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Expression of the intestinal biomarkers Guanylyl cyclase C and CDX2 in poorly differentiated colorectal carcinomas
Brody Winn1, Rosemarie Tavares, Andres Matoso
1Department of Pathology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.
Abstract:
Guanylyl cyclase C, a receptor for bacterial diarrheagenic enterotoxins, is expressed selectively by intestinal epithelium and is an endogenous downstream target of CDX2. The expression of Guanylyl cyclase C is preserved throughout the adenoma/carcinoma sequence in the colorectum. Detection of Guanylyl cyclase C expression by reverse transcriptase-polymerase chain reaction is currently being validated as a technique to identify occult lymph node metastases in patients with colorectal cancer and for circulating cells in the blood for postoperative surveillance. Although Guanylyl cyclase C is widely expressed by well-differentiated colorectal cancer, its expression in poorly differentiated colorectal cancer has not been evaluated. A tissue microarray was created from 69 archival specimens including 44 poorly differentiated, 15 undifferentiated or medullary, and 10 signet ring cell colorectal carcinomas. Matched normal colonic mucosa was used as a positive control. Immunohistochemical staining for Guanylyl cyclase C and CDX2 was evaluated as positive or negative based on at least a 10% extent of staining. Of the 69 tumor samples, 75%, 47%, and 90% of the poorly differentiated, medullary, and signet ring cell tumors were positive for Guanylyl cyclase C and 75%, 40% and 90% of these subsets were positive for CDX2, respectively. There was excellent correlation between Guanylyl cyclase C and CDX2 expression on a case-per-case basis (P < .0001). There was also a statistically significant difference in the Guanylyl cyclase C staining pattern between medullary carcinomas and poorly differentiated, not otherwise specified (P = .05). Immunopositivity for Guanylyl cyclase C was greater than 95% in a separately stained microarray series of well/moderately differentiated colorectal carcinomas. In conclusion, Guanylyl cyclase C expression is lost in a quarter of poorly differentiated and half of undifferentiated colorectal carcinomas. Therefore, the utility of Guanylyl cyclase C expression as a diagnostic marker for colorectal carcinoma may be questionable in poorly differentiated colorectal neoplasms.
Insights
Guanylyl cyclase C (GCC) expression is common in well-differentiated colorectal cancer but decreases in poorly differentiated tumors. Its utility as a diagnostic marker for advanced colorectal cancer may be limited.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Guanylyl cyclase C (GCC) is selectively expressed in intestinal epithelium and is a target of CDX2.
- GCC expression is maintained throughout colorectal adenoma/carcinoma progression.
- GCC detection is being validated for identifying occult metastases and for postoperative surveillance in colorectal cancer patients.
Purpose of the Study:
- To evaluate Guanylyl cyclase C (GCC) expression in poorly differentiated colorectal carcinomas.
- To assess the correlation between GCC and CDX2 expression in these tumors.
- To determine the diagnostic utility of GCC in poorly differentiated colorectal neoplasms.
Main Methods:
- A tissue microarray of 69 archival colorectal carcinoma specimens (poorly differentiated, undifferentiated/medullary, signet ring cell) was analyzed.
- Immunohistochemical staining was performed for Guanylyl cyclase C (GCC) and CDX2.
- Staining was evaluated based on a minimum 10% extent, with matched normal colonic mucosa as a positive control.
Main Results:
- 75% of poorly differentiated, 47% of medullary, and 90% of signet ring cell tumors showed GCC positivity.
- CDX2 positivity was observed in 75%, 40%, and 90% of these subsets, respectively.
- Excellent correlation (P < .0001) was found between GCC and CDX2 expression; GCC staining differed significantly in medullary carcinomas (P = .05).
Conclusions:
- Guanylyl cyclase C (GCC) expression is lost in approximately 25% of poorly differentiated and 50% of undifferentiated colorectal carcinomas.
- GCC expression is significantly reduced in certain poorly differentiated subtypes.
- The diagnostic utility of GCC as a marker for colorectal carcinoma may be limited in poorly differentiated neoplasms.
