Analysis Of Outcome In Patients With Gallbladder Carcinoma Diagnosed Intra-Operatively

ObjectiveOur main aim of the study is to find out the way?right therapy?that will help to improve survival of the patients with gallbladder carcinoma diagnosed intra-operatively.BackgroundGallbladder carcinoma is the sixth most common malignancy of entire gastrointestinal tract but most common malignant tumor of the biliary tract.Autopsy reports from around the world reveals that this cancer represents 80-95%of biliary tract cancer worldwide.It is more common in women throughout the world especially after the age of 65.Remarkable geographic pattern throughout the world has been recorded in patients having gallbladder carcinoma with varying incidence rates among different geographic areas and ethnicities.The incidence is highest in Asia?India,Pakistan?and Latin America,comparatively high in Eastern Europe and South America,and low in United States and Mediterranean European countries.Ethnically,gall bladder carcinoma is more prevalent in Chilean Mapuche Indians,American Indians,Native Indian women,Pakistani females as well as Korean males.Gallstone?mainly larger stones?is an important and major risk factor for the development of gall bladder carcinoma.Chronic and repeated inflammation that occurs in chronic cholecystitis helps in the development of carcinoma.Other conditions with increased risk includes porcelain gallbladder,chronic bacterial infection,anomalous pancreaticobiliary duct junction,gallbladder polyp?>10mm?,primary sclerosing cholangitis,prolonged exposure to estrogen,positive family history,obesity,smoking as well as occupational exposure to carcinogens.The pathological change ranges from metaplasia to dysplasia to carcinoma in situ which after many years eventually becomes invasive carcinoma.The proposed genetic changes include,activation of oncogenes?e.g.KRAS?and inactivation of tumor suppressor genes?e.g.P53?.About 60%of gallbladder carcinomas are found in the fundus and most of them areadenocarcinomas?90%?.Gallbladder carcinoma is very difficult to diagnose,because most patients are asymptomatic until the disease is advanced.The presenting symptoms in variable frequencies are jaundice,nausea and vomiting,pallor,anorexia,weight loss,abdominal distention,fever,ascites and abdominal mass.Ultrasonography?USG?,Computed Tomography?CT?,Magnetic Resonance Imaging?MRI?and Magnetic Resonance Cholangiopancreatography?MRCP?are the main imaging techniques that are used to evaluate the patient with suspected gallbladder carcinoma.Ca19-9,CEA,CA125 as well as CA242are the tumor markers that are mostly detected in patients with gallbladder carcinoma.In advanced stage of gallbladder carcinoma,CA19-9 and CEA are mostly elevated,but they have low specificity.Surgery,in the form of complete local or extensive radical resection is the mainstay of treatment and hope for long term survival.Adjuvant therapies in the form of chemotherapy and radiotherapy may help to improve the prognosis but they are usually ineffective.Survival of patients with gallbladder carcinoma is poor.Survival mainly depends upon the tumor stage?T?of the disease at the time of presentation,lymph node status,gallbladder lesion histories,surgical procedures as well as radicality.Mean overall survival is 6 month and 5-year survival is only 5%.MethodsWe performed a retrospective study on patients who were intraoperatively diagnosed to have gallbladder carcinoma,aged between 50-80 years and presented in hepatobiliary and pancreatic surgery department of second hospital of Jilin University,Changchun,China from2012-2016.On the basis of computer database registry search of Second Hospital of Jilin University,from January 2012 to December 2016,a total of 38 patients who received cholecystectomy were diagnosed to have primary gallbladder carcinoma intraoperatively.Among them,we analyzed 20 cases who met our inclusion criteria.From their medical registry,age,sex,surgical procedures and pathological findings during and after surgery was recorded.Current status of the patients was confirmed using the telephone call provided by the visitors at the time of discharge.In our institution,the main goal of surgical resection is to achieve R0 margin.Single staged approach was used in all of incidentally detected GBC patients.Simple cholecystectomy was performed and thought to be adequate for early stage of GBC.Radical cholecystectomy along with lymphadenectomy was the most commonly performed procedure for remaining stages of tumor.Radical cholecystectomy included cholecystectomy with resection of gallbladder bed for at least 2-3 cm of normal liver parenchyma and/or combined sub-segmental resection of liver segments IVb and V near gallbladder bed and/or removal of extrahepatic bile ducts depending upon the extent of tumor spread.Lymphadenectomy included removal of lymph nodes along hepatoduodenal ligaments or more extensive dissection of celiac and superior mesenteric artery nodes.For patients with advanced disease,palliative procedures were performed.Clinical staging of the disease was evaluated intra and postoperatively based upon UICC/TNM classification of malignant tumors of gallbladder 8^thh edition.Collected data were analyzed and interpreted using SPSS Statistics 20 software.Mean age was calculated.Cumulative survival rates were calculated for each T,N,stage of the tumor,type of surgery,as well as for surgical margin of the tumor after resection.Kaplan-Meier method was used to calculate the cumulative and median survival rates?survival curves?and log rank test was used to compare the difference between the survival rates.Cox stepwise backward regression was used to identify the important prognostic factors after treatment.P value was calculated and was considered statistically significant if P was less than 0.05.ResultsOf the analyzed 20 cases,4 were men?20%?and 16 were female?80%?.The ratio of Male to Female was 1:4.The mean age of patients was 66.7?6.45 years?mean?SD?,?range 50-80 years?.65%of the patients were in between the age of 60-70 years?n=13?,20%were in between the age of 70-80 years?n=4?,and 15%were in between the age of 50-60 years?n=3?.The median survival was 16 month.Radical cholecystectomy with extended lymphadenectomy was most commonly performed surgical procedure in 8 cases?40%?,followed by palliative surgery in 6 cases?30%?,RC with lymphadenectomy in 4 cases?20%?and simple laparoscopic cholecystectomy in remaining 2 cases?10%?.Adenocarcinoma was most commonly encountered pathological type of tumor and found in 17 cases?85%?,whereas adenosquamous carcinoma was encountered in remaining 3 cases?15%?.On the basis of 8^th edition UICC/TNM classification of malignant tumors,2 patients were in T1a?10%?,1 was in T1b?5%?,1 was in T2a?5%?,4 were in T2b?20%?,8 were in T3?40%?,and 4 were in T4?20%?respectively.The 2-year survival rates in patients who received surgical resection with T1a,T1b,T2a,T2b,T3,and T4 stages of GBC were 100%,0%,100%,75%,37.5%and 0%respectively??49?=0.001?.There was no statistically significant difference in outcome of patients with T2b and T3 after surgery?P=0.220?,but patients with T2b?P=0.007?and T3?P=0.004?had better outcome after surgery than patient with T4tumor.No regional lymph node metastasis?N0?was found in 11 cases?55%?,metastasis to1-3 regional lymph node?N1?was found in 4?20%?cases and metastasis to 3 or more regional lymph nodes?N2?was found in 5?25%?cases respectively.The 6-month,1-year and 2-year survival rates in patients who received surgical resection with N0 disease were91%,82%and 62.4%,with N1 disease were 50%,50%and 50%and with N2 disease were20%,20%,and 0%respectively?P=0.002?.Patients without lymph node metastasis?N0?had better overall survival after surgery than patient with 4 or more regional nodal metastasis?N2??P=0.000?.No significant overall survival benefit was noted between patients of N0 and N1 disease?P=0.447?,and N1 and N2 disease?P=0.203?after surgical resection.According to stage,2 patients were in stage IA?10%?,1 was in stage IB?5%?,1 was in stage IIA?5%?,2 were in stage IIB?10%?,4 were in stage IIIA?20%?,4 were in IIIB?20%?,1 was in stage IVA?5%?,and 5 were in stage IVB?25%?respectively.The 2-year survival rates in patients who received surgical therapy with stage IA,IB,IIA,IIB,IIIA,IIIB,IVA,and IVB was 100%,0%,100%,100%,50%,50%,0%,and 0%respectively?P=0.011?.The 6-month,1-year,and 2-year survival rates of the patients with simple cholecystectomy were 100%,100%,and 100%,RC combined with lymphadenectomy were100%,100%,and 66.7%,RC combined with extended lymphadenectomy were 75%,62.5%,and 50%and palliative resection were 16.7%,16.7%,and 0%respectively?P=0.005?.The 6-month,1-year,and 2-year survival rates in patients who received surgery with curative intent were 85.7%,78.5%,and 63.4%vs those with palliative surgery were 16.7%,16.7%,and 0%respectively?P=0.001?.On the basis of this finding,the efficacy of radical cholecystectomy with lymphadenectomy and radical cholecystectomy with extended lymphadenectomy on survival of patients with GBC was compared and no difference was found statistically between the superiority of either procedure to one another?P=0.373?.Resected margin of tumor was macroscopically and microscopically negative?R0?in11 cases?55%?,whereas it was positive?R1?in remaining 9 cases?45%?.The 6-month,1-year,and 2-year survival rates in patients who received R0 resection were 100%,100%,and80.9%compared to 22.2%,11.1%,and 0%respectively in patients who received R1resection?P=0.000?.Multivariate analysis revealed depth of invasion of tumor?T??P=0.023?and status of lymph nodes?N??P=0.005?as an independent prognostic factor for overall survival as calculated by Cox regression analysis.ConclusionSurgery in the form of curative intent was the best treatment method for improvedoverall survival in patients with GBC than palliative one.Prognosis of patients after surgical resection for T1a stage of GBC is better which suggests simple cholecystectomy is adequate surgical procedure if R0 resection can be achieved for this stage.For other stages of GBC,operation in the form of radical cholecystectomy with lymphadenectomy or radical cholecystectomy with extended lymphadenectomy is the best method of treatment to achieve improved outcome.If possible,radical surgery should be selected over palliative procedure.The type of surgery should be selected upon surgeon's experience,the depth of tumor invasion and extent of lymph node involvement.The goal of surgical resection is to achieve negative surgical margin,which will help to improve overall survival.