1. Carcinoma of Gallbladder - an update on surgical management Dr Alfred C C Wong, Department of Surgery, Ruttonjee & Tang Shiu Kin Hospital.

2. Introduction gallbladder carcinoma is a relatively rare disease gallbladder carcinoma is a relatively rare disease in the United States, approximately 1.2 cases/100,000 population per year in the United States, approximately 1.2 cases/100,000 population per year worldwide it is the most common cancer of the biliary tract worldwide it is the most common cancer of the biliary tract 5th most common malignancy of the GI Tract 5th most common malignancy of the GI Tract

3. Introduction 5836 cases in world ’ s literature from 1960- 1978 5836 cases in world ’ s literature from 1960- 1978 outcome of gallbladder cancer was poor, 5 years survival rate less than 5% outcome of gallbladder cancer was poor, 5 years survival rate less than 5% median survival 5 – 8 months median survival 5 – 8 months 25% treated by surgery with curative intent, only 16.5% survived 5 years 25% treated by surgery with curative intent, only 16.5% survived 5 years Piehler & Crichlow Surg Gynecol Obstet 1978 (Germany)

4. Introduction median survival 3-5 months median survival 3-5 months 1 year survival rate 14% 1 year survival rate 14% 5-year survival rate ~ 5% 5-year survival rate ~ 5% stage I & II: 12% 5-year survival rate stage I & II: 12% 5-year survival rate Stage III & IV: median survival was only 46 days without surgery Stage III & IV: median survival was only 46 days without surgery Perpetuo et al Cancer 1978 (USA) Cubertafond et al Ann Surg 1994 (France) Wilkinson Aust N Z J Surg 1995 (Australia)

5. Introduction surgery is the only hope of cure / prolonged survival surgery is the only hope of cure / prolonged survival chemotherapy / radiotherapy: unequivocal results chemotherapy / radiotherapy: unequivocal results

6. Morbidity & mortality of resection of gallbladder AuthorYear No. of cases Procedure Morbidity (%) Mortality (%) Ouchi198712 Extended procedure -21 Nakamura198913 460 Donohue199017 50 Todoroki199127 Extended procedure + IORT -7 Nimura199114 Hepatopancreatioc- duodenectomy -21 Gall19918 Extended procedure -0 Ogura1991695 222 302 Hepatic lobectomy 4818 150 Hepatopancreatioc- duodenectomy 5415 De Aretxabala 199225 Extended procedure -0 Matsumoto199235 154 Chijiiwa199430 -3 Bartlett199623 260

7. morbidity and mortality rates of major liver resections have decreased in recent reports, even in the aged population morbidity and mortality rates of major liver resections have decreased in recent reports, even in the aged population most recent series report a mortality rate of 5% or less even with extensive liver resections most recent series report a mortality rate of 5% or less even with extensive liver resections Matsumato et al Am J Surg 1992 de Aretxabala et al Cancer 1992 Tsau et al Ann Surg 1993 Fong et al Ann Surg 1995 Bartlett et al Ann Surg 1996 Fong et al Ann Surg 2000

8. Incidental gallbladder carcinoma long term survivors after radical surgery from incidental carcinoma of gallbladder long term survivors after radical surgery from incidental carcinoma of gallbladder defines as carcinoma of gallbladder first diagnosed at the histological examination of the resected gallbladder defines as carcinoma of gallbladder first diagnosed at the histological examination of the resected gallbladder

9. Incidental gallbladder carcinoma 1-2% operation for biliary tract 1-2% operation for biliary tract 0.35% of cholecystectomy for benign disease 0.35% of cholecystectomy for benign disease Affects <0.5% of patients with gallstones Affects <0.5% of patients with gallstones 90% of gallbladder are removed by laparoscopic cholecystectomy 90% of gallbladder are removed by laparoscopic cholecystectomy new entity “ laparoscopic discovered gallbladder carcinoma ” new entity “ laparoscopic discovered gallbladder carcinoma ”

10. How to handle gallbladder cancer in laparoscopic era? tumor seedings? port site metastasis? tumor seedings? port site metastasis? incidental cancer warrants second radical operations? incidental cancer warrants second radical operations? advanced disease justifies radical operations? advanced disease justifies radical operations? choice of radical operations? choice of radical operations?

11. Tumor seedings & port site metatstasis laparoscopic cholecystectomy is associated with dissemination of tumor cells when an incidental gallbladder cancer is removed laparoscopic cholecystectomy is associated with dissemination of tumor cells when an incidental gallbladder cancer is removed Fong et al Arch Surg 1993 Ndaka et al Br J Surg 1994 Paolucci et al World J Surg 1999

12. Tumor seedings & port site metatstasis 70/409 (17.1%) cases with incidental gallbladder cancer over a median of 180 days following laparoscopic cholecystectomy 70/409 (17.1%) cases with incidental gallbladder cancer over a median of 180 days following laparoscopic cholecystectomy 8 out 0f 70 using plastic bag 8 out 0f 70 using plastic bag only 49 from extraction site only 49 from extraction site 6/409 (1.5%) carcinomatosis peritonei 6/409 (1.5%) carcinomatosis peritonei Paolucci et al World J Surg 1999

13. Tumor seedings & port site metatstasis 174 cases of port site metastasis of malignancy after laparoscopic cholecystectomy 174 cases of port site metastasis of malignancy after laparoscopic cholecystectomy 12 cases of recurrence in surgical scar after converted or open cholecystectomy 12 cases of recurrence in surgical scar after converted or open cholecystectomy 14% of port site metastasis 7 months after laparoscopic cholecystectomy for cancer 14% of port site metastasis 7 months after laparoscopic cholecystectomy for cancer similar incidence for open cholecystectomy similar incidence for open cholecystectomy Paolucci J Hepatobiliary Pancreat Surg 2001

14. Tumor seedings & port site metatstasis perforation of gallbladder during laparoscopic cholecystectomy worsens survival perforation of gallbladder during laparoscopic cholecystectomy worsens survival Yoshida et al J Am Coll Surg 2000 Ouchi et al J Hepatobiliary Pancreat Surg 2002

15. Recommendations port sites excision in second radical procedure port sites excision in second radical procedure open cholecystectomy if pre- operatively suspected carcinoma of gallbladder open cholecystectomy if pre- operatively suspected carcinoma of gallbladder avoid bile spillage avoid bile spillage

16. Surgical Management controversy exists regarding the extent of surgical resection controversy exists regarding the extent of surgical resection T-stage is most important prognostic factor T-stage is most important prognostic factor simple cholecystectomy to ultra- aggressive resections consisting of combined major liver resection and pancreaticoduodenectomy +/- adjacet organ resection simple cholecystectomy to ultra- aggressive resections consisting of combined major liver resection and pancreaticoduodenectomy +/- adjacet organ resection

17. Staging multiple staging systems multiple staging systems –American Joint Committee on Cancer – Union Internationale Contre le Cancer TNM staging system –modified Nevin system –Japanese Biliary Surgical Society system

18. AJCC-UICC TNM staging system

19. AJCC-UICC TMN staging Primary tumor (T) Primary tumor (T) –Tx: cannot be assessed –T0: no evidence of primary tumor –Tis: carcinoma in situ –T1: 1a invades mucosa 1b invades muscle layers 1b invades muscle layers –T2: invades peri-muscular connective tissue; not beyond serosa or into liver –T3: perforates serosa or invades into liver (<2cm) and/or adjacent organ –T4: invades liver >2cm and/or into 2 or more adjacent organs

21. T1 disease

22. StudyYear No. of cases Procedure 3-Y survival (%) 5-Y survival (%) Ouchi198714 Not specified 7871.4 Yamaguchi198811 100NR Donohue19906 83% simple cholecystectomy 100100 Gall19917 Simple cholecystectomy 8686 Ogura1991366 Not specified 8778 Yamaguchi19926 Simple cholecystectomy 100100 Shirai199256 100100 38 Extended cholecystectomy 100100 Matsumoto19924 100100 Oertli19936 Simple cholecystectomy 100100 De Aretxabala 199732 69% simple cholecystectomy 9494 Survival after resection of Stage I carcinoma of gallbladder

23. T1 disease cured by simple cholecystectomy alone cured by simple cholecystectomy alone 5-year survival rate: 86% to 100% 5-year survival rate: 86% to 100% importance of cystic duct margin importance of cystic duct margin if all margins are negative  no therapy necessary if all margins are negative  no therapy necessary if the cystic duct margin is positive  consider common bile duct excision and biliary reconstruction to improve survival if the cystic duct margin is positive  consider common bile duct excision and biliary reconstruction to improve survival

24. no benefit of second radical operation for early incidental gallbladder carcinoma if the surgical margins were tumor free no benefit of second radical operation for early incidental gallbladder carcinoma if the surgical margins were tumor free Shirai et al Eu J Surg 1992 Wakai et al Br J Surg 2001

25. T2 disease

26. StudyYear No. of cases Procedure 3-Y survival (%) 5-Y survival (%) Shirai199235 Simple cholecystectomy 5740.5 10 extended cholecystectomy 9090 Yamaguchi199225 Simple cholecystectomy 3636 Matasumoto19929 extended cholecystectomy 100100 Oerttli199313 simple cholecystectomy 2924 Bartlett19968 extended cholecystectomy 10088 Paquet19985 10080 De Aretxabala 199718 Simple cholecystectomy NR20 20 extended cholecystectomy NR70 Fong200037 6859 Survival after Resection of Stage II (T2) Gallbladder Cancers

27. T2 disease tumor remains sub-serosal tumor remains sub-serosal recommends second radical surgery recommends second radical surgery –plane between liver & gallbladder –high incidence of regional LN metastasis Radical cholecystectomy: Radical cholecystectomy: –wedge resection of gallbladder bed / segmentectomy –regional lymphadenopathy –+/- CBD resection for better lymphatic clearence

28. T3 & T4 disease

29. StudyYear No. of cases Stage 3-Y Survival (%) 5-Y Survival (%) Donohue199017III/IV5029 Ogura1991453IV188 Todoroki199127IV7- Gall19918III/IV50- Nimura199114IV10- Matsumoto19928III38- 27IV25- Shirai199220III/IV-45 Onoyama199512III4444 14IV88 Bartlett19968III6363 7IV2525 Fong200036III-21 27IV-28 Survival after resection of Stage III & IV carcinoma of gallbladder

30. T3 and T4 disease area of great controversy area of great controversy perceived poor long term prognosis perceived poor long term prognosis literature provides support for aggressive approach by confirming a possibility for long-term survival after resection of locally advanced disease literature provides support for aggressive approach by confirming a possibility for long-term survival after resection of locally advanced disease

31. Presentation, operative data, complications, and survival were examined for 410 patients presenting between July 1986 and March 2000

32. Overall survival for patients treated with no surgery (open box), simple cholecystectomy or bypass (open triangle), or resection (solid circles). Patients treated by surgical resection clearly demonstrated much improved outcome compared to those treated without surgery (P <.0001). Fong et al Ann Surg 2000

33. Effect of clinical and pathologic parameter on long-term outcome after resection. Fong et al Ann Surg 2000

34. Survival according to T-stage of disease for patients resected of gallbladder cancer. T2 (cross), T3 (solid circles), and T4 (open circles) are compared (P =.003) Fong et al Ann Surg 2000

35. Outcome according to node status for patients resected of gallbladder cancer, showing positive (n = 36; open circles) and negative (n = 64; solid circles) for nodal metastases (P =.002) Fong et al Ann Surg 2000

36. Effect of prior surgery on outcome for those patients resected with curative intent for gallbladder cancer. Survival for patients presenting with no prior surgical therapy (circles) are compared to those presenting for definitive therapy after prior surgical exploration (squares) (P = NS) Fong et al Ann Surg 2000

37. Multivariate analysis for predictors of long-term outcome for resected patients Fong et al Ann Surg 2000

38. Radical operative procedure Wedge liver resection 8 Wedge liver, LND 23 Wedge liver, LND, CBD resection & reconstruction 8 Segment 4/5, LND 3 Segment 4/5, LND, CBD resection & reconstruction 16 Rt lobectomy, LND 2 Rt lobectomy, LND, CBD resection & reconstruction 6 Rt trisegmentectomy, LND 2 Rt trisegmentectomy, LND, CBD resection & reconstruction 31 Lt trisegmentectomy, caudate, LND, CBD resection & reconstruction 1 Total100 Fong et al Ann Surg 2000

39. Conclusion T1: simple cholecystectomy T1: simple cholecystectomy T2: recommends second radical operation + excision of port sites T2: recommends second radical operation + excision of port sites T3/4: may prolonged survival with radical operation T3/4: may prolonged survival with radical operation Importance of tertiary referral centre

43. Risk factors female sex female sex high parity high parity increasing age increasing age gallstones gallstones anomalous pancreatico-biliary duct junction anomalous pancreatico-biliary duct junction chronic typhoid infection chronic typhoid infection inflammatory bowel disease inflammatory bowel disease porcelain gallbladder porcelain gallbladder single, sessile polyp >10mm in size single, sessile polyp >10mm in size Methyldopa, oral contraceptives, isoniazid, chemicals used in the rubber industry Methyldopa, oral contraceptives, isoniazid, chemicals used in the rubber industry

44. StageTMN Modified Nevin System Japanese Biliary Surgical Society System I Mucosal or muscular invasion (T1N0M0) In situ carcinoma Confined to gallbladder capsule II Transmural invasion (T2N0M0) Mucosal or muscular invasion N1 lymph nodes; minimal liver or bile duct invasion III Liver invasion <2 cm; lymph node metastases (T3N1M0) Transmural direct liver invasion N2 lymph nodes; marked liver or bile duct invasion IV A: liver invasion >2 cm (T4N0M0, TXN1M0) Lymph node metastasis Distant metastasis B: distant metastasis (TXN2M0, TXNXM1) V Distant metastasis

45. Fong et al Ann Surg 2000

46. Outcomes of patients with T2 gallbladder cancers. Patients undergoing radical resection (box) are compared to patients undergoing cholecystectomy (open circle) (P <.05) Fong et al Ann Surg 2000

47. Survival of patients after resection for gallbladder cancer according to (A) TNM or (B) modified Nevin staging. (A) TNM stage 2 (cross), stage 3 (open triangles), or stage 4 (solid triangles);P =.003. (B) Modified Nevin stage 2 (cross), stage 3 (solid circles), stage 4 (open triangles), and stage 5 (solid triangles);P =.0001 Fong et al Ann Surg 2000