The Clinicopathology And Prognostic Role Of Cribriform Comedo-type Adenocarcinoma In Colorectal Cancer

Background:Colorectal carcinoma (CRC) is one of the most common cancers all over the world. In China, with the rapidly improvement of economy and changed life style, an increasing trend in the incidence of colorectal carcinoma has been noticed. Though the TNM classification as a convention standard to discriminates patients with early-stage disease from those with advanced disease, it is unsatisfactory with respect to prognostication of patients with tumors of the same pathologic stage. In fact, the clinical outcome of CRC intensely associates not only with disease stage, but also with the histopathology classification. More than90%of CRC are adenocarcinomas, which including mucinous adenocarcimoma, signet ring cell carcinoma, medullary carcinoma, serrated adenocarcinoma, cribriform comedo-type adenocarcinoma, invasive micropapillary carcinoma and other rare variants. Cribriform comedo-type adenocarcinoma is a new subtype defined by the newest edition of WHO classification. So far, the studies about this new type are rare.In recent years, with the development of tumor molecular biology, the studies of molecular mark which have connection with the development and prognosis of CRC have significant importance for the treatment of colorectal cancer. Necrosis as a special histopathological feature may have relation with cell proliferation, hypoxia and angiogenesis, which contribute to the development of tumor microenvironment. CD34and Ki67are weakly expressed in normal tissues, while strongly in malignant tumor tissue. CD34is he highly sensitive marker for endothelial cell differentiation and always been studied as marker for microvessel density (MVD) in tumor tissue. CD34and pyruvate kinase isoenzyme type M2(PKM2) are significant factors to regulate tumor cell metabolism and proliferation. Numerous studies have showed both at mRNA and protein level the expression of c-myc and PKM2were increased in primary human colorectal adenocarcinoma as compared to adjacent normal mucosa. Moreover, recent study showed that c-Myc played an important role in colorectal tumor angiogenesis.The aim of the present study was to evaluate the expression levels of CD34, Ki67, c-myc, PKM2in human primary colorectal adenocarcinomas by immunohistochemisty (IHC). We investigated the association between these proteins overexpression in common adenocarcinomas and cribriform comedo-type adenocarcinoma. In addition, whether the overexpression is correlated with a variety of clinicopathological features including survival and prognosis was determined.Objective:To investigate the difference of tumor characteristics between the colorectal common adenocarcinoma and cribriform comedo-type adenocarcinoma, analyze the protein expression of CD34, Ki67, c-myc, PKM2in human primary colorectal adenocarcinomas, and to assess the association of clinicopathological parameters with survival and prognosis.Methods: Colorectal adenocarcinoma samples were obtained from395patients who underwent surgery during the years2007-2009at the Second Affiliated Hospital of Zhejiang University School of Medicine. Of395analyzed tumor samples96were cribriform comedo-type adenocarcinoma and299were common colorectal adenocarcinoma.Immunohistochemistry (IHC) was performed to analyze the expression of CD34, Ki67, c-myc, PKM2in96patientes with cribriform comedo-type adenocarcinoma and130patinets random selected form299patients with common adenocarcinoma.Statistical analysis was done using SPSS, version20. Tumor characteristics were assessed using the chi-square test or Fisher’s exact test. Survival was calculated by Kaplan-Meier method. Difference in survival distributions is test with log rank statistics. Cox regression analyses were used for univariate and multivariate overall survival. The Cox proportional hazards model was used to determine the hazard ratio (HR) of explanatory variables on overall survival. P-values<0.05were considered statistically significant.Result:Of395analyzed tumor samples,96cases (24.3%) were cribriform comedo-type adenocarcinoma and299cases (75.7%) were common colorectal adenocarcinoma. The chi-square test showed that the size of tumor, clinical stage, T classification and vascular invasion were statistically different in cribriform comedo-type adenocarcinoma and common colorectal adenocarcinoma (P<0.05), and that other parameters such as age, sex, N classification had no notable difference (P>0.05).The median survival in cribriform comedo-type adenocarcinoma and common colorectal adenocarcinoma were61.49and69.53months respectively, five-year survival rates of cribriform comedo-type adenocarcinoma and common adenocarcinoma were 0.606and0.740respectively, which has significant difference (P<0.05). Univariate Cox regression analysis showed that tumor pathology type (cribriform comedo-type adenocarcinoma or common colorectal adenocarcinoma), clinical stage, T classification, N classification vascular invasion and neuronal invasion were significantly associated with prognosis (P<0.05). Multivariate Cox regression analysis showed that T classification and N classification were independent factors whereas the pathologic type was not the independent factor. In patients below60years old, pathologic type (P<0.05) and N classification (P<0.05) were independent prognosis factors. Log-rank test showed the median survival in patients with vascular invasion and no vascular invasion were68.7and57.96months respectively (P<0.05) and five-year survival rates0.580and0.719respectively.The expression of c-myc in cribriform comedo-type adenocarcinoma was significant higher than in common adenocarcinoma. The proportions strong positive of Ki67in common adenocarcinoma and cribriform comedo-type adenocarcinoma were76.2%and52.1%respectively. The expression of Ki67in common adenocarcinoma was higher in cribriform comedo-type adenocarcinoma which has significant difference. The expression of PKM2in the two types of colorectal adenocarcinoma had no statistical difference (P>0.05). The median MVD in cribriform comedo-type adenocarcinoma and common colorectal adenocarcinoma was14.90and12.38respectively. The MVD in cribriform comedo-type adenocarcinoma had notable increased. The expression of CD34has associated with vascular invasion (P<0.05). Pearson correction showed that the expression of c-myc had positive connection with the expression of CD34.Conclusion:1The cribriform comedo-type adenocarcinoma and common adenocarcinoma of colorectal cancer have significant difference in tumor size, clinical stage, T classification and vascular invasion. 2The patients with cribriform comedo-type adenocarcinoma have worse prognosis than those with common adenocarcinoma. The feature of extensive large cribriform glands with central necrosis may be an independent prognosis factors for patients whose age was below60years old.3Compared to common adenocarcinoma, the expression of c-myc in cribriform comedo-type adenocarcinoma was notably higher, but the expression of Ki67was remarkably lower.4The MVD in cribriform comedo-type adenocarcinoma was significant increased.5The expression of c-myc has correction with MVD.