The development and implementation of pathological parameters and molecular testing impact prognosis of colorectal adenocarcinoma

Objective:This study aims to analyze how changes in pathological diagnosis practice and molecular detection technology have affected clinical outcomes for colorectal cancer(CRC)patients in Fudan University Shanghai Cancer Center(FUSCC).Methods:This retrospective cohort study analyzed 21,141 pathologically confirmed CRC cases diagnosed at FUSCC from 2008 to 2020.Patients were divided into five groups for different analytical purposes:(1)the before vs.since 2014 groups to analyze the influence of the changes in the classification criteria of pT3 and pT4 staging on the survival of patients;(2)the partial vs.total mesorectal excision(TME)groups to analyze whether evaluation of completeness of the mesorectum have impact on the survival of patients;(3)the tumor deposit(TD)(+)N0 vs.TD(+)N1c groups to analyze the influence of the changes in the pN staging on the survival of patients with positive TD and negative regional lymph node metastasis(LNM);(4)the before vs.since 2013 groups to analyze the influence of the changes in the testing process of deficient mismatch repair on the survival of patients;and(5)the groups with vs.without RAS/BRAF gene mutation testing to analyze the influence of these testing on the survival of patients.Patients’clinicopathological parameters,including age at diagnosis,sex,tumor size,location,differentiation,mucinous subtype,TD,lymphovascular invasion,perineural invasion,tumor depth,LNM and distant metastasis,and tumor-node-metastasis(TNM)stage,were compared between groups.Kaplan-Meier analysis with log rank method was performed for patients’overall survival(OS)and disease-free survival(DFS)analyses.Results:In pathological reports,there were three parameter changes that impacted patient outcomes.Firstly,changes in the pT staging criteria led to a shift of the ratio of patients with stage pT3 to stage pT4 from 1:110.9 to 1:0.26.In comparison to patients admitted before 2014(n=4,754),a significant difference in prognosis between pT3 and pT4 stages was observed since 2014(n=9,965).Secondly,we began to evaluate the completeness of the mesorectum since 2016.As a result,91.0%of patients with low rectal cancer underwent TME(n=4,111)surgery,and patients with TME had significantly better OS compared with partial mesorectal excision(PME,n=409).Thirdly,we began to stage TD(+)LNM(-)as N1c since 2017.The results showed that N1c(n=127)but not N0(n=39)can improve the prognosis of patients without LNM and distal metastasis.In molecular testing,there have been three and five iterations of updates regarding mismatch repair(MMR)/microsatellite instability(MSI)status and RAS/BRAF gene mutation detection,respectively.The standardization of MMR status testing has sharply decreased the proportion of deficient MMR(dMMR)patients(from 32.5%to 7.4%)since 2013.The prognosis of patients underwent MMR status testing since 2013(n=867)were significantly better than patients before 2013(n=1,313).In addition,detection of RAS/BRAF gene mutation status(n=5,041)resulted in better DFS but not OS,for patients with stage I-III disease(n=16,557).Conclusion:Over the past few decades,updates in elements in pathological reports,as well as the development of standardized tests for MMR/MSI status and RAS/BRAF gene mutations have significantly improved patient outcomes.

Mesenchymal-epithelial transition factor amplification correlates with adverse pathological features and poor clinical outcome in colorectal cancer

BACKGROUND Colorectal cancer(CRC)is the third most common cancer and the second most common cause of cancer-related mortality worldwide.Mesenchymal-epithelial transition factor(MET)gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor treatment.MET amplification has been reported in CRC,but data are very limited.Investigating pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical practice.AIM To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy.METHODS A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited.All patients were without RAS/RAF mutation or microsatellite instability-high.MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization(FISH)and immunohistochemistry(IHC),respectively.Correlations between MET aberration and pathological features were detected using the chi-squared test.Progression free survival(PFS)during the two-year follow-up was detected using the Kaplan-Meier method and log rank test.The results of MET FISH and IHC were com pared using one-way ANOVA.RESULTS Polysomy-induced MET amplification was observed in 14.4%of cases,and focal MET amplification was not detected.Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis(LNM)(P<0.001)and higher tumor budding grade(P=0.02).In the survival analysis,significant difference was detected between patients with amplified-and non-amplified MET in a two-year follow-up after the first diagnosis(P=0.001).C-MET scores of 0,1+,2+,and 3+were observed in 1.4%,24.9%,54.7%,and 19.0%of tumors,respectively.C-MET overexpression correlated with higher frequency of LNM(P=0.002),but no significant difference of PFS was detected between patients with different protein levels.In terms of concordance between MET FISH and IHC results,MET copy number showed no difference in c-MET IHC 0/1+(3.35±0.18),2+(3.29±0.11)and 3+(3.58±0.22)cohorts,and the MET-to-CEP7 ratio showed no difference in three groups(1.09±0.02,1.10±0.01,and 1.09±0.03).CONCLUSION In CRC,focal MET amplification was a rare event.Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis.IHC was a poor screening tool for MET amplification.

Prediction of clinically actionable genetic alterations from colorectal cancer histopathology images using deep learning

BACKGROUND Identifying genetic mutations in cancer patients have been increasingly important because distinctive mutational patterns can be very informative to determine the optimal therapeutic strategy. Recent studies have shown that deep learning-based molecular cancer subtyping can be performed directly from the standard hematoxylin and eosin(H&E) sections in diverse tumors including colorectal cancers(CRCs). Since H&E-stained tissue slides are ubiquitously available, mutation prediction with the pathology images from cancers can be a time-and cost-effective complementary method for personalized treatment.AIM To predict the frequently occurring actionable mutations from the H&E-stained CRC whole-slide images(WSIs) with deep learning-based classifiers.METHODS A total of 629 CRC patients from The Cancer Genome Atlas(TCGA-COAD and TCGA-READ) and 142 CRC patients from Seoul St. Mary Hospital(SMH) were included. Based on the mutation frequency in TCGA and SMH datasets, we chose APC, KRAS, PIK3CA, SMAD4, and TP53 genes for the study. The classifiers were trained with 360 × 360 pixel patches of tissue images. The receiver operating characteristic(ROC) curves and area under the curves(AUCs) for all the classifiers were presented.RESULTS The AUCs for ROC curves ranged from 0.693 to 0.809 for the TCGA frozen WSIs and from 0.645 to 0.783 for the TCGA formalin-fixed paraffin-embedded WSIs.The prediction performance can be enhanced with the expansion of datasets. When the classifiers were trained with both TCGA and SMH data, the prediction performance was improved.CONCLUSION APC, KRAS, PIK3CA, SMAD4, and TP53 mutations can be predicted from H&E pathology images using deep learning-based classifiers, demonstrating the potential for deep learning-based mutation prediction in the CRC tissue slides.

Correlation between Calcified Liver Metastases and Histopathology of Primary Colorectal Carcinoma in Chinese

The study examined the association between calcified liver metastases and the histopathology of the primary colorectal carcinoma in Chinese.The clinical,pathological and CT data were retrospectively analyzed in 210 patients (mean age:54.2 years) with liver metastases from colorectal carcinoma.Plain CT scanning and contrast-enhanced scanning were performed in all the patients.For the contrast-enhanced examination,iohexol was injected by using a high pressure syringe at a flow rate of 2.5-3.0 mL/s.The arterial phase lasted approximately 25 s and the portal venous phase about 60 s.All patients had no history of chronic liver diseases and had never received interventional treatments.χ 2-test was used to analyze the rate of calcification in the liver metastasis from colorectal cancer of different differentiation degrees.Among the 210 cases of liver metastases,22 patients (10.5%) were found to have calcified liver metastases on CT scan.Two patients with calcified liver metastasis received lumpectomy and developed calcification in recurrent tumors.Another two patients had calcification in newly developed tumor masses.And the calcification in the newly developed masses was similar to that of their primary counterparts in terms of morphology and distribution.On the enhanced CT scan,the tumors exhibited no enhancement during hepatic arterial phase and showed slight rim enhancement during portal venous scan in the 22 cases.The calcification became obscure on contrast-enhanced scans.Histopathologically,the primary tumors were well-differentiated adenocarcinoma in 6 cases,moderately-differentiated adenocarcinoma in 10,poorly-differentiated adenocarcinoma in 4 and mucinous adenocarcinoma in 2 among the 22 cases.No statistical correlation was noted between the incidence of calcified liver metastasis and the pathological subtypes and differentiation degrees of the primary colorectal carcinoma.It was concluded that calcified liver metastases may result from colorectal adenocarcinomata of different differentiation degrees or mucinous adenocarcinomata in Chinese population.There is no correlation between calcification of liver metastases and the pathological subtype of the primary colorectal carcinoma in Chinese,which is different from the findings that calcified metastases were associated with colorectal mucinous adenocarcinoma in other ethnic groups.

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases

Background: Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorecal cancer patients with liver metastases who underwent hepatectomy.However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients.Patients and methods: In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients.The pathologic response was evaluated according to the tumor regression grade(TRG).The prognostic role of pathologic response in recurrence-free survival(RFS) and overall survival(OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests.Results: Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy(median RFS: 9.9 vs.6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors,and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases(all P < 0.05). A decrease in the serum carcinoembryonic antigen(CEA) level after preoperative chemotherapy predicted an increased pathologic response rate(P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens.Conclusions: We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

Preoperative carcinoembryonic antibody is predictive of distant metastasis in pathologically T1 colorectal cancer after radical surgery

AIM:To identify the predictors of distant metastasis in pathologically T1(pT1)colorectal cancer(CRC)after radical resection. METHODS:Variables including age,gender,preoperative carcinoembryonic antibody(CEA)level,tumor location,tumor size,lymph node status,and histological grade were recorded.Patients with and without metastasis were compared with regard to age,gender,CEA level and pathologic tumor characteristics using the independent t test orχ 2 test,as appropriate.Risk factors were determined by logistic regression analysis. RESULTS:Metastasis occurred in 6(3.8%)of the 159 patients during a median follow-up of 67.0(46.5%) mo.The rates of distant metastasis in patients with pT1 cancer of the colon and rectum were 6.7%and 2.9%, respectively(P<0.001).The rates of distant metastasis between male and female patients with T1 CRC were 6.25%and 1.27%,respectively(P<0.001).The most frequent site of distant metastasis was the liver. Age(P=0.522),gender(P=0.980),tumor location(P =0.330),tumor size(P=0.786),histological grade(P =0.509),and high serum CEA level(P=0.262)were not prognostic factors for lymph node metastasis.Univariate analysis revealed that age(P=0.231),gender(P =0.137),tumor location(P=0.386),and tumor size (P=0.514)were not risk factors for distant metastasis after radical resection for T1 colorectal cancer.Postoperative metastasis was only significantly correlated with high preoperative serum CEA level(P=0.001).Using multivariate logistic regression analysis,high preoperative serum CEA level(P=0.004;odds ratio 15.341; 95%CI 2.371-99.275)was an independent predictor for postoperative distant metastasis. CONCLUSION:The preoperative increased serum CEA level is a predictive risk factor for distant metastasis in CRC patients after radical resection.Adjuvant chemotherapy may be necessary in such patients,even if they have pT1 colorectal cancer.

Prognostic and predictive role of immune microenvironment in colorectal cancer

Colorectal cancer(CRC)represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide.The traditional classification of CRC is based on pathomorphological and molecular character-istics of tumor cells(mucinous,ring-cell carcinomas,etc.),analysis of mechanisms of carcinogenesis involved(chromosomal instability,microsatellite instability,CpG island methylator phenotype)and mutational statuses of commonly altered genes(KRAS,NRAS,BRAF,APC,etc.),as well as expression signatures(CMS 1-4).It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC.According to the latest data,the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors.In this review,we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

Endoscopic and pathological characteristics of de novo colorectal cancer:Retrospective cohort study

BACKGROUND Endoscopy has rapidly developed in recent years and has enabled further investigation into the origin and features of intestinal tumors.The small size and concealed position of these tumors make it difficult to distinguish them from nonneoplastic polyps and carcinoma in adenoma(CIA).The invasive depth and metastatic potential determine the operation regimen,which in turn affects the overall survival and distant prognosis.The previous studies have confirmed the malignant features and clinicopathological features of de novo colorectal cancer(CRC).AIM To provide assistance for diagnosis and treatment,but the lack of a summary of endoscopic features and assessment of risk factors that differ from the CIA prompted us to conduct this retrospective study.METHODS In total,167 patients with small-sized CRCs diagnosed by endoscopy were reviewed.The patients diagnosed as advanced CRCs and other malignant cancers or chronic diseases that could affect distant outcomes were excluded.After screening,63 cases were excluded,including 33 de novo and 30 CIA cases.Patient information,including their follow-up information,was obtained from an electronic His-system.The characteristics between two group and risk factors for invasion depth were analyzed with SPSS 25.0 software.RESULTS Nearly half of the de novo CRCs were smaller than 1 cm(n=16,48.5%)and the majority were located in the distal colon(n=26,78.8%).The IIc type was the most common macroscopic type of de novo CRC.In a Pearson analysis,the differential degree,Sano,JNET,and Kudo types,surrounding mucosa,and chicken skin mucosa(CSM)were correlated with the invasion depth(P<0.001).CSM was a significant risk factor for deep invasion and disturbed judgment of endoscopic ultrasound.A high degree of tumor budding and tumor-infiltrating lymphocytes are accompanied by malignancy.Finally,de novo CRCs have worse outcomes than CIA CRCs.CONCLUSION This is the first comprehensive study to analyze the features of de novo CRCs to distinguish them from nonneoplastic polyps.It is also the first study paying attention to CSM invasive depth measurement.This study emphasizes the high metastatic potential of de novo CRCs and highlights the need for more research on this tumor type.

Clinicopathological Features of Non-familial Colorectal Cancer with High-frequency Microsatellite Instability

Objective To explore the clinicopathological features of non-familial colorectal cancer with high-frequency microsatellite instability (MSI-H). Methods One hundred and fifty patients with colorectal cancer who had no family history were enrolled in this study from June 2006 to June 2008. Five standard microsatellite loci including BAT25, BAT26, D2S123, D5S346, and D17S250 were amplified with immunofluorescent polymerase chain reaction. The patient information including age, sex, and tumor location was recorded. Pathological features including differentiation, mucinous differentiation, histological heterogeneity, and Crohn's-like reaction were observed under light microscope. The presence of tumor-infiltrating lymphocytes (TLs, CD4+ and CD8+) was detected by means of immunohistochemistry. A regression equation was obtained by stepwise logistic regression analysis to evaluate the relationship between MSI-H phenotype in colorectal cancer ands pathological features. Results MSI-H phenotype occurred in 13.33% of the 150 patients with non-familial colorectal cancer. Poor differentiation, histological heterogeneity, Crohn's-like reaction, and presence of TLs were found to be independent factors to identify MSI-H non-familial colorectal cancer. Logistic regression equation showed an overall sensitivity of 70.0%, specificity of 99.2%, and accuracy of 95.3% in identifying MSI-H non-familial colorectal cancer. Conclusion MSI-H non-familial colorectal cancer manifests specific pathological features, which may be relied upon for effective identification of that disease.

Impact of homogeneous pathologic response to preoperative chemotherapy in patients with multiple colorectal liver metastases

AIM To analyze the homogeneity of pathologic response to preoperative chemotherapy(PRPC) after chemotherapy in patients with multiple liver metastases(LM).METHODS From September 2011 to August 2014,patients with at least two LM undergoing preoperative chemotherapy prior to resection were included in this retrospective,single-center study. The endpoints were PRPC homogeneity(according to both the Rubbia-Brandt and MD Anderson classifications),the impact of PRPC on the MDT decision,factors associated with homogeneous PRPC and overall survival of patients with vs. without homogeneous PRPC.RESULTS seventy-three patients with a total of 88 liver resections(including 15 two-stage procedures) were included in the study. The homogeneous PRPC rate was 55% according to the Rubbia-Brandt classification and 53% according to the MD Anderson classification. The MDT decision was modified by the PRPC in only 2.7% of patients(n = 2). CONCLUSION The PRPC was homogeneous in only one half of patients and had very little influence on the MDT decision.

Research Progress in Early-onset Colorectal Cancer

Colorectal cancer used to be a common disease among middle-aged and elderly people.In recent years,the incidence of colorectal cancer(Early-onset colorectal cancer,EOCRC)under 50 years old has increased year by year.Different from the traditional late-onset colon cancer(LOCRC),the diagnosis stage of EOCRC is mostly in the late stage,with poor cell differentiation and poor diagnosis,and there is a layer of consensus and guidance on the diagnosis,treatment or screening of EOCRC at presentation.Therefore,fully understanding the disease characteristics and risk exposure factors of EOCRC is helpful to guide early screening and treatment,which ultimately reduces the mortality of EOCRC.In this review article,we summarized the epidemiology,physiology,risk exposure factors and pathological diagnosis of EOCRC,and discussed the diagnosis and treatment prospect of EOCRC.

Colorectal carcinoma in Lagos and Sagamu,Southwest Nigeria:A histopathological review

AIM： To study the frequency, gender and age distribution as well as pathological characteristics of colorectal carcinoma （CRC） in Lagos and Sagamu in SW Nigeria. METHODS： This is a retrospective pathological review of histologically diagnosed CRC from 5 laboratories inLagos ＆ Sagamu. The clinical data, such as age, sex and clinical summary were extracted from demographic information. Cases of anal cancer were excluded from this study. RESULTS： There were 420 cases （237 males and 183 females） of CRC. It peaked in the 60-69 year age group （mean： 50.7; SD： 16.2）, M：F ratio 1.3：1 and 23% occurred below 40 years. The majority was well to moderately differentiated adenocarcinoma 321 （76.4%）, rnucinous carcinoma 45 （10.7%） and signet ring carcinoma 5 （1.2%）, and more common in patients under 40 years compared to well differentiated tumors. The recto-sigmoid colon was the most common site （58.6%）. About 51% and 34% of cases presented at TNM stages Ⅱand Ⅲ, respectively. CONCLUSION： CRC is the commonest malignant gastrointestinal （GIT） tumor most commonly located in the recto-sigmoid region. The age and sex prevalence and histopathological features concur with reports from other parts of the world.

Development and validation of an online calculator to predict the pathological nature of colorectal tumors

BACKGROUND No single endoscopic feature can reliably predict the pathological nature of colorectal tumors(CRTs).AIM To establish and validate a simple online calculator to predict the pathological nature of CRTs based on white-light endoscopy.METHODS This was a single-center study.During the identification stage,530 consecutive patients with CRTs were enrolled from January 2015 to December 2021 as the derivation group.Logistic regression analysis was performed.A novel online calculator to predict the pathological nature of CRTs based on white-light images was established and verified internally.During the validation stage,two series of 110 images obtained using white-light endoscopy were distributed to 10 endoscopists[five highly experienced endoscopists and five less experienced endoscopists(LEEs)]for external validation before and after systematic training.RESULTS A total of 750 patients were included,with an average age of 63.6±10.4 years.Early colorectal cancer(ECRC)was detected in 351(46.8%)patients.Tumor size,left semicolon site,rectal site,acanthosis,depression and an uneven surface were independent risk factors for ECRC.The C-index of the ECRC calculator prediction model was 0.906(P=0.225,Hosmer-Lemeshow test).For the LEEs,significant improvement was made in the sensitivity,specificity and accuracy(57.6%vs 75.5%;72.3%vs 82.4%;64.2%vs 80.2%;P<0.05),respectively,after training with the ECRC online calculator prediction model.CONCLUSION A novel online calculator including tumor size,location,acanthosis,depression,and uneven surface can accurately predict the pathological nature of ECRC.

Rare synchronous colorectal carcinoma with three pathological subtypes: A case report and review of the literature

BACKGROUND Synchronous colorectal carcinomas(SCRC)are two or more primary colorectal carcinomas identified simultaneously or within 6 mo of the initial presentation in a single patient.Their incidence is low and the number of pathological types of SCRC is usually no more than two.It is very unusual that the pathological findings of a patient with SCRC show more than two different pathological subtypes.Here,we report a rare case of SCRC with three pathological subtypes.CASE SUMMARY A 75-year-old woman who had no previous medical history or family history was admitted to the hospital because of intermittent hematochezia for more than a month.Colonoscopy displayed an irregularly shaped neoplasm of the rectum,a tumor-like lesion causing intestinal stenosis in the descending colon,and a polypoidal neoplasm in the ileocecum.Subsequently,she underwent total colectomy,abdominoperineal resection for rectal cancer,and ileostomy.After operation,the pathological report showed three pathological subtypes including well-differentiated adenocarcinoma of the ascending colon,moderately differen-tiated adenocarcinoma of the descending colon,and mucinous adenocarcinoma of the rectum.She is now recovering well and continues to be closely monitored during follow-up.CONCLUSION Preoperative colonoscopy examination,imaging examination,and extensive intraoperative exploration play important roles in reducing the number of missed lesions.

Changing patterns of colorectal cancer in China over a period of 20 years

AIM： To determine whether any changes have occurred on the patterns of colorectal cancer in China. METHODS： Data from 21 Chinese articles published from 1980 to 1999, were used to analyze the time trend of colorectal cancer according to the patients＇age at diagnosis, sex, the site of the tumor, stage, and the pathology. RESULTS： From 1980s to 1990s, the mean age of the colorectal cancer patients has increased. The percentage of the female patients rose. The distribution of colorectal carcinoma shows a predominance of rectal cancer. However, the proportion of proximal colon cancer （induding transverse and ascending colon） increased significantly accompanied by a decline in the percentage of rectal cancer. Similarity in the percentage of distal colon cancer between two decades was revealed. In the 1990s, statistically more Stage B patients were found than those in 1980s. In addition, databases show a significant decrease in the Stage D cases. The proportion of adenocarcinoma increased, but the mucinous adenocarcinoma decreased during two decades. CONCLUSION： These findings indicate that the pattern of colorectal cancer in China has been changing. Especially, a proximal shift due to the increasing proportion of ascending and transverse colon cancer has occurred in China.

p16 gene methylation in colorectal cancers associated with Duke's staging

AIM: To explore the association of methylation of the CpG island in the promotor of the p16 tumor suppressor gene with the clinicopathological characteristics of the colorectal cancers. METHODS: Methylation-specific PCR (MSP) was used to detect p16 methylation of 62 sporadic colorectal cancer specimens. RESULTS: p16 methylation was detected in 42% of the tumors.Dukes'staging was associated with p16 methylation status.p16 methylation occurred more frequently in Dukes'C and D patients (75.9%) than in Dukes'A and B patients (12.1%). CONCLUSION: p16 methylation plays a role in the carcinogenesis of a subset of colorectal cancer, and it might be linked to poor prognosis.

RELATIONSHIP BETWEEN PROLIFERATING CELL NUCLEARANTIGEN EXPRESSION AND ITS MALIGNANCY POTENTIAL IN COLORECTAL CARCINOMA

Objective: To study the relationship between proliferating cell nuclear antigen expression and its malignancy potential in colorectal carcinoma. Methods: Paraffin sections of 86 patients with advanced colorectal carcinoma were assessed by immunohistochemical study, using a mouse monoclonal antibody (pc-10, DAKO Co. USA) to check proliferating cell nuclear antigen (PCNA). To compare PCNA with conventional clinicopathologic factor, including p53 overexpression, tissue carcinoembnyonic antigen immunoreactivity pattern and flow cytometric DNA ploidy for assessing tumor malignancy potential. In addition, recurrence and survival of patients with advanced colorectal carcinoma after curative resection were analyzed in accordance with degree of PCNA expression. Results: PCNA-labeling index (PCNA-LI) increased significantly as the tumor stage advanced (p=0.0001). Strong correlations were observed between PCNA-LI and various pathologic parameters, including histologic differentiation (P=0.0027), lymphatic invasion (P=0.0001), vascular invasion (P=0.0001), lymph node metastasis (P=0.0001), and liver metastasis (P=0.0036). Mean PCNA-LI was also significantly higher in tumor with DNA aneuploidy (P=0.0006) and negative (P=0.01). Linear relationships were demonstrated between PCNA-LI and clinical outcomes; Recurrence rate was significantly greater in the group with higher than the mean PCNA-LI, who underwent curative resection (P<0.01), and three-year survival rates for curative cases with higher than the mean PCNA-LI were significantly poorer than those with lower than mean PCNA-LI (P<0.005). Conclusion: There were correlations between PCNA-LI and various pathologic parameters, PCNA-LI increased significantly as the tumor stage advanced in colorectal carcinoma, the rates of recurrence and death got higher as PCNA-LI increased after curative resection for colorectal carcinoma.

Molecular classification of colorectal carcinomas:The genotype-to-phenotype relation

Colorectal carcinomas(CRCs)are frequently found in industrialized countries and lead to a high incidence of malignancy-related mortality.Defined by histomorphological features,CRCs and their pre-invasive lesions are quite heterogeneous.The underlying molecular mechanisms include genomic instability,genomic mutation of tumor suppressor genes or oncogenes,epigenetic changes,and the microRNA network.The molecular mechanisms are guided by repeated clonal selections.The genotype-to-phenotype relation is assumed to be the great challenge of cancer research and the development of effective targeted therapies.At present a strong genotype-to-phenotype relation is characterized only for a minority of CRCs.Consequently,the molecular characterization of CRCs is essential to interpret histological patterns and to identify prognostic groups as well as patients for targeted therapy.

Correlation between Helicobacter pylori-associated gastric diseases and colorectal neoplasia

AIM: To explore the correlation between Helicobacter pylori(H. pylori)-associated gastric diseases and colorectal neoplasia.METHODS: Patients included in this study underwent a colonoscopy and esophago-gastro-duodenoscopy(EGD) along with histopathological measurement between March 2012 and March 2015 at Qi-Lu Hospital of Shandong University, who also had results of H. pylori detection. A total of 233 cases were selected. Demographic data, H. pylori infection status(including results of rapid urease tests and gastric mucosa pathological examinations) and histopathological examination results of gastric and colorectal mucosa were gathered and analyzed. The statistical analysis focused on the prevalence of colorectal neoplasms among patients with various histopathological categories of the stomach. ORs and their 95%CI were calculated to describe the strengths of the associations.RESULTS: The incidence rates of colorectal adenoma without high-grade intraepithelial neoplasia(HGIEN)(OR = 2.400, 95%CI: 0.969-5.941), adenoma with HGIEN(5.333, 1.025-27.758) and adenocarcinoma(1.455, 0.382-5.543) were all higher for patients with H. pylori-associated gastritis than for those in the control group. The incidence rate of colorectal adenoma with HGIEN(3.218, 0.767-13.509) was higher in patients with intestinal metaplasia than in the control group, while the incidence rates of adenoma without HGIEN(0.874, 0.414-1.845) and adenocarcinoma(0.376, 0.096-1.470) were lower in the intestinal metaplasia group than in the control group. The incidence rate of colorectal adenoma without HGIEN(3.111, 1.248-7.753) was significantly higher in the gastric intraepithelial neoplasia group than in the control group, while the rates of adenoma with HGIEN(1.481, 0.138-15.941) and adenocarcinoma(2.020, 0.561-7.272) were higher in the gastric intraepithelial neoplasia group. Incidence rates of colorectal adenoma without HGIEN(1.067, 0.264-4.314), adenoma with HGIEN(2.667, 0.231-30.800) and adenocarcinoma(2.182, 0.450-10.585) were all higher in the gastric adenocarcinoma group than in the control group.CONCLUSION: H. pylori infection as well as H. pylori-associated gastric diseases are risk factors for colorectal neoplasia.

Immunohistochemical study on endocrine-like tumor cells in colorectal carcinomas

AIM To evaluate the clinical significance of endocrine like tumor cells in human colorectal carcinomas. METHODS The immunohistochemistry method (ABC) with polyclonal antibody of rabbit anti human chromogranin A (CGA) was used to determine the alteration of endocrine like tumor cells in surgically resected colorectal carcinoma tissues from patients (35 males and 27 females, aged from 19 to 78 years, with a mean age of 50 3 years). Of the 62 specimens, 44 were rectal carcinomas, 18 colonic carcinomas, 14 lymph node involvement and 48 non involvement. Dukes classification revealed 19 cases in stage A, 29 cases in stage B and 14 cases in stage C. All the specimens were fixed with 10% formalin, embedded with paraffin and sectioned at 5μm. In addition, the correlations among CGA postive tumor cells and the clinicopathologic data, the age and sex of the patients were also investigated. RESULTS CGA positive tumor cells were found in 35 5% of the patients with colorectal cancers, 20 0% (5 of 25) and 45 9% (17 of 37) in the aged and the nonaged ones respectively. The difference was significant (χ 2 test, P <0 05). No significant correlation was found among the CGA positive tumor cells and the sex, Dukes stages, tumor location, degree of histogical differentiation and the lymph node metastasis. CONCLUSION Low incidence of endocrine like tumor cells in the aged patients may be a new pathological feature for colorectal carcinomas which may contribute to explaining why the aged patients usually have a better prognosis. Its exact significance needs to be further characterized.