Chromogranin A-, serotonin-, synaptophysin- and vascular endothelial growth factor-positive endocrine cells and the prognosis of colorectal cancer: an immunohistochemical and ultrastructural study.
OBJECTIVE
Endocrine differentiation in colorectal adenocarcinoma has been reported but its significance as a prognostic marker remains uncertain. The aim of the present study was to analyze the prognostic significance of endocrine differentiation in colorectal cancer.


METHODS
The presence of endocrine cells (EC) was determined in 137 colorectal cancers using light and electron immunohistochemistry and the immunogold method with chromogranin A, serotonin and synaptophysin. Vascular endothelial growth factor (VEGF) expression in tumor biopsies was also analyzed applying anti-VEGF antibodies.


RESULTS
EC labeled with at least one of the studied markers were detected in 47 (34.3%) primary colorectal cancers (30% chromogranin A-positive, 33% synaptophysin-positive and 18% serotonin-positive). In 23% of tumor biopsies, VEGF-positive EC were also detected. The immunostaining on serial sections showed that some chromogranin A-, synaptophysin- or serotonin-positive EC also contained VEGF immune deposits. By the immunogold method, the presence of VEGF was localized to the granules of EC. Tumors with VEGF-positive EC appeared to have significantly higher vascularization, detected as systematic microvessel density (28.89 vs 15.22 vessels/mm(2), P = 0.044, Mann-Whitney U-test) compared to those without VEGF-positive EC. Ultrastructurally, EC in the tumor tissue displayed some features different from those in the normal colon. The survival analyses revealed that patients with EC in primary tumor tissues had a worse prognosis after surgical therapy than those without endocrine cell differentiation (P < 0.05, log-rank test).


CONCLUSIONS
Endocrine differentiation is not an uncommon event in primary colorectal cancer and it could be a useful marker for a worse prognosis after the surgical therapy. Tumors positive for VEGF and containing VEGF-positive EC have higher vascularization, which probably also contributes to the unfavorable prognosis of patients.
Gulubova
Maya
M
Department of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria. mgulubova@hotmail.com
Vlaykova
Tatyana
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002454:Cell Differentiation; D053379:Chromogranin A / Q000032:analysis*; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000401:mortality / Q000601:surgery / Q000648:ultrastructure; D055098:Endocrine Cells / Q000737:chemistry / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000737:chemistry / Q000648:ultrastructure; D053208:Kaplan-Meier Estimate; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D012701:Serotonin / Q000032:analysis*; D016708:Synaptophysin / Q000032:analysis*; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis*
D014408:Biomarkers, Tumor; D053379:Chromogranin A; D016708:Synaptophysin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D012701:Serotonin