Pathological Types,Expression of Mismatch Repair Protein,Human Epidermal Growth Factor Receptor 2,and Pan-TRK,and Eostein-Barr Virus Infection in Patients With Colorectal Cancer Resected in Tibet / 中国医学科学院学报

Objective To study the pathological types,expression of mismatch repair protein,human epidermal growth factor receptor 2(HER2),and Pan-TRK,and Epstein-Barr virus(EBV)infection in patients with colorectal cancer resected in Tibet. Methods A total of 79 patients with colorectal cancer resected in Tibet Autonomous Region People's Hospital from December 2013 to July 2021 were enrolled in this study.The clinical and pathological data of the patients were collected.The expression of mismatch repair protein,HER2,and Pan-TRK was detected by immunohistochemical(IHC)staining,and detection of HER2 gene by fluorescence in situ hybridization(FISH)in the patients with HER2 IHC results of 2+ or above.EBV was detected by in situ hybridization with EBV-encoded small RNA. Results A total of 79 colorectal cancer patients were included in this study,with the male-to-female ratio of 1.26:1 and the mean age of(57.06±12.74)years(24-83 years).Among them,4 patients received preoperative neoadjuvant therapy.Colonic cancer and rectal cancer occurred in 57(57/79,72.15%,including 31 and 26 in the right colon and left colon,respectively)and 22(22/79,27.85%)patients,respectively.The maximum diameter of tumor varied within the range of 1-20 cm,with the mean of(6.61±3.33)cm.Among the 79 colorectal cancer patients,75(75/79,94.94%)patients showed adenocarcinoma.Lymph node metastasis occurred in 12(12/21,57.14%)out of the 21 patients with severe tumor budding,13(13/23,56.52%)out of the 23 patients with moderate tumor budding,and 2(2/31,6.45%)out of the 31 patients with mild tumor budding,respectively.The lymph node metastasis rate showed differences between the patients with severe/moderate tumor budding and the patients with mild tumor budding(all P<0.001).The IHC staining showed that mismatch repair protein was negative in 10(10/65,15.38%)patients,including 5 patients with both MSH2 and MSH6 negative,4 patients with both MLH1 and PMS2 negative,and 1 patient with MSH6 negative.Pan-TRK was negative in 65 patients.The IHC results of HER2 showed 0 or 1+ in 60 patients and 2+ in 5 patients.FISH showed no positive signal in the 5 patients with HER2 IHC results of 2+.The detection with EBV-encoded small RNA showed positive result in 1(1/65,1.54%)patient. Conclusions Non-specific adenocarcinoma of the right colon is the most common in the patients with colorectal cancer resected in Tibet,and 15% of the patients showed mismatch repair protein defects.EBV-associated colorectal carcer is rare,Pan-TRK expression and HER2 gene amplification are seldom.The colorectal cancer patients with moderate and severe tumor budding are more likely to have lymph node metastasis.

Prevalence estimation of microsatellite instability in colorectal cancers using tissue microarray based methods – A tertiary care center experience

Aim: Microsatellite instability (MSI) pathway is known to be implicated in carcinogenesis of 15% colorectal carcinomas (CRC), including 2%–3% of cases of Lynch syndrome, as per western literature. MSI status has important prognostic and therapeutic implications. The prevalence of MSI in Indian CRC patients is unknown. We aimed to determine the prevalence by studying 231 consecutive unselected cases of CRC. Methods: Tissue microarrays using duplicate cores per case for 141 cases, and whole tissue sections for 90 cases, were used. Immunohistochemistry with four mismatch repair (MMR) markers – MLH1, MSH2, MSH6, and PMS2 was performed. Molecular analysis for MSI status was performed in 18 randomly selected cases. Correlation with various clinical and histopathological features was done using univariate and multivariate analysis. Results: Loss of MMR immunohistochemical (IHC) was seen in 53/231 cases, i.e. 22.94% (95% confidence interval 17.52%–28.36%). MLH1-PMS2 dual loss comprised 13.9%, MSH2-MSH6 7.4%, and isolated PMS2 loss in 1.73% of cases. Univariate analysis showed significant association with age (<60 years), right-sided tumor location, histologic type, high grade, the presence of severe intratumoral lymphocytic (ITL) and peri-tumoral lymphocytic response, and N0 nodal stage. On multivariate analysis, independent variables were age < 60 years, right-sided location, and severe ITL. Molecular testing for MSI corroborated with the IHC results. Conclusion: The study results show a slightly higher prevalence of MSI-H phenotype, compared to Western literature, stressing the need for more widespread testing for better clinical management and identification of possible hereditary colon cancer syndrome.

Expression of hMLH1 and hMSH2 in suspected hereditary non-polyposis colorectal cancer / 实用医学杂志

Objective To analyse the suspected hereditary non-polyposis colorectal cancer (HNPCC) in mismatch repair protein (MMR) expression of hMLH1 and hMSH2. Methods Immunohistochemical staining method was used for the detection of hMLH1 and hMSH2 protein expression in 193 cases suspected HNPCC patients, the deletion of MMR proteins was identified as highly suspected HNPCC cases. Results Of the 193 patients with suspected HNPCC hMLH1/hMSH2 abnormal expression rate was 29.02%; ≤30 years old was 40%, 31 ~ 40 years old was 28.05%, 41 ~ 50 years old was 28.71%,3 suspected HNPCC showed the deletion of hMLH1/hMSH2 protein expression at the same time ,; In the right colon , the left half colon and rectal anomaly detection rates were 40.74%, 32.65%and 18.89%; hMLH1/hMSH2 deletion was 46.15%with family history. Conclusions The deletion of MMR protein is closely related to age,site and family history in suspected HNPCC, and the deletion of hMLH1 is an important factor to induce early-set colorectal cancer. The deletion of hMLH1/hMSH2 at the same time indicates that hMLH1/hMSH2 genes may play important role in the incidence of HNPCC.

Clinicopathologic Features of Sporadic Colorectal Cancer with MLH1/MSH2 Loss of Expression - Reduced Likelihood of Metastases

PURPOSE: This study was designed to determine the frequency of MMR defective sporadic colorectal cancer (CRC) by using immunohistochemistry and to investigate the correlation between the MMR status and the metastatic potential. METHODS: The study included 249 patients with sporadic colorectal cancer who underwent surgical resection. The MMR status was determined by using an immunohistochemical analysis of MLH1 and MSH2 expression. RESULTS: Twenty seven (10.8%) carcinomas showed abnormal MMR protein expression (18 MLH1 negative and 9 MSH2 negative) and were classified as MMR defective tumors whereas 222 tumors demonstrated normal MLH1/MSH2 immunoreactivity (MMR intact tumor). MMR defective tumors developed at significantly higher frequencies in a proximal site (59.3% vs. 27.5%, P=0.001) and tended to be larger in size (6.3+/-2.4 cm vs. 5.1+/-2.1 cm, P=0.026). They showed significantly lower overall stage, N stage, and M stage at the time of diagnosis (P=0.002, P=0.014, P=0.010, respectively). In patients who had MMR defective tumors, lymphocytic infiltration (40.7% vs. 8.7%, P<0.001) and poor differentiation (22.2% vs. 11.7%, P=0.012) were more frequently observed. Less frequently MMR defective tumors displayed lymphatic invasion (40.7% vs. 67.1%, P=0.007) and infiltrative borders (22.2% vs. 51.8%, P=0.004). The MMR defect was strongly associated with a decreased likelihood of lymph node (odds ratio: 0.34, 95% CI: 0.13~0.95) and distant organ metastases at diagnosis (odds ratio: 0.09, 95% CI: 0.01~0.94), independent of the clinicopathologic features. CONCLUSIONS: mmunohistochemical analysis revealed that 10.8% of sporadic CRC cases showed no staining for MLH1 or MSH2. Lymphatic invasion and distant metastases were found at lower rates in these MMR defective tumors.

COX-2 and iNOS Expression and Microvessel Density by Microsatellite Instability in Colorectal Cancer

PURPOSE: We tried to identify the overall incidence of microsatellite instability (MSI) and the utility of mismatch repair (MMR) protein expression in sporadic colorectal cancers in Korean. We also investigate the role of angiogenesis in colorectal cancers by MSI status. METHODS: A total 85 resected colorectal cancers were submitted for MSI study using PCR methods with 5 markers and immunohistochemistry (IHS) for hMLH1 and hMSH2. Expression of COX-2 and iNOS and microvessel density by IHS were correlated with various clinicopathologic prognostic factors. RESULTS: Among 85 cases of sporadic colorectal cancers, MSI was observed in 11 cases (12.9%) including 10 MSI-H and 1 MSI-L cases. Patients with MSI (+) showed female prevalence (1.75 : 1), low Dukes stage, mucinous histologic type, and Crohn-like lymphoid reaction than those with MSS. Overall sensitivity of hMLH1 and/or hMSH2 expression was 98.6% and specificity was 72.7%. iNOS expression was significantly correlated with COX-2 expression in tumor cells (P=0.006), however, they were not correlated with MSI status. High microvessel density was correlated with hMLH1 expression (P=0.025), COX-2 expression (P= 0.05), and Crohn-like lymphoid reaction (P=0.041). CONCLUSIONS: IHS for MMR proteins is a valuable substitute of MSI status and COX-2 related neoangiogenesis is thought to be related to inhibition of microsatellite unstable colorectal cancer progression via decreased microvessel density.