Combined Loss of E-cadherin and Aberrant -Catenin Protein Expression Correlates With a Poor Prognosis for Small Intestinal Adenocarcinomas

Dept of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
American Journal of Clinical Pathology (Impact Factor: 2.51). 02/2013; 139(2):167-76. DOI: 10.1309/AJCPS54RTFCTHGWX
Source: PubMed


Small intestinal adenocarcinomas (SIACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and β-catenin, we performed immunohistochemistry for E-cadherin and β-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant β-catenin expression were observed in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant β-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with both loss of E-cadherin and aberrant β-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant β-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC.

Download full-text


Available from: Hee Jin Lee, Oct 21, 2014
10 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Small bowel cancers account for 3% of all gastrointestinal malignancies and small bowel adenocarcinomas represent a third of all small bowel cancers. Rarity of small bowel adenocarcinomas restricts molecular understanding and presents unique diagnostic and therapeutic challenges. Better cross-sectional imaging techniques and development of enteroscopy and capsule endoscopy have facilitated earlier and more-accurate diagnosis. Surgical resection remains the mainstay of therapy for locoregional disease. In the metastatic setting, fluoropyrimidine and oxaliplatin-based chemotherapy has shown clinical benefit in prospective non-randomized trials. Although frequently grouped under the same therapeutic umbrella as large bowel adenocarcinomas, small bowel adenocarcinomas are distinct clinical and molecular entities. Recent progress in molecular characterization has aided our understanding of the pathogenesis of these tumours and holds potential for prospective development of novel targeted therapies. Multi-institutional collaborative efforts directed towards cogent understanding of tumour biology and designing sensible clinical trials are essential for developing improved therapeutic strategies. In this Review, we endeavour to outline an evidence-based approach to present-day management of small bowel adenocarcinoma, describe contemporary challenges and uncover evolving paradigms in the management of these rare 'orphan' neoplasias.
    Nature Reviews Clinical Oncology 07/2013; 10(9). DOI:10.1038/nrclinonc.2013.132 · 14.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Due to the rarity of small intestine adenocarcinoma (SIAC), estimating the prognosis for patients with surgically resected SIAC is difficult. Overexpression of S100A4 has been linked to worse patient survival in several malignant neoplasms, but its significance in SIAC has not been determined. S100A4 protein expression was assessed in 197 surgically resected SIAC cases and compared with clinicopathological factors, including patient survival. A progressive increase in S100A4 labelling was observed in normal intestinal epithelium, adenoma and adenocarcinoma (p<0.001), and 50 SIAC cases (26.2%) showed strong S100A4 expression. Patients with SIAC with strong S100A4 expression had a higher pT classification (p=0.05), as well as increased lymph node metastasis (p=0.009) and perineural invasion (p=0.002). Patients with SIAC with strong S100A4 expression had significantly worse survival (median survival, 21 months) than those with weak/no S100A4 expression (42.5 months) by univariable (p=0.04) and multivariable (p=0.01) analyses. S100A4 overexpression is observed in a subset of SIACs, is associated with advanced disease and can be used as a prognostic indicator of poor prognosis in patients with SIAC.
    Journal of clinical pathology 09/2013; 67(3). DOI:10.1136/jclinpath-2013-201883 · 2.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking. Methods: Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated. Results: We obtained samples from 63 SBA patients (tumour stages: I–II: 30% III: 35% IV: 32% locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P<0.001), WHO PS 0–1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0–1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0–1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS. Conclusion: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.
    British Journal of Cancer 11/2013; 109(12). DOI:10.1038/bjc.2013.677 · 4.84 Impact Factor
Show more