Clinical Value Of Serum Tumor Markers In The Diagnosis And Prognosis Of Gallbladder Cancer

[Background and objective]Gallbladder cancer (GBC) is one of the most common and aggressive malignant neoplasms of the biliary system. Early-stage GBC lacks typical clinical manifestations, therefore, the5-year survival is poor. Most patients are at the advanced stage at the time of diagnosis and thus lose the chance of radical cure. It is therefore important to diagnose GBC earlier. Currently, the diagnosis of GBC mainly depends on noninvasive auxiliary imaging and invasive examination such as laparoscopy and biopsy. However, there is no ideal single tumor marker for the diagnosis and prognosis of GBC.Tumor markers such as carcinoembryonic antigen (CEA)、carbohydrate antigen (CA)125、CA242and CA199have been widely used for the diagnosis of different types of cancer, such as liver, gastric, colorectal and pancreatic cancer. However, when these markers are used individually for the diagnosis of GBC, inconsistent results have been obtained. A recent study reported that S1P1overexpression or ERp29absence is related to carcinogenesis and progression, and are potential biomarkers for early detection of gallbladder adenocarcinoma. We therefore hypothesized whether the combined use of tumor markers could avoid inconsistent results and increase the diagnostic sensitivity for GBC.Postoperative tumor recurrence and metastasis are major causes of death in patients with GBC after operation. To achieve a comprehensive and accurate understanding about the probability of postoperative recurrence and metastasis of GBC, efforts have been made to explore more effective clinical predictors. The tumor-related indicators in all individuals cannot be detected systemically and comprehensively due to limited economics and techniques, and therefore joint detection of specific tumor markers is of great significance and has practically value in clinical appliance.The aims of this study were to determine whether the combined use of tumor markers CA199、CA242、CA125and CEA could increase the sensitivity for the diagnosis of GBC and the clinicopathological prognostic factors affecting survival and recurrence.[Methods]CA199、CA242、CA125and CEA levels were detected by electroimmuno-luminescence immunoassay at the Department of Biliary Surgery of the Eastern Hepatobiliary Surgery Hospital affiliated to the Second Military Medical University, Shanghai, China.78patients with GBC (30male and48female),78patients with benign gallbladder diseases (cholecystitis, gallbladder polyps and gallbladder stones) who were admitted to Yangpu District Central Hospital and Eastern Hepatobiliary Surgery Hospital (Shanghai, China), and78healthy people who underwent physical examinations in the same hospitals between January2010and September2012. The normal reference values were as follows:CEA≤10μg/L, CA125≤35U/mL, CA242≤15U/mL, and CA199≤39U/mL. CA199、CA242、CA125and CEA levels and positive rates were analyzed and evaluated pre-and post-operatively. Measurement data between groups were compared with the t test, while enumerative data were compared with the χ2test. Receiver operator characteristic curves were used to determine diagnostic sensitivity and specificity of GBC. Survival time analysis including survival curves, and multivariate survival analysis of a Cox proportional hazards model was performed to evaluate the independent prognostic factors.[Results]1.There were significant differences in the mean serum level and positive rate of CA199、CA242. CA125and CEA between the GBC and the other two groups (P<0.01), while there was no significant difference between the healthy control and benign gallbladder disease groups (P>0.05). There was no significant difference in serum CA199、CA242、CA125and CEA levels with respect to age and sex in the GBC group (P>0.05). The results showed that CA125、CA199and CA242levels in patients with gallbladder neck cancer were significantly higher than in those with cancer in the bottom portion. In addition, there were significant differences in serum CA125、CA199and CA242levels between GBC cases at different stages, tumor size and differentiation.2.According to the stage, location and histological differentiation, the GBC group was subclassified by tumor location stage、size and pathological type for calculation of the positive rate of the four serum tumor markers, using combined qualitative detection by a pathologist. Analysis of the sensitivity of the four serum tumor markers at different stages of GBC showed that the sensitivity of CA199、CA242and CA125strengthened gradually with the progression of the clinical stages. There were significant differences between stage ⅣA, ⅣB and Ⅱ (P<0.05). The sensitivity of CA242in stage Ⅱ GBC was significantly better than that of CA125and CA199(P<0.05), and therefore, CA242could be regarded as a tumor marker of GBC infiltration in the early stage.CA199alone had the highest sensitivity of71.7%, and CA242alone had the highest specificity of98.7%for the diagnosis of GBC. CA199and CA242had the most exactly validity. These results suggested that diagnosis of GBC based on combined detection of the tumor markers could increase the specificity but not sensitivity of diagnosis.The sensitivity of CA199and CA242increased with progression of GBC and advanced lymph node metastasis (P<0.05).3.During the follow-up period from6mo to1year,17patients died, and31patients lost contact for various reasons. The survival time in each patient was defined as the interval between the date of definitive resection and the date of last follow-up or death. In the30patients who completed the follow-up study, six experienced recurrence. Serum CA199、CA242and CA125levels in the recurrence group were significantly higher than those in the non-recurrence group6mo postoperatively (P<0.01). Serum CA199、CA242and CA125levels in the non-recurrence group were significantly lower than those in the GBC group preoperatively (P<0.01). Multivariate survival analysis using the Cox proportional hazards model showed that cancer of the gallbladder neck and CA199expression level were independent prognostic factors. Survival curves are shown in Figure2.[Conclusion]1.The expression of CA199、CA242and CA125has an important application in assessing LN metastasis, monitoring recurrence, and clinical staging of tumors.2.Joint detection of CA199. CA242and-CA125may prove to be useful for the diagnosis of GBC, assessment of therapeutic effect and prediction of prognosis.3.CA242could be a marker of GBC infiltration in the early stage.4.Cancer of the gallbladder neck and CA199expression level were independent prognostic factors.