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SEMINAR CARCINOMA GALL BLADDERDR AMOL KUMAR DR HARI KISHAN

Epidemiology-The incidence of Gall Bladder cancer is extremely variable by geographic regions & racial-ethinic groups -Incidence -Highest- Chileans, Northeastern Europeans, Israelies, American Indian & Americans of Mexican origin -Intermediate- Japan -Lowest- Black Zimbabweans Black Americans & the People of Spain & India - Sex- M:F::1:2-6 - Age - incidence with age, reaching its maximum in the seventh decade of life

Risk Factors-Cholelithiasis usually cholesterol type stones -Anomalous pancriaticobiliary duct junction -Chronic typhoid infection -Inflammatory bowel diseases -Porcelain gallbladder - Chemicals like methyldopa oral contraceptives isoniazid chemicals used in rubber industry - Gall bladder Polyps

Etiology-It is likely to be the chronic inflammation that predisposes to neoplasia, regardless of the cause of inflammation -A higher concentration of free radical oxidation products and a higher conc. Of sec.bile acids

Pathologic featuresCa gallbladder Fundus (60%) Body(30%) Neck(10%)

Ca gallbladder1. Infiltrative -Most common type -causes thickning & induration of gb wall -difficult to distinguish from a chronically inflamed but benign gb - Tumor to be disseminated by cholicystectomy

2. Nodular - More distinctive - Early invasion - Easier to control surgically

3. Papillary -polypoid appearance -low invasiveness

4. Combined form

-much batter prognosis

Histopathological classificationMALIGNENT EPITHELIAL TUMORS (99%) Adenocarcinoma Well-differentiated Papillary Intestinal type Pleomorphic giant cell Poorly-differentiated, small cell Signet ring cell Clear cell Colloid With choriocarcinoma-like areas Squamous Adenosquamous Oat cell carcinoma MALIGNANT MESENCHYMAL TUMORS Embryonal rhabdomyosarcoma Leiomyosarcoma Malignant fibrous histiocytoma Angiosarcoma Oat cell carcinoma

TUMOUR BIOLOGYActivation of protoncogenes Cell Inactivation of tumour separessor genes Gene mutation related to gall bladder carcinoma P53 , K- ras, C-ergB-2 genes, nm23 Tumor

PATTERN OF SPREADDirect Lymphatic Haematogenous Through small veins directly into the portal venous system Via-large veins to the portal venous branch of segments IV & V of liver Iatrogenic Leproscopic colistictomy FNAC Direct spread to liver Cystic & other adjacent organ - Favourable factors for direct spread Pericholedochal

- Thin gall bladder wall - Narrow lamina propria - Only single muscle layer

Posterosuperior Pancreaticoduodenal Superior mesenteric Retroportal Celiac Interaortocaval nodes

CLINICAL PRESENTATIONHistory: The symptoms of gallbladder cancer overlap with the symptoms of gallstones and biliary colic. Abdominal pain may be of a more diffuse and persistent nature than the classic right upper quadrant pain of gallstone disease. Jaundice, anorexia, and weight loss often indicate more advanced disease. Physical: Jaundice Palpable mass in the right upper quadrant (Courvoisier sign, if this is due to a palpable gallbladder) Periumbilical lymphadenopathy (Sister Mary Joseph nodes) Left supraclavicular adenopathy (Virchow node) Pelvic seeding: Mass is palpated on digital rectal examination (Blumer shelf)

INVESTIGATIONSLab Studies: Tumor marker CA 19-9 with 79.4% sensitivity & 79.2% specificity -CA 19-9 may be significantly elevated in both cholangiocarcinoma and gallbladder cancer. -CA 19-9 tests may be helpful in the appropriate situation if the clinical suspicion for gallbladder cancer is high. Liver function tests: Elevated alkaline phosphatase and bilirubin levels are often found with more advanced disease. BUN, creatinine, UA: Assess renal function prior to performing an enhanced CT scan. CBC: Anemia may be an indicator of more advanced disease.

IMAGING STUDIESUltrasonography- is a standard initial study . A mass can be identified in 5075% of patients with gallbladder cancer. It also can delineate metastatic lesions in the liver. Computed tomography- demonstrate tumor invasion outside of the gallbladder and identify metastatic disease elsewhere in the abdomen or pelvis. Liver invasion occurs in 60% of cases, and the combination of CT scan and US provides accurate details of disease extension. Magnetic resonance imaging- useful in examining for disease extension into other tissues or metastatic disease in the liver. It can provide details of the vasculature for preoperative planning via magnetic resonance angiogram (MRA) and bile duct passages via magnetic resonance cholangiogram (MRCP). Cholangiography, via a percutaneous route, or endoscopic retrograde cholangiography (ERCP) may establish the diagnosis of gallbladder cancer by bile cytology. Endoscopic ultrasonography can be useful to assess regional lymphadenopathy in conjunction with other studies. Angiography may confirm encasement of the portal vein or hepatic artery, and assist in preoperative planning for definitive resection. A routine chest radiograph should also be obtained.

PROCEDURESERCP can demonstrate the site of the obstruction by direct retrograde dye injection, as well as excluding ampullary pathology by endoscopic evaluation. Brush cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide material for histology. Palliative stenting to relieve biliary obstruction can be performed at the time of the evaluation. Percutaneous transhepatic cholangiography (PTC) may allow access to the proximal biliary tree that has become obstructed by extensive tumor growth from the gallbladder. Material for cytology can be obtained and drainage performed as well. Other methods to obtain tissue include CT or ultrasound needle aspiration, if a mass lesion is present, and endoscopic ultrasonographic (EUS) fine-needle aspiration.

STAGINGThe AJCC 6th edition guidelines follow the TNM system, with depth of tumor penetration and regional spread defined pathologically . Survival is correlated directly with stage of disease. Primary tumor Category T TX - Primary tumor cannot be assessed T0 - No evidence of primary tumor Tis - Carcinoma in situ T1 - Tumor invades lamina propria or muscle layer T1a - Tumor invades lamina propria T1b - Tumor invades muscle layer T2 - Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3 - Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts T4 - Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures Regional lymph node Category N NX - Regional lymph nodes cannot be assessed N0 - No metastases in regional lymph nodes N1 - Metastases in regional lymph nodes Distant metastases Category M MX - Presence of metastases cannot be assessed M0 - No distant metastases M1 - Distant metastases

TNM Groupings by stageStage 0 Tis N0 M0 Stage IA - T1 N0 M0 Stage IB - T2 N0 M0 Stage IIA - T3 N0 M0 Stage IIB - T1 N1 M0 T2N1M0 T3N1M0 Stage III - T4 any N M0 Stage IV - any T any N M1

MANAGEMENTSurgical Medical

- SurgicalT1diseases1. Most often presents after the gall bladder has already been removed by simple colecystectomy for presumed gall stone disease. 2. Reviewed pathologic findings to ensure that margins are negative 3. Particular attention is paid to the cystic duct margin -ve - no other therapy Margin < +ve common bile duct excision & biliary reconstruction 4. 5 years survival rate is 85% to 100%

Management contd.T2 diseases2 reasons to perform more extensive surgery in T2 disease 1. The plane i.e., generally taken between the liver and gall bladder is subserosal and may violate T2 tumor along the liver interphase 2. T2 tumour are associated with a high incidence of regional nodal metastasis 3. Therefore most reasonable primary operation is radicle colecystectomy 4. This includes a wedge resesction of the gall bladder bed and lymph node of hepatico duodenal ligament 5. 5 yrs survival after radical colecystectomy is 80-90% as compared to 40% 5 yrs survival with simple colecystectomy

Management contd.T3 T4 diseases (advance tumour) Recently the literature absunds with review of radical surgery for advanced disease and many centre reports long term survivous after aggressive surgical management In Japan they report a 63.6% 5 yrs survival for Japanese Biliary Surgical Society Stage II and 44.4% 5 yrs survival for stage III disease after extended colecystectomy This stage combined represent AJCC stage III

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Management contd.

Management contd.

Management contd.Laproscopically discovered gall bladder cancer Standard technique for treatment of symptomatic gall stone disease is laproscopic colecystectomy With the proliferation of laproscopic cholecyetectomy a new scenario now encountered namely gb cancer discovered at or after laproscopic chlecystectomy M/m is re exploration & complete excision of laproscopically

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Discovered GB carcinoma

Medical care

Management contd.

Radiotherapy1-the role of adjuvant radiation the therapy is to control microscopic residual deposits of carcinoma in tumour bed and regional lymph node 2-palliation in unresectable diseases The role of RT for carcinoma gall bladder is unclear but data support the following statements Radiotherapy has been delivered in a variety of situations including after curative resection with close or positive microscopic margins gross macroscopic residual disease and palliative debulking with bypass -Post op RT increases survival in T2 and advance carcinoma

-Chemotherapy-CT 5FU based CT is usually given in conjunction with concurrent RT both in the adjuvent and palliative settings -Adriamycin, mitomycin cisp