0.CO;2-U]
118. De Bruin, P.C.; Connolly, C.E.; Oudejans, J.J.; Kummer, J.A.; Jansen, W.; Mccarthy, C.F.; Meijer, C.J.L.M. Enteropathy-associated T-cell lymphomas have a cytotoxic T-cell phenotype. Histopathology; 1997; 31, pp. 313-317. [DOI: https://dx.doi.org/10.1046/j.1365-2559.1997.2660862.x]
119. Daum, S.; Weiss, D.; Hummel, M.; Ullrich, R.; Heise, W.; Stein, H.; Riecken, E.O.; Foss, H.D. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut; 2001; 49, pp. 804-812. [DOI: https://dx.doi.org/10.1136/gut.49.6.804]
120. Verkarre, V.; Asnafi, V.; Lecomte, T.; Patey Mariaud-de Serre, N.; Leborgne, M.; Grosdidier, E.; Le Bihan, C.; Macintyre, E.; Cellier, C.; Cerf-Bensussan, N. et al. Refractory coeliac sprue is a diffuse gastrointestinal disease. Gut; 2003; 52, pp. 205-211. [DOI: https://dx.doi.org/10.1136/gut.52.2.205]
121. Verbeek, W.H.M.; Goerres, M.S.; von Blomberg, B.M.E.; Oudejans, J.J.; Scholten, P.E.T.; Hadithi, M.; Al-Toma, A.; Schreurs, M.W.J.; Mulder, C.J.J. Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in Refractory Celiac Disease. Clin. Immunol.; 2008; 126, pp. 48-56. [DOI: https://dx.doi.org/10.1016/j.clim.2007.09.002]
122. Hussein, S.; Gindin, T.; Lagana, S.M.; Arguelles-Grande, C.; Krishnareddy, S.; Alobeid, B.; Lewis, S.K.; Mansukhani, M.M.; Green, P.H.R.; Bhagat, G. Clonal T cell receptor gene rearrangements in coeliac disease: Implications for diagnosing refractory coeliac disease. J. Clin. Pathol.; 2018; 71, pp. 825-831. [DOI: https://dx.doi.org/10.1136/jclinpath-2018-205023]
123. Celli, R.; Hui, P.; Triscott, H.; Bogardus, S.; Gibson, J.; Hwang, M.; Robert, M.E. Clinical Insignficance of Monoclonal T-Cell Populations and Duodenal Intraepithelial T-Cell Phenotypes in Celiac and Nonceliac Patients. Am. J. Surg. Pathol.; 2019; 43, pp. 151-160. [DOI: https://dx.doi.org/10.1097/PAS.0000000000001172]
124. Patey-Mariaud De Serre, N.; Cellier, C.; Jabri, B.; Delabesse, E.; Verkarre, V.; Roche, B.; Lavergne, A.; Brière, J.; Mauvieux, L.; Leborgne, M. et al. Distinction between coeliac disease and refractory sprue: A simple immunohistochemical method. Histopathology; 2000; 37, pp. 70-77. [DOI: https://dx.doi.org/10.1046/j.1365-2559.2000.00926.x]
125. Rubio-Tapia, A.; Kelly, D.G.; Lahr, B.D.; Dogan, A.; Wu, T.T.; Murray, J.A. Clinical Staging and Survival in Refractory Celiac Disease: A Single Center Experience. Gastroenterology; 2009; 136, pp. 99-107. [DOI: https://dx.doi.org/10.1053/j.gastro.2008.10.013]
126. Liu, H.; Brais, R.; Lavergne-Slove, A.; Jeng, Q.; Payne, K.; Ye, H.; Liu, Z.; Carreras, J.; Huang, Y.; Bacon, C.M. et al. Continual monitoring of intraepithelial lymphocyte immunophenotype and clonality is more important than snapshot analysis in the surveillance of refractory coeliac disease. Gut; 2010; 59, pp. 452-460. [DOI: https://dx.doi.org/10.1136/gut.2009.186007]
127. Al-Toma, A.; Goerres, M.S.; Meijer, J.W.R.; Peña, A.S.; Crusius, J.B.A.; Mulder, C.J.J. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin. Gastroenterol. Hepatol.; 2006; 4, pp. 315-319. [DOI: https://dx.doi.org/10.1016/j.cgh.2005.12.011]
128. Wolters, V.M.; Verbeek, W.H.M.; Zhernakova, A.; Onland-Moret, C.; Schreurs, M.W.J.; Monsuur, A.J.; Verduijn, W.; Wijmenga, C.; Mulder, C.J.J. The MYO9B Gene Is a Strong Risk Factor for Developing Refractory Celiac Disease. Clin. Gastroenterol. Hepatol.; 2007; 5, pp. 1399-1405.e2. [DOI: https://dx.doi.org/10.1016/j.cgh.2007.08.018]
129. Zettl, A.; Ott, G.; Makulik, A.; Katzenberger, T.; Starostik, P.; Eichler, T.; Puppe, B.; Bentz, M.; Müller-Hermelink, H.K.; Chott, A. Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma. Am. J. Pathol.; 2002; 161, pp. 1635-1645. [DOI: https://dx.doi.org/10.1016/S0002-9440(10)64441-0]
130. Baumgärtner, A.K.; Zettl, A.; Chott, A.; Ott, G.; Müller-Hermelink, H.K.; Starostik, P. High Frequency of Genetic Aberrations in Enteropathy-Type T-Cell Lymphoma. Lab. Investig.; 2003; 83, pp. 1509-1516. [DOI: https://dx.doi.org/10.1097/01.LAB.0000090157.13040.58] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14563952]
131. Cording, S.; Lhermitte, L.; Malamut, G.; Berrabah, S.; Trinquand, A.; Guegan, N.; Villarese, P.; Kaltenbach, S.; Meresse, B.; Khater, S. et al. Oncogenetic landscape of lymphomagenesis in coeliac disease. Gut; 2021; [DOI: https://dx.doi.org/10.1136/gutjnl-2020-322935] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33579790]
132. Roshan, B.; Leffler, D.A.; Jamma, S.; Dennis, M.; Sheth, S.; Falchuk, K.; Najarian, R.; Goldsmith, J.; Tariq, S.; Schuppan, D. et al. The incidence and clinical spectrum of refractory celiac disease in a north american referral center. Am. J. Gastroenterol.; 2011; 106, pp. 923-928. [DOI: https://dx.doi.org/10.1038/ajg.2011.104]
133. Raderer, M.; Troch, M.; Kiesewetter, B.; Püspök, A.; Jaeger, U.; Hoffmann, M.; Chott, A. Second line chemotherapy in patients with enteropathy-associated T cell lymphoma: A retrospective single center analysis. Ann. Hematol.; 2012; 91, pp. 57-61. [DOI: https://dx.doi.org/10.1007/s00277-011-1236-x]
134. Hönemann, D.; Prince, H.M.; Hicks, R.J.; Seymour, J.F. Enteropathy-associated T-cell lymphoma without a prior diagnosis of coeliac disease: Diagnostic dilemmas and management options. Ann. Hematol.; 2005; 84, pp. 118-121. [DOI: https://dx.doi.org/10.1007/s00277-004-0953-9]
135. Egan, L.; Walsh, S.; Stevens, F.; Connolly, C.; Egan, E.; McCarthy, C. Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era. J. Clin. Gastroenterol.; 1995; 21, pp. 123-129. [DOI: https://dx.doi.org/10.1097/00004836-199509000-00012]
136. Wöhrer, S.; Chott, A.; Drach, J.; Püspök, A.; Hejna, M.; Hoffmann, M.; Raderer, M. Chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone (CHOEP) is not effective in patients with enteropathy-type intestinal T-cell lymphoma. Ann. Oncol.; 2004; 15, pp. 1680-1683. [DOI: https://dx.doi.org/10.1093/annonc/mdh427]
137. Sieniawski, M.; Angamuthu, N.; Boyd, K.; Chasty, R.; Davies, J.; Forsyth, P.; Jack, F.; Lyons, S.; Mounter, P.; Revell, P. et al. Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. Blood; 2010; 115, pp. 3664-3670. [DOI: https://dx.doi.org/10.1182/blood-2009-07-231324]
138. Kluin-Nelemans, H.C.; van Marwijk Kooy, M.; Lugtenburg, P.J.; van Putten, W.L.J.; Luten, M.; Oudejans, J.; van Imhoff, G.W. Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma. Ann. Oncol.; 2011; 22, pp. 1595-1600. [DOI: https://dx.doi.org/10.1093/annonc/mdq635]
139. Trumper, L.H.; Wulf, G.; Ziepert, M.; D’Amore, F.; Held, G.; Greil, R.; Tournilhac, O.; Relander, T.; Viardot, A.; Wilhelm, M. et al. Alemtuzumab added to CHOP for treatment of peripheral T-cell lymphoma (pTNHL) of the elderly: Final results of 116 patients treated in the international ACT-2 phase III trial. J. Clin. Oncol.; 2016; 34, 7500. [DOI: https://dx.doi.org/10.1200/JCO.2016.34.15_suppl.7500]
140. Wulf, G.G.; Altmann, B.; Ziepert, M.; D’Amore, F.; Held, G.; Greil, R.; Tournilhac, O.; Relander, T.; Viardot, A.; Wilhelm, M. et al. Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: The DSHNHL2006-1B/ACT-2 trial. Leukemia; 2021; 35, pp. 143-155. [DOI: https://dx.doi.org/10.1038/s41375-020-0838-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32382083]
141. Gallamini, A.; Zaja, F.; Patti, C.; Billio, A.; Specchia, M.R.; Tucci, A.; Levis, A.; Manna, A.; Secondo, V.; Rigacci, L. et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: Results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood; 2007; 110, pp. 2316-2323. [DOI: https://dx.doi.org/10.1182/blood-2007-02-074641] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17581918]
142. Soldini, D.; Mora, O.; Cavalli, F.; Zucca, E.; Mazzucchelli, L. Efficacy of alemtuzumab and gemcitabine in a patient with enteropathy-type T-cell lymphoma. Br. J. Haematol.; 2008; 142, pp. 484-486. [DOI: https://dx.doi.org/10.1111/j.1365-2141.2008.07202.x]
143. Kircher, S.M.; Gurbuxani, S.; Smith, S.M. CHOP Plus Alemtuzumab can Induce Metabolic Response by FDG-PET but has Minimal Long-term benefits: A Case Report and Literature Review. J. Gastrointest. Cancer; 2007; 38, pp. 59-62. [DOI: https://dx.doi.org/10.1007/s12029-008-9010-6]
144. Al-toma, A.; Goerres, M.S.; Meijer, J.W.R.; von Blomberg, B.M.E.; Wahab, P.J.; Kerckhaert, J.A.M.; Mulder, C.J.J. Cladribine Therapy in Refractory Celiac Disease With Aberrant T Cells. Clin. Gastroenterol. Hepatol.; 2006; 4, pp. 1322-1327. [DOI: https://dx.doi.org/10.1016/j.cgh.2006.07.007]
145. Tack, G.J.; Verbeek, W.H.M.; Al-Toma, A.; Kuik, D.J.; Schreurs, M.W.J.; Visser, O.; Mulder, C.J.J. Evaluation of cladribine treatment in refractory celiac disease type II. World J. Gastroenterol.; 2011; 17, pp. 506-513. [DOI: https://dx.doi.org/10.3748/wjg.v17.i4.506]
146. Piekarz, R.L.; Frye, R.; Prince, H.M.; Kirschbaum, M.H.; Zain, J.; Allen, S.L.; Jaffe, E.S.; Ling, A.; Turner, M.; Peer, C.J. et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood; 2011; 117, pp. 5827-5834. [DOI: https://dx.doi.org/10.1182/blood-2010-10-312603]
147. Khalaf, W.F.; Caldwell, M.E.; Reddy, N. Brentuximab in the treatment of CD30-positive enteropathy-associated T-cell lymphoma. J. Natl. Compr. Canc. Netw.; 2013; 11, pp. 137-140. [DOI: https://dx.doi.org/10.6004/jnccn.2013.0021]
148. Nijeboer, P.; Malamut, G.; Mulder, C.J.; Cerf-Bensussan, N.; Sibon, D.; Bouma, G.; Cellier, C.; Hermine, O.; Visser, O. Enteropathy-associated T-cell lymphoma: Improving treatment strategies. Dig. Dis.; 2015; 33, pp. 231-235. [DOI: https://dx.doi.org/10.1159/000369542]
149. Blystad, A.; Enblad, G.; Kvaløy, S.; Berglund, Å.; Delabie, J.; Holte, H.; Carlson, K.; Kvalheim, G.; Bengtsson, M.; Hagberg, H. High-dose therapy with autologous stem cell transplantation in patients with peripheral T cell lymphomas. Bone Marrow Transplant.; 2001; 27, pp. 711-716. [DOI: https://dx.doi.org/10.1038/sj.bmt.1702867]
150. Okuda, M.; Nomura, J.; Tateno, H.; Kameoka, J.; Sasaki, T. CD56 Positive Intestinal T-Cell Lymphoma: Treatment with High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation. Intern. Med.; 2002; 41, pp. 734-737. [DOI: https://dx.doi.org/10.2169/internalmedicine.41.734] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12322803]
151. Chonabayashi, K.; Kondo, T.; Tanaka, Y.; Ichinohe, T.; Ishikawa, T.; Uchiyama, T. Sustained complete remission of refractory enteropathy-type T-cell lymphoma following reduced-intensity unrelated cord blood transplantation. Bone Marrow Transplant.; 2007; 40, pp. 905-906. [DOI: https://dx.doi.org/10.1038/sj.bmt.1705828] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17704787]
152. Jantunen, E.; Juvonen, E.; Wiklund, T.; Putkonen, M.; Nousiainen, T. High-dose Therapy Supported by Autologous Stem Cell Transplantation in Patients with Enteropathy-associated T-cell Lymphoma. Leuk. Lymphoma; 2003; 44, pp. 2163-2164. [DOI: https://dx.doi.org/10.1080/1042819031000123456]
153. Rongey, C.; Micallef, I.; Smyrk, T.; Murray, J. Successful Treatment of Enteropathy-Associated T Cell Lymphoma with Autologous Stem Cell Transplant. Dig. Dis. Sci.; 2006; 51, pp. 1082-1086. [DOI: https://dx.doi.org/10.1007/s10620-006-8013-z]
154. Al-toma, A.; Verbeek, W.H.M.; Visser, O.J.; Kuijpers, K.C.; Oudejans, J.J.; Kluin-Nelemans, H.C.; Mulder, C.J.J.; Huijgens, P.C. Disappointing outcome of autologous stem cell transplantation for enteropathy-associated T-cell lymphoma. Dig. Liver Dis.; 2007; 39, pp. 634-641. [DOI: https://dx.doi.org/10.1016/j.dld.2007.03.009]
155. Nava, V.E.; Cohen, P.; Bishop, M.; Fowler, D.; Jaffe, E.S.; Ozdemirli, M. Enteropathy-type T-cell Lymphoma After Intestinal Diffuse Large B-cell Lymphoma. Am. J. Surg. Pathol.; 2007; 31, pp. 476-480. [DOI: https://dx.doi.org/10.1097/01.pas.0000213391.49698.57] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17325491]
156. Reimer, P.; Rüdiger, T.; Geissinger, E.; Weissinger, F.; Nerl, C.; Schmitz, N.; Engert, A.; Einsele, H.; Müller-Hermelink, H.K.; Wilhelm, M. Autologous Stem-Cell Transplantation As First-Line Therapy in Peripheral T-Cell Lymphomas: Results of a Prospective Multicenter Study. J. Clin. Oncol.; 2009; 27, pp. 106-113. [DOI: https://dx.doi.org/10.1200/JCO.2008.17.4870]
157. Prochazka, V.; Faber, E.; Raida, L.; Papajik, T.; Vondrakova, J.; Rusinakova, Z.; Kucerova, L.; Myslivecek, M.; Indrak, K. Long-term outcome of patients with peripheral T-cell lymphoma treated with first-line intensive chemotherapy followed by autologous stem cell transplantation. Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc. Czech Repub.; 2011; 155, pp. 63-69. [DOI: https://dx.doi.org/10.5507/bp.2011.009]
158. Nijeboer, P.; de Baaij, L.R.; Visser, O.; Witte, B.I.; Cillessen, S.A.G.M.; Mulder, C.J.; Bouma, G. Treatment response in enteropathy associated T-cell lymphoma; survival in a large multicenter cohort. Am. J. Hematol.; 2015; 90, pp. 493-498. [DOI: https://dx.doi.org/10.1002/ajh.23992] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25716069]
159. Leslie, L.A.; Lebwohl, B.; Neugut, A.I.; Gregory Mears, J.; Bhagat, G.; Green, P.H.R. Incidence of lymphoproliferative disorders in patients with celiac disease. Am. J. Hematol.; 2012; 87, pp. 754-759. [DOI: https://dx.doi.org/10.1002/ajh.23237] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22641457]
160. du Pré, M.F.; Blazevski, J.; Dewan, A.E.; Stamnaes, J.; Kanduri, C.; Sandve, G.K.; Johannesen, M.K.; Lindstad, C.B.; Hnida, K.; Fugger, L. et al. B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. J. Exp. Med.; 2020; 217, e20190860. [DOI: https://dx.doi.org/10.1084/jem.20190860]
161. Ansell, P.; Simpson, J.; Lightfoot, T.; Smith, A.; Kane, E.; Howell, D.; Newton, R.; McGonagle, D.; Jack, A.; Roman, E. Non-Hodgkin lymphoma and autoimmunity: Does gender matter?. Int. J. Cancer; 2011; 129, pp. 460-466. [DOI: https://dx.doi.org/10.1002/ijc.25680] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20853323]
162. Halfdanarson, T.R.; Rubio-Tapia, A.; Ristow, K.M.; Habermann, T.M.; Murray, J.A.; Inwards, D.J. Patients With Celiac Disease and B-Cell Lymphoma Have a Better Prognosis Than Those With T-Cell Lymphoma. Clin. Gastroenterol. Hepatol.; 2010; 8, pp. 1042-1047. [DOI: https://dx.doi.org/10.1016/j.cgh.2010.09.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20851210]
163. Ludvigsson, J.F.; Lebwohl, B.; Rubio-Tapia, A.; Murray, J.A.; Green, P.H.R.; Ekbom, A.; Granath, F. Does celiac disease influence survival in lymphoproliferative malignancy?. Eur. J. Epidemiol.; 2013; 28, pp. 475-483. [DOI: https://dx.doi.org/10.1007/s10654-013-9789-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23463575]
164. Giuffrida, P.; Vanoli, A.; Arpa, G.; Bonometti, A.; Luinetti, O.; Solcia, E.; Corazza, G.; Paulli, M.; Di Sabatino, A. Small Bowel Carcinomas Associated with Immune-Mediated Intestinal Disorders: The Current Knowledge. Cancers; 2018; 11, 31. [DOI: https://dx.doi.org/10.3390/cancers11010031] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30597986]
165. Aparicio, T.; Zaanan, A.; Svrcek, M.; Laurent-Puig, P.; Carrere, N.; Manfredi, S.; Locher, C.; Afchain, P. Small bowel adenocarcinoma: Epidemiology, risk factors, diagnosis and treatment. Dig. Liver Dis.; 2014; 46, pp. 97-104. [DOI: https://dx.doi.org/10.1016/j.dld.2013.04.013]
166. Bilimoria, K.Y.; Bentrem, D.J.; Wayne, J.D.; Ko, C.Y.; Bennett, C.L.; Talamonti, M.S. Small bowel cancer in the United States: Changes in epidemiology, treatment, and survival over the last 20 years. Ann. Surg.; 2009; 249, pp. 63-71. [DOI: https://dx.doi.org/10.1097/SLA.0b013e31818e4641]
167. Faivre, J.; Trama, A.; De Angelis, R.; Elferink, M.; Siesling, S.; Audisio, R.; Bosset, J.F.; Cervantes, A.; Lepage, C. RARECARE Working Group. Incidence, prevalence and survival of patients with rare epithelial digestive cancers diagnosed in Europe in 1995-2002. Eur. J. Cancer; 2012; 48, pp. 1417-1424. [DOI: https://dx.doi.org/10.1016/j.ejca.2011.10.038]
168. Elfström, P.; Granath, F.; Ye, W.; Ludvigsson, J.F. Low risk of gastrointestinal cancer among patients with celiac disease, inflammation, or latent celiac disease. Clin. Gastroenterol. Hepatol.; 2012; 10, pp. 30-36. [DOI: https://dx.doi.org/10.1016/j.cgh.2011.06.029]
169. Emilsson, L.; Semrad, C.; Lebwohl, B.; Green, P.H.R.; Ludvigsson, J.F. Risk of Small Bowel Adenocarcinoma, Adenomas, and Carcinoids in a Nationwide Cohort of Individuals With Celiac Disease. Gastroenterology; 2020; 159, pp. 1686-1694.e2. [DOI: https://dx.doi.org/10.1053/j.gastro.2020.07.007]
170. Rampertab, S.D.; Forde, K.A.; Green, P.H.R. Small bowel neoplasia in coeliac disease. Gut; 2003; 52, pp. 1211-1214. [DOI: https://dx.doi.org/10.1136/gut.52.8.1211]
171. Vanoli, A.; Di Sabatino, A.; Furlan, D.; Klersy, C.; Grillo, F.; Fiocca, R.; Mescoli, C.; Rugge, M.; Nesi, G.; Fociani, P. et al. Small bowel carcinomas in coeliac or Crohn’s disease: Clinico-pathological, molecular, and prognostic features. A study from the small bowel cancer Italian consortium. J. Crohn’s Colitis; 2017; 11, pp. 942-953. [DOI: https://dx.doi.org/10.1093/ecco-jcc/jjx031]
172. Potter, D.D.; Murray, J.A.; Donohue, J.H.; Burgart, L.J.; Nagorney, D.M.; Van Heerden, J.A.; Plevak, M.F.; Zinsmeister, A.R.; Thibodeau, S.N. The role of defective mismatch repair in small bowel adenocarcinoma in celiac disease. Cancer Res.; 2004; 64, pp. 7073-7077. [DOI: https://dx.doi.org/10.1158/0008-5472.CAN-04-1096]
173. Diosdado, B.; Buffart, T.E.; Watkins, R.; Carvalho, B.; Ylstra, B.; Tijssen, M.; Bolijn, A.S.; Lewis, F.; Maude, K.; Verbeke, C. et al. High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas. Clin. Cancer Res.; 2010; 16, pp. 1391-1401. [DOI: https://dx.doi.org/10.1158/1078-0432.CCR-09-1773]
174. Bruno, C.J.; Batts, K.P.; Ahlquist, D.A. Evidence against flat dysplasia as a regional field defect in small bowel adenocarcinoma associated with celiac sprue. Mayo Clin. Proc.; 1997; 72, pp. 320-322. [DOI: https://dx.doi.org/10.4065/72.4.320]
175. Schottenfeld, D.; Beebe-Dimmer, J.L.; Vigneau, F.D. The Epidemiology and Pathogenesis of Neoplasia in the Small Intestine. Ann. Epidemiol.; 2009; 19, pp. 58-69. [DOI: https://dx.doi.org/10.1016/j.annepidem.2008.10.004]
176. Goodman, M.T.; Matsuno, R.K.; Shvetsov, Y.B. Racial and ethnic variation in the incidence of small-bowel cancer subtypes in the United States, 1995–2008. Dis. Colon Rectum; 2013; 56, pp. 441-448. [DOI: https://dx.doi.org/10.1097/DCR.0b013e31826b9d0a] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23478611]
177. Caio, G.; Volta, U.; Ursini, F.; Manfredini, R.; De Giorgio, R. Small bowel adenocarcinoma as a complication of celiac disease: Clinical and diagnostic features. BMC Gastroenterol.; 2019; 19, 45. [DOI: https://dx.doi.org/10.1186/s12876-019-0964-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30917787]
178. Vanoli, A.; Di Sabatino, A.; Martino, M.; Klersy, C.; Grillo, F.; Mescoli, C.; Nesi, G.; Volta, U.; Fornino, D.; Luinetti, O. et al. Small bowel carcinomas in celiac or Crohn’s disease: Distinctive histophenotypic, molecular and histogenetic patterns. Mod. Pathol.; 2017; 30, pp. 1453-1466. [DOI: https://dx.doi.org/10.1038/modpathol.2017.40]
179. Grolleau, C.; Pote, N.M.; Guedj, N.S.; Zappa, M.; Theou-Anton, N.; Bouhnik, Y.; Panis, Y.; Cazals-Hatem, D.L. Small bowel adenocarcinoma complicating Crohn’s disease: A single-centre experience emphasizing the importance of screening for dysplasia. Virchows Arch.; 2017; 471, pp. 611-617. [DOI: https://dx.doi.org/10.1007/s00428-017-2125-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28421339]
180. Rashid, A.; Hamilton, S.R. Genetic alterations in sporadic and Crohn’s-associated adenocarcinomas of the small intestine. Gastroenterology; 1997; 113, pp. 127-135. [DOI: https://dx.doi.org/10.1016/S0016-5085(97)70087-8]
181. Warth, A.; Kloor, M.; Schirmacher, P.; Bläker, H. Genetics and epigenetics of small bowel adenocarcinoma: The interactions of CIN, MSI, and CIMP. Mod. Pathol.; 2011; 24, pp. 564-570. [DOI: https://dx.doi.org/10.1038/modpathol.2010.223] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21297586]
182. Overman, M.J.; Pozadzides, J.; Kopetz, S.; Wen, S.; Abbruzzese, J.L.; Wolff, R.A.; Wang, H. Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine. Br. J. Cancer; 2010; 102, pp. 144-150. [DOI: https://dx.doi.org/10.1038/sj.bjc.6605449]
183. Bojesen, R.D.; Riis, L.B.; Høgdall, E.; Nielsen, O.H.; Jess, T. Inflammatory Bowel Disease and Small Bowel Cancer Risk, Clinical Characteristics, and Histopathology: A Population-Based Study. Clin. Gastroenterol. Hepatol.; 2017; 15, pp. 1900-1907.e2. [DOI: https://dx.doi.org/10.1016/j.cgh.2017.06.051]
184. Rizzo, F.; Vanoli, A.; Sahnane, N.; Cerutti, R.; Trapani, D.; Rinaldi, A.; Sellitto, A.; Ciacci, C.; Volta, U.; Villanacci, V. et al. Small-bowel carcinomas associated with celiac disease: Transcriptomic profiling shows predominance of microsatellite instability-immune and mesenchymal subtypes. Virchows Arch.; 2020; 476, pp. 711-723. [DOI: https://dx.doi.org/10.1007/s00428-019-02675-w]
185. Schrock, A.B.; Devoe, C.E.; McWilliams, R.; Sun, J.; Aparicio, T.; Stephens, P.J.; Ross, J.S.; Wilson, R.; Miller, V.A.; Ali, S.M. et al. Genomic profiling of small-bowel adenocarcinoma. JAMA Oncol.; 2017; 3, pp. 1546-1553. [DOI: https://dx.doi.org/10.1001/jamaoncol.2017.1051]
186. Aparicio, T.; Svrcek, M.; Zaanan, A.; Beohou, E.; Laforest, A.; Afchain, P.; Mitry, E.; Taieb, J.; Di Fiore, F.; Gornet, J.M. et al. Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study. Br. J. Cancer; 2013; 109, pp. 3057-3066. [DOI: https://dx.doi.org/10.1038/bjc.2013.677]
187. Svrcek, M.; Piton, G.; Cosnes, J.; Beaugerie, L.; Vermeire, S.; Geboes, K.; Lemoine, A.; Cervera, P.; El-Murr, N.; Dumont, S. et al. Small bowel adenocarcinomas complicating Crohn’s disease are associated with dysplasia: A pathological and molecular study. Inflamm. Bowel Dis.; 2014; 20, pp. 1584-1592. [DOI: https://dx.doi.org/10.1097/MIB.0000000000000112]
188. Younes, N.; Fulton, N.; Tanaka, R.; Wayne, J.; Straus, F., 2nd; Kaplan, E. The presence of K-12 ras mutations in duodenal adenocarcinomas and the absence of ras mutations in other small bowel adenocarcinomas and carcinoid tumors. Cancer; 1997; 79, pp. 1804-1808. [DOI: https://dx.doi.org/10.1002/(SICI)1097-0142(19970501)79:9<1804::AID-CNCR24>3.0.CO;2-0]
189. Bläker, H.; Helmchen, B.; Bönisch, A.; Aulmann, S.; Penzel, R.; Otto, H.F.; Rieker, R.J. Mutational activation of the RAS-RAF-MAPK and the wnt pathway in small intestinal adenocarcinomas. Scand. J. Gastroenterol.; 2004; 39, pp. 748-753. [DOI: https://dx.doi.org/10.1080/00365520410005847] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15513360]
190. Lee, H.J.; Lee, O.J.; Jang, K.T.; Bae, Y.K.; Chung, J.Y.; Eom, D.W.; Kim, J.M.; Yu, E.; Hong, S.M. Combined loss of e-cadherin and aberrant β-catenin protein expression correlates with a poor prognosis for small intestinal adenocarcinomas. Am. J. Clin. Pathol.; 2013; 139, pp. 167-176. [DOI: https://dx.doi.org/10.1309/AJCPS54RTFCTHGWX] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23355201]
191. Laforest, A.; Aparicio, T.; Zaanan, A.; Silva, F.P.; Didelot, A.; Desbeaux, A.; Le Corre, D.; Benhaim, L.; Pallier, K.; Aust, D. et al. ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. Eur. J. Cancer; 2014; 50, pp. 1740-1746. [DOI: https://dx.doi.org/10.1016/j.ejca.2014.04.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24797764]
192. Perzin, K.H.; Bridge, M.F. Adenomas of the small intestine: A clinicopathologic review of 51 cases and a study of their relationship to carcinoma. Cancer; 1981; 48, pp. 799-819. [DOI: https://dx.doi.org/10.1002/1097-0142(19810801)48:3<799::AID-CNCR2820480324>3.0.CO;2-Q]
193. Genta, R.M.; Feagins, L.A. Advanced precancerous lesions in the small bowel mucosa. Best Pract. Res. Clin. Gastroenterol.; 2013; 27, pp. 225-233. [DOI: https://dx.doi.org/10.1016/j.bpg.2013.03.013] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23809242]
194. Raghav, K.; Overman, M.J. Small bowel adenocarcinomas—existing evidence and evolving paradigms. Nat. Rev. Clin. Oncol.; 2013; 10, pp. 534-544. [DOI: https://dx.doi.org/10.1038/nrclinonc.2013.132] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23897080]
195. Tomba, C.; Sidhu, R.; Sanders, D.S.; Mooney, P.D.; Branchi, F.; Locatelli, M.; Roncoroni, L.; Conte, D.; Bardella, M.T.; Elli, L. Celiac Disease and Double-Balloon Enteroscopy: What Can We Achieve? The Experience of 2 European Tertiary Referral Centers. J. Clin. Gastroenterol.; 2016; 50, pp. 313-317. [DOI: https://dx.doi.org/10.1097/MCG.0000000000000424]
196. Tomba, C.; Elli, L.; Bardella, M.T.; Soncini, M.; Contiero, P.; Roncoroni, L.; Locatelli, M.; Conte, D. Enteroscopy for the early detection of small bowel tumours in at-risk celiac patients. Dig. Liver Dis.; 2014; 46, pp. 400-404. [DOI: https://dx.doi.org/10.1016/j.dld.2013.12.009]
197. Overman, M.J.; Hu, C.-Y.; Kopetz, S.; Abbruzzese, J.L.; Wolff, R.A.; Chang, G.J. A Population-Based Comparison of Adenocarcinoma of the Large and Small Intestine: Insights Into a Rare Disease. Ann. Surg. Oncol.; 2012; 19, pp. 1439-1445. [DOI: https://dx.doi.org/10.1245/s10434-011-2173-6]
198. Dabaja, B.S.; Suki, D.; Pro, B.; Bonnen, M.; Ajani, J. Adenocarcinoma of the small bowel. Cancer; 2004; 101, pp. 518-526. [DOI: https://dx.doi.org/10.1002/cncr.20404]
199. Halfdanarson, T.R.; McWilliams, R.R.; Donohue, J.H.; Quevedo, J.F. A single-institution experience with 491 cases of small bowel adenocarcinoma. Am. J. Surg.; 2010; 199, pp. 797-803. [DOI: https://dx.doi.org/10.1016/j.amjsurg.2009.05.037]
200. Aparicio, T.; Henriques, J.; Manfredi, S.; Tougeron, D.; Bouché, O.; Pezet, D.; Piessen, G.; Coriat, R.; Zaanan, A.; Legoux, J.-L. et al. Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients. Int. J. Cancer; 2020; 147, pp. 967-977. [DOI: https://dx.doi.org/10.1002/ijc.32860]
201. Veyrières, M.; Baillet, P.; Hay, J.M.; Fingerhut, A.; Bouillot, J.L.; Julien, M. Factors influencing long-term survival in 100 cases of small intestine primary adenocarcinoma. Am. J. Surg.; 1997; 173, pp. 237-239. [DOI: https://dx.doi.org/10.1016/S0002-9610(97)89599-2]
202. Palascak-Juif, V.; Bouvier, A.M.; Cosnes, J.; Flourié, B.; Bouché, O.; Cadiot, G.; Lémann, M.; Bonaz, B.; Denet, C.; Marteau, P. et al. Small bowel adenocarcinoma in patients with Crohn’s disease compared with small bowel adenocarcinoma de novo. Inflamm. Bowel Dis.; 2005; 11, pp. 828-832. [DOI: https://dx.doi.org/10.1097/01.mib.0000179211.03650.b6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16116317]
203. Weber, N.K.; Fletcher, J.G.; Fidler, J.L.; Barlow, J.M.; Pruthi, S.; Loftus, E.V.; Pardi, D.S.; Smyrk, T.C.; Becker, B.D.; Pasha, S.F. et al. Clinical characteristics and imaging features of small bowel adenocarcinomas in Crohn’s disease. Abdom. Imaging; 2015; 40, pp. 1060-1067. [DOI: https://dx.doi.org/10.1007/s00261-014-0144-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24760323]
204. Giuffrida, P.; Arpa, G.; Grillo, F.; Klersy, C.; Sampietro, G.; Ardizzone, S.; Fociani, P.; Fiocca, R.; Latella, G.; Sessa, F. et al. PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability. Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc.; 2020; 33, pp. 1398-1409. [DOI: https://dx.doi.org/10.1038/s41379-020-0497-0]
205. Vanoli, A.; Grillo, F.; Guerini, C.; Neri, G.; Arpa, G.; Klersy, C.; Nesi, G.; Giuffrida, P.; Sampietro, G.; Ardizzone, S. et al. Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas. Ann. Surg. Oncol.; 2021; 28, pp. 1167-1177. [DOI: https://dx.doi.org/10.1245/s10434-020-08926-4]
206. Locher, C.; Batumona, B.; Afchain, P.; Carrère, N.; Samalin, E.; Cellier, C.; Aparicio, T.; Becouarn, Y.; Bedenne, L.; Michel, P. et al. Small bowel adenocarcinoma: French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO). Dig. Liver Dis.; 2018; 50, pp. 15-19. [DOI: https://dx.doi.org/10.1016/j.dld.2017.09.123]
207. Santini, D.; Fratto, M.E.; Spoto, C.; Russo, A.; Galluzzo, S.; Zoccoli, A.; Vincenzi, B.; Tonini, G. Cetuximab in small bowel adenocarcinoma: A new friend. Br. J. Cancer; 2010; 103, 1305. [DOI: https://dx.doi.org/10.1038/sj.bjc.6605898]
208. Falcone, R.; Roberto, M.; Filetti, M.; Anselmi, E.; Marchetti, P. Anti epidermal growth factor receptor therapy in small bowel adenocarcinoma. Medicine; 2018; 97, e9672. [DOI: https://dx.doi.org/10.1097/MD.0000000000009672]
209. Gulhati, P.; Raghav, K.; Shroff, R.; Varadhachary, G.; Javle, M.; Qiao, W.; Wang, H.; Morris, J.; Wolff, R.; Overman, M.J. Phase II Study of Panitumumab in RAS Wild-Type Metastatic Adenocarcinoma of Small Bowel or Ampulla of Vater. Oncologist; 2018; 23, 277. [DOI: https://dx.doi.org/10.1634/theoncologist.2017-0568]
210. Hamad, A.; Singhi, A.D.; Bahary, N.; McGrath, K.; Amarin, R.; Zeh, H.J.; Zureikat, A.H. Neoadjuvant treatment with trastuzumab and folfox induces a complete pathologic response in a metastatic ERBB2 (HER2)-Amplified Duodenal Cancer. JNCCN J. Natl. Compr. Cancer Netw.; 2017; 15, pp. 983-988. [DOI: https://dx.doi.org/10.6004/jnccn.2017.0140]
211. Le, D.T.; Durham, J.N.; Smith, K.N.; Wang, H.; Bartlett, B.R.; Aulakh, L.K.; Lu, S.; Kemberling, H.; Wilt, C.; Luber, B.S. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science; 2017; 357, pp. 409-413. [DOI: https://dx.doi.org/10.1126/science.aan6733]
212. Lebwohl, B.; Stavsky, E.; Neugut, A.I.; Green, P.H.R. Risk of colorectal adenomas in patients with coeliac disease. Aliment. Pharmacol. Ther.; 2010; 32, pp. 1037-1043. [DOI: https://dx.doi.org/10.1111/j.1365-2036.2010.04440.x]
213. Landgren, A.M.; Landgren, O.; Gridley, G.; Dores, G.M.; Linet, M.S.; Morton, L.M. Autoimmune disease and subsequent risk of developing alimentary tract cancers among 4.5 million US male veterans. Cancer; 2011; 117, pp. 1163-1171. [DOI: https://dx.doi.org/10.1002/cncr.25524]
214. Volta, U.; Vincentini, O.; Quintarelli, F.; Felli, C.; Silano, M. Low risk of colon cancer in patients with celiac disease. Scand. J. Gastroenterol.; 2014; 49, pp. 564-568. [DOI: https://dx.doi.org/10.3109/00365521.2014.893012]
215. Ludvigsson, J.F.; West, J.; Ekbom, A.; Stephansson, O. Reduced risk of breast, endometrial and ovarian cancer in women with celiac disease. Int. J. Cancer; 2012; 131, pp. E244-E250. [DOI: https://dx.doi.org/10.1002/ijc.26454]
216. Persson, I. Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from epidemiological findings. J. Steroid Biochem. Mol. Biol.; 2000; 74, pp. 357-364. [DOI: https://dx.doi.org/10.1016/S0960-0760(00)00113-8]
217. Olén, O.; Montgomery, S.M.; Marcus, C.; Ekbom, A.; Ludvigsson, J.F. Coeliac disease and body mass index: A study of two Swedish general population-based registers. Scand. J. Gastroenterol.; 2009; 44, pp. 1198-1206. [DOI: https://dx.doi.org/10.1080/00365520903132013]
218. Michels, K.B.; Ekbom, A. Caloric restriction and incidence of breast cancer. JAMA; 2004; 291, pp. 1226-1230. [DOI: https://dx.doi.org/10.1001/jama.291.10.1226]
219. Ahlgren, M.; Melbye, M.; Wohlfahrt, J.; Sørensen, T.I.A. Growth patterns and the risk of breast cancer in women. N. Engl. J. Med.; 2004; 351, pp. 1619-1626. [DOI: https://dx.doi.org/10.1056/NEJMoa040576]
220. Ludvigsson, J.F.; Ansved, P.; Fälth-Magnusson, K.; Hammersjö, J.-A.; Johansson, C.; Edvardsson, S.; Ljungkrantz, M.; Stenhammar, L.; Ludvigsson, J. Symptoms and signs have changed in Swedish children with coeliac disease. J. Pediatr. Gastroenterol. Nutr.; 2004; 38, pp. 181-186. [DOI: https://dx.doi.org/10.1097/00005176-200402000-00015] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14734881]
221. Ludvigsson, J.F.; Fall, K.; Montgomery, S. Risk of prostate cancer in a population-based cohort of men with coeliac disease. Br. J. Cancer; 2012; 106, pp. 217-221. [DOI: https://dx.doi.org/10.1038/bjc.2011.536] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22134505]
222. Kent, L.; McBride, R.; McConnell, R.; Neugut, A.I.; Bhagat, G.; Green, P.H.R. Increased risk of papillary thyroid cancer in celiac disease. Dig. Dis. Sci.; 2006; 51, pp. 1875-1877. [DOI: https://dx.doi.org/10.1007/s10620-006-9240-z]
223. Volta, U.; Vincentini, O.; Silano, M. Papillary cancer of thyroid in celiac disease. J. Clin. Gastroenterol.; 2011; 45, pp. e44-e46. [DOI: https://dx.doi.org/10.1097/MCG.0b013e3181ea11cb]
224. Ludvigsson, J.F.; Lebwohl, B.; Kämpe, O.; Murray, J.A.; Green, P.H.; Ekbom, A. Risk of thyroid cancer in a nationwide cohort of patients with biopsy-verified celiac disease. Thyroid; 2013; 23, pp. 971-976. [DOI: https://dx.doi.org/10.1089/thy.2012.0306]
225. Lebwohl, B.; Eriksson, H.; Hansson, J.; Green, P.H.R.; Ludvigsson, J.F. Risk of cutaneous malignant melanoma in patients with celiac disease: A population-based study. J. Am. Acad. Dermatol.; 2014; 71, pp. 245-248. [DOI: https://dx.doi.org/10.1016/j.jaad.2014.03.029]
226. Pereyra, L.; Gonzalez, R.; Mohaidle, A.; Fischer, C.; Mella, J.M.; Panigadi, G.N.; Manazzoni, D.; Matoso, M.D.; Lasa, J.S.; Novillo, A. et al. Risk of colorectal neoplasia in patients with celiac disease: A multicenter study. J. Crohns. Colitis; 2013; 7, pp. e672-e677. [DOI: https://dx.doi.org/10.1016/j.crohns.2013.06.005]
227. Silano, M.; Volta, U.; De Vincenzi, A.; Dessì, M.; Vincenzi, M. De Effect of a gluten-free diet on the risk of enteropathy-associated T-cell lymphoma in celiac disease. Dig. Dis. Sci.; 2008; 53, pp. 972-976. [DOI: https://dx.doi.org/10.1007/s10620-007-9952-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17934841]
228. Olén, O.; Askling, J.; Ludvigsson, J.F.; Hildebrand, H.; Ekbom, A.; Smedby, K.E. Coeliac disease characteristics, compliance to a gluten free diet and risk of lymphoma by subtype. Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver; 2011; 43, pp. 862-868. [DOI: https://dx.doi.org/10.1016/j.dld.2011.07.012] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21880561]
229. Mukherjee, R.; Kelly, C.P.; Leffler, D.A. Gastrointestinal cancer in celiac disease: “the first days are the hardest days, don’t you worry anymore?. Clin. Gastroenterol. Hepatol.; 2012; 10, pp. 4-6. [DOI: https://dx.doi.org/10.1016/j.cgh.2011.09.028] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21982968]
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; Marsilio, Ilaria 1 ; Fassan, Matteo 2
; Piazza, Francesco 3
; Barberio, Brigida 1 ; Anna D’Odorico 1 ; Savarino, Edoardo V 1
; Farinati, Fabio 1 ; Zingone, Fabiana 1 1 Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy;
2 Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University Hospital of Padova, 35128 Padova, Italy;
3 Department of Medicine, Hematology, University Hospital of Padova, 35128 Padova, Italy;