Abstract
Simple SummarySince small bowel adenocarcinoma may mimic a colorectal primary neoplasm histologically, it is pivotal to find biomarkers to discriminate these two biologically distinct neoplasms. The aim of our study was to evaluate the expression of special AT-rich sequence-binding protein 2 (SATB2), expressed in the vast majority of colorectal carcinomas, and other gastrointestinal phenotypic markers, such as cytokeratin 7, cytokeratin 20 and caudal type homeobox 2 (CDX2), in 100 small bowel adenocarcinomas. We identified 20 SATB2-positive small bowel adenocarcinomas, including nine sporadic cancers, seven celiac disease-associated cancers and four Crohn’s disease-associated small bowel adenocarcinomas. Six small bowel adenocarcinomas, including two cases associated with celiac disease and four sporadic, displayed a full colorectal carcinoma-like immunoprofile. Unlike SATB2, cytokeratin patterns stratified small bowel adenocarcinoma patient prognosis. The small bowel should be considered as one of the possible sites of origin in cancers of unknown primary, even when the neoplasm shows a colorectal carcinoma-like immunoprofile.Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn’s disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7−/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7−/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7−/CK20− or CK7−/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20− or CK7+/CK20+ cancers (p = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7−/CK20− cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.
Highlights
Primary non-ampullary small bowel adenocarcinoma (SBA) accounts for less than 3% of malignant neoplasms of the gastrointestinal (GI) tract, despite the fact that the small bowel covers more than90% of the whole GI surface area [1]
When SATB2+ SBAs were tested for alpha-methylacyl-CoA racemase (AMACR) expression, we identified a subset of six SBAs displaying an AMACR positive staining in addition to a CK7-/CK20+/Caudal type homeobox 2 (CDX2)+/SATB2+
We found that 20% of SBAs expressed the lower GI marker SATB2, while 6% of SBAs exhibited a complete CRC-like immunoprofile (i.e., CK7−/CK20+/CDX2+/SATB2+/AMACR+)
Summary
Primary non-ampullary small bowel adenocarcinoma (SBA) accounts for less than 3% of malignant neoplasms of the gastrointestinal (GI) tract, despite the fact that the small bowel covers more than90% of the whole GI surface area [1]. Primary non-ampullary small bowel adenocarcinoma (SBA) accounts for less than 3% of malignant neoplasms of the gastrointestinal (GI) tract, despite the fact that the small bowel covers more than. In the US population, SBA represents the second most common cancer histotype in the small bowel, following neuroendocrine tumors, and accounts for. Predisposing conditions for the SBA development include both hereditary syndromes and immune-mediated disorders, such as Crohn’s disease and celiac disease [3,4,5]. The duodenum is the most frequently involved segment (55–82%), followed by the jejunum (25–29%) and ileum (10–13%), the latter representing the predominant site in Crohn’s disease-associated SBAs [1,2]. SBA is a neoplasm similar to or indistinguishable from lower GI tract adenocarcinomas, a higher incidence of poorly differentiated tumors has been described in SBAs [1]. SBAs, show some important epidemiological, clinical and molecular differences when compared with colorectal carcinomas (CRCs): (i) the incidence of CRC is declining, while that of SBAs is increasing [2]; (ii) SBA patients have a worse prognosis in comparison with CRC patients, as the five-year survival rate is 35% for SBA versus 51.5% for CRC [6]; (iii) unique molecular differences between SBA and CRC exist with regard to the percentage of several genetic driver mutations, such as TP53 (58.4% in SBA vs. 75.0% in CRC), APC (26.8% vs. 75.9%) and CDKN2A (14.5% vs. 2.6%), leading to potential therapeutic implications [7]
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