Small bowel adenocarcinoma complicating Crohn’s disease: a single-centre experience emphasizing the importance of screening for dysplasia

Abstract

Small bowel adenocarcinoma (SBA) complicating Crohn's disease (CD) is rare and generally found incidentally on surgical specimens. We report our experience in CD-associated SBA observed this last decade in a tertiary referral centre in order to update its incidence, clinical presentation and pathological features. All SBAs diagnosed in patients who underwent surgery for CD between 2006 and 2016 were retrospectively included. Clinico-pathological characteristics were reviewed, and follow-up was updated. SBA was diagnosed in 9 (1.7%) of 522 patients who underwent SB resection(s) after a median CD duration of 15 years [0-32]. The median age at diagnosis was 46 years. Seven (78%) patients had obstructive symptoms refractory to medical treatment. Pre-operative biopsy revealed neoplasia in five (56%) patients (dysplasia in three and SBA in two) justifying the surgery. Two (29%) of the seven patients with imaging had features suggestive of cancer. In all specimens, SBA developed in active ileitis with adjacent dysplasia. Stage I low-grade tubulo-glandular adenocarcinoma was observed in 33% of patients. Stage IV high-grade adenocarcinoma was observed in 56% of patients, and mucinous/signet ring cell differentiation predominated in 44% of patients. Molecular analysis showed no BRAF mutation, a KRAS mutation in one case and a microsatellite instability phenotype suggestive of Lynch syndrome in one case. After a median follow-up of 24 months [7-82], four (44%) patients died with advanced stage IV SBA. This surgical series confirms that CD-associated SBA is rare with an incidence of 1.7%. Adjacent dysplasia was present in all specimens and was identified before surgery in all patients who benefit from ileal biopsies. This strengthens the importance of screening all longstanding CD by endoscopy if surgery is not considered.

Small Bowel Carcinomas Associated with Immune-Mediated Intestinal Disorders: the Current Knowledge

“…To the best of our knowledge, there are no data on SMAD4 mutation frequency in CD-SBC and CrD-SBC. BRAF V600E mutation, which is extremely rare in spo-SBC [51], is also absent in both CD-SBC and CrD-SBC [2,10,11] or detected up to 7% of CrD-SBC in other studies [8,12]. Therefore, unlike colorectal cancer [53,54], BRAF mutation does not seem to play a role in inducing MLH1 gene methylation, a frequent finding in CD-SBC [2,5].…”

“…Nevertheless, medullary-type cancers have been reported in association with CD-SBC [7,41] Table 3 shows the studies investigating molecular alteration in the cohorts including at least 5 cases of CD-SBC and/or CrD-SBC. MSI, which is a consequence of defective DNA mismatch repair and is verified by mean of molecular and/or immunohistochemical analysis, is found in around one third of all non-familial SBC with significant differences between CD-SBC (65-73% MSI) [2,5,5], CrD-SBC (0-16% MSI) [2,8,[10][11][12], and spo-SBC (9-35%) ( Table 1, Table 3) Promoter hypermethylation of APC has been demonstrated in 73% of CD-SBC, whereas nonsense APC mutations have not been reported in CD-SBC. 5 Likewise, allelic loss of APC gene was rare in CrD-SBC [10].…”

“…Although dysplastic lesions adjacent to CD-SBC are remarkably rare [7,21,56], the recurrent presence of dysplasia in the superficial part of CrD-SBC as well as in that of spo-SBC has been identified [7,8,57,58]. In particular, in both CrD-SBC and CD-SBC, dysplasia has been described as either flat or raised [7,8,[10][11][12]56]. Dysplasia is distant or adjacent to CrD-SBC [7,8,[10][11][12], while no dysplasia distant from SBC has been reported in coeliac patients [7,56].…”

“…On the other hand, SBC often localise in the inflamed ileum in CrD [2,8], a form of relapsing transmural inflammatory bowel disease due to an abnormal immune response to commensal microbiota [9]. Most CrD-SBC are microsatellite stable, have low TILs and often show a non-glandular histotype coupled with a non-intestinal phenotype [2,7,8,[10][11][12].…”

“…On the other hand, small bowel resection and use of salicylates for more than two years protect against SBC in patients with CrD. 25 As regards gender, the rates of female prevalence are extremely heterogeneous in both CD-SBC (25-62%) [2,5,5,20,21] and CrD-SBC (29-60%) [2,8,[10][11][12][22][23][24][25][26][27][28][29] so that it is hard to assess a gender predominance in either conditions. However, considering the strong prevalence of CD in women [4], these data may suggest that male gender is at higher risk to develop CD-SBC.…”