Signet ring cell differentiation in mucinous colorectal carcinoma

Approximately 10% of all colorectal carcinomas are mucinous carcinomas, characterized by extracellular mucin. Occasionally, mucin accumulates intracellularly in these tumours, causing signet ring cell differentiation. We hypothesized that signet ring cells arise from a separate genetic pathway. In t...

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Bibliographic Details
Published in:The Journal of pathology 2007-07, Vol.212 (3), p.278-286
Main Authors: Börger, ME, Gosens, MJEM, Jeuken, JWM, van Kempen, LCLT, van de Velde, CJH, van Krieken, JHJM, Nagtegaal, ID
Format: Article
Language:English
Subjects:
Adenocarcinoma, Mucinous - pathology
Analysis of Variance
beta Catenin - analysis
beta Catenin - genetics
Biological and medical sciences
Cadherins - analysis
Cadherins - genetics
Carcinoma, Signet Ring Cell - pathology
Cell Differentiation
Cell Line
colorectal carcinoma
Colorectal Neoplasms - pathology
DNA Probes - genetics
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression
Genes, bcl-2
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Investigative techniques, diagnostic techniques (general aspects)
Medical sciences
Mucin-2
Mucins - analysis
Mucins - genetics
Neoplasm Staging
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Peptides - analysis
Peptides - genetics
RNA, Messenger - analysis
signet ring cell carcinoma
Statistics, Nonparametric
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Trefoil Factor-2
Tumors
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Summary:Approximately 10% of all colorectal carcinomas are mucinous carcinomas, characterized by extracellular mucin. Occasionally, mucin accumulates intracellularly in these tumours, causing signet ring cell differentiation. We hypothesized that signet ring cells arise from a separate genetic pathway. In this study the molecular background of signet ring cell differentiation was investigated by analysing genetic changes, changes in the expression of adhesion molecules, and mucin content. Furthermore, its clinical relevance was addressed. Cell lines of colorectal tumours with non‐mucinous (AC), mucinous (MC), and signet ring cell phenotype (MCSRC) were used for Multiplex Ligation‐dependent Probe Amplification to detect deletions and amplifications in specific oncogenes and tumour suppressor genes. Furthermore, the expression of E‐cadherin, β‐catenin, ITF (intestinal trefoil factor), and MUC2 in signet ring cells was studied by immunohistochemistry, immunofluorescence, and mRNA in situ hybridization. Results were validated using a large cohort of rectal carcinomas from which clinicopathological data were available. Specific amplifications and deletions in cell lines of AC, MC, and MCSRC were detected. Bcl‐2 was amplified in MCSRC and MC cell lines, but not in AC cell lines. Bcl‐2 FISH analysis confirmed this in patient material. Signet ring cells had decreased expression of adhesion molecules (E‐cadherin, β‐catenin) and were strongly positive for ITF and MUC2, two peptides which are normally only produced by goblet cells. RNA in situ hybridization confirmed the production of ITF. Mucinous carcinomas with signet ring cell differentiation presented at a higher T stage than adenocarcinomas and mucinous carcinomas (16% pT4 versus 3‐5%, p < 0.001) and were more frequently node positive (77% vs 39–44%; p < 0.001). Prognosis was significantly worse. In conclusion, the presence of signet ring cells in carcinomas with mucinous differentiation correlates with increased T‐stage and poor prognosis. These cells, characterized by ITF and MUC2 production, show disruption of the E‐cadherin/β‐catenin complex, as well as amplification of Bcl‐2. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.2181