Gall bladder carcinoma

Gall bladder carcinoma seen in Indian popluation most common in women and presents at a very late stage .Survival is in months hence palliative treatment is being preferred .

1. Gall Bladder Carcinoma Presenter- Dr.Pooja Pandey PGJR-2 Moderator-Dr. S.P.Sharma Ass.Professor Department of General Surgery

2. Gall Bladder Carcinoma Learning Objective Introduction Epidemiology Cause Clinical picture Investigation TNM Classification Treatment Survival References

3. Gall Bladder Carcinoma Introduction Aggressive malignant disease. Extremely poor prognosis. No specific presenting symptoms. High proportion of patients - advanced disease. Earlier stage disease- a more aggressive surgical approach.

4. Gall Bladder Carcinoma Epidemiology Incidence 6 th and 7 th decades of life 2-3 F>M Ethnicity –highest incidence in India and Pakistan . Worldwide, the highest incidence rates (up to 8.0 / 100,000 in men and 22 / 100,000 in women) occur among populations in the Indian subcontinent. Among North American populations , Native Americans and immigrants from Latin America have the highest rates.

5. Gall Bladder Carcinoma Cause Chronic inflammation with subsequent cellular proliferation. Risk factor – cholelithiasis (7times,90%) 3% of gall stone with cholecystitis Relative risk- less –size <2cm,2-3cm It is 10 or more with >3cm Xanthogranulomatous cholecystitis .

6. Gall Bladder Carcinoma Cause Porcelain gall bladder (25%) and 90% of them are inoperable tumours . Gallbladder polyp > 10 mm(1cm), >3in no, adenomatous polyp. Other risk factors – choledochal cysts Cholesteroses of gallbladder Primary Sclerosing Cholangitis .

7. Gall Bladder Carcinoma Cause Anomalous pancreaticobiliary duct junction ( APBDJ )( 20 %) Chronic typhoid carriers, I nflammatory bowel disease, Hepatitis B and Hepatitis C virus infection . Nitrosamines Carcinogen (radon)

8. Gall Bladder Carcinoma Types Gross Types of Carcinoma Gallbladder Polypoid /papillary—better prognosis . Scirrhous / nodular . Proliferative/infiltrative .

9. Gall Bladder Carcinoma Pathology and staging Microscopy Commonly - adenocarcinoma (90%); occasionally squamous cell carcinoma, small cell carcinoma ,lymphoma , sarcoma , adenosquamous or carcinoid tumor . 25% show only localized disease; 35% have lymph node spread; 40% have distant spread at the time of first diagnosis.

10. Gall Bladder Carcinoma Pathology and staging contd.. Dysplasia to carcinoma in situ to invasive carcinoma. Altered genes include p53, k- ras , p16ink4a , and erbb2/her2 . Papillary subtype-indolent course , limited to gall bladder wall , better prognosis . Most gallbladder carcinomas- systemic disease at the time of presentation, with 35% nodal disease and 40% distant metastases.

11. Gall Bladder Carcinoma Pathology and staging contd … Adenomas -high prevalence β -catenin mutations. Dysplastic lesions and cancers associated with APBD - high prevalence of K - ras mutations and a low prevalence of β -catenin mutations. p53 and P16INK4A mutations are not seen in adenomas or dysplastic lesions, and thus appear to be later events in gallbladder carcinogenesis

12. Gall Bladder Carcinoma Pathology and staging contd.. Draining nodal basin -hepatoduodenal ligament periaortic nodes near the celiac axis or pancreaticoduodenal nodes around the superior mesenteric artery . Direct spread to liver (segment IV and V), bile duct, duodenum , colon and kidney . Blood spread—to liver, lungs and bones . Perineural spread Transperitoneal spread.

13. Gall Bladder Carcinoma Staging Nevin’s staging : Stage I – Intramural Stage II – Spread to muscularis propria Stage III – Spread to serosa Stage IV – Spread to cystic lymph node of Lund Stage V – Direct spread to adjacent organs/metastases

14. Gall Bladder Carcinoma Staging AJCC 8 th Edition

15. Gall Bladder Carcinoma Staging

16. Gall Bladder Carcinoma Staging

17. Gall Bladder Carcinoma Clinical presentation Location - Fundus and body of gall bladder Acute cholecystitis to chronic cholecystitis features Weight loss Jaundice Abdominal mass Chronic epigastric pain Early satiety Fullness Hepatomegaly Ascites

18. Gall Bladder Carcinoma Three clinical presentations – 1 . Clinically obvious type - pain, obstructive jaundice, mass . 2. Early GB cancer mimics GB stone disease. 3 . Atypical as unusual features

19. Gall Bladder Carcinoma Investigations Ultrasound abdomen. CT abdomen to see operability. US-guided FNAC. Liver function tests. MRCP. Laparoscopy. CA 19-9 is elevated in 80% of cases

20. Gall Bladder Carcinoma Investigation contd … Ultrasound of abdomen- irregularly shaped lesion in the subhepatic space, heterogeneous mass in the gallbladder lumen , and asymmetrically thickened gallbladder wall . Polyp larger than 10 mm should raise the suspicion of gallbladder cancer.

21. Gall Bladder Carcinoma Investigation contd.. CT abdomen- staging and treatment Peritoneal metastases, Hepatic parenchymal metastases, Lymphadenopathy, And adjacent vascular involvement . Triphasic CT can be used to identify Hepatic arterial or portal venous involvement. Percutaneous tissue diagnosis.

22. Gall Bladder Carcinoma Treatment Resection - remains the only potential for cure. Patients with gallbladder cancer can be divided into four S pecific subgroups of presentation :- P atients with an incidental polyp on imaging , P atients with an incidental finding of gallbladder cancer at the time of or after cholecystectomy , P atients suspected of having gallbladder cancer preoperatively, and Patients with advanced disease at presentation.

23. Gall Bladder Carcinoma Treatment Gallbladder polyp- > 10 mm-Open cholecystectomy laparoscopic - may convert a potentially curable disease into an incurable one . Gallbladder cancer after cholecystectomy- Depends on depth of penetration of the gallbladder wall and surgical margins. T1a (lamina propria)- cholecystectomy (nodal disease<3%) T1b-( muscularis,no CT )- cholecystectomy as long as margins are – ve T1b (with perineural ,lymphatic and vascular invasion )-Extended cholecystectomy (Ro resection ) Port site recurrence- excision of all port site

24. Gall Bladder Carcinoma

25. Gall Bladder Carcinoma Treatment Gallbladder cancer after cholecystectomy- T2 lesions- muscularis &<= serosa -radical cholecystectomy. Standard cholecystectomy alone is not done - 40 % of these patients have lymph node metastases and up to 25% have positive margins. Gallbladder cancer is generally unresponsive to other therapies, the presence of any residual disease after operative intervention predicts poor outcome .

26. Gall Bladder Carcinoma Treatment Patients suspected of having gallbladder cancer preoperatively. Resectable cases without metastasis- open cholecystectomy Unresectable - diagnostic laparoscopy - to identify small volume peritoneal or hepatic metastases that would preclude a resection, thereby avoiding an unnecessary operation.

27. Gall Bladder Carcinoma Treatment Patients suspected of having gallbladder cancer preoperatively . Palliative T3and T4- Radical resection - segments IVB and V but more often requires a central hepatectomy, including all of segments IV, V , and VIII. For Ro- Direct extension of tumor into adjacent structures such as the hepatic flexure is not a contraindication to resection as long as negative margins can be obtained. Debulking without possibility of complete resection has no role in the management of gallbladder cancer .

28. Gall Bladder Carcinoma Radical resection

29. Gall Bladder Carcinoma

30. Gall Bladder Carcinoma Treatment Patients with advanced disease at presentation( unresctable and metastatic) Advanced Biliary Cancer (ABC)-02 trial , 2010 - locally advanced or metastatic biliary tract cancer (of whom ~36% had gallbladder cancer) demonstrated that the combination of gemcitabine + cisplatin ( 11.7months) is associated with improved overall and progression-free survival compared to gemcitabine alone(8.1months) Pembrolizumab is now approved for the treatment of patients with all metastatic and unresectable solid tumors having defective mismatch repair who have progressed through prior therapy and for whom there are no satisfactory treatment alternatives.

31. Gall Bladder Carcinoma Treatment Patients with advanced disease at presentation . G oal of therapy - palliation of symptoms . Jaundice – Endoscopic biliary stent and self expanding endobiliary metal stent.

32. Gall Bladder Carcinoma Treatment Patients with advanced disease at presentation. Pain- oral narcotics ,parenteral opioids and Percutaneous neurolysis of the celiac ganglion. Intestinal obstruction-usually gastric outlet obstruction from local extension of tumor - an endoscopic duodenal wall stent.

33. Gall Bladder Carcinoma Adjuvant therapy Neither chemotherapy nor radiation therapy - survival benefit. External beam or intraoperative radiation therapy alone or in combination with 5-flourouracil (5-fu) has been associated with diminished rates of local recurrence. Recently results, of the phase iii multicenter BILCAP trial from the United K ingdom, were reported. Subgroup analysis from an older phase iii trial adjuvant treatment with fluorouracil and mitomycin c or observation showed improved survival with adjuvant treatment for patients with gallbladder cancer but not cholangiocarcinoma .

34. Gall Bladder Carcinoma Survival Dependent on the stage of disease at presentation and whether surgical resection is performed . T1a &T1b- excellent prognosis. T2 lesions depends on nodal status, and radical resection improves 5-year survival from approximately 20% to >60 %.

35. Gall Bladder Carcinoma Survival contd … 5-year survival rates for patients with T1N0, T2N0, and T3N0 (or no depositive ) disease are 39%, 15%, and 5%, respectively . The 5-year survival of patients with T3 tumors is < 20%, and T4 lesions –months M etastatic disease at presentation - median survival of 13 months .

36. Gall Bladder Carcinoma References Sabiston text book of surgery 20 th edition pg no-1512-1514. SRB manual of surgery 5 th edition pg no 659-660 Maingot’s abdominal operation 13 th edition pg no 2989-3009. Bailey & Love’s short practice of surgery ,27 th edition ,volume 2, pg no 1209-1211 Pandey M, Shukla VK. Lifestyle, parity, menstrual and reproductive factors and risk of gallbladder cancer. Eur J Cancer Prevent . Aug 2003; 12(4):269-272. Elnemr A, Ohta T, Kayahara M, et al. Anomalous pancreaticobiliary ductal junction without bile duct dilatation in gallbladder cancer. Hepatogastroenterology . Mar-Apr 2001;48(38):382-386 .

37. Gall Bladder Carcinoma References Primrose JN, Fox R, Palmer DH et al. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. Journal of Clinical Oncology 35, no. 15_suppl (May 20 2017) 4006-4006. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. Oct 15 2002;95(8):1685-95. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer . N Engl J Med . Apr 8 2010;362(14): 1273-1281. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. Jul 28 2017; 357(6349):409-413.

38. Gall Bladder Carcinoma Thank You!