Gallbladder Cancer and Cholangiocarcinoma Yuman Fong, MD Upper Gastrointestinal Cancer Seminar Copenhagen, Denmark 2009
A.A. Blalock, Johns Hopkins Hosp. Bull. 35:391, 1924 "...in malignancy of the gallbladder, when a diagnosis can be made without exploration, no operation should be performed, inasmuch as it only shortens the patient's life."
Gallbladder Cancer Natural History 5,836 patients in literature (1960-1978) 1978) Overall 5-year 5 survival of 4.1% Resection resulted in 16.5% 5-year 5 survival One 5-yr 5 survivor out of 2,115 non-resected patients Overall mean survival 2-52 5 months Piehler, SG&O, 147:929, 1978 (collected review)
Gallbladder Cancer Epidemiology 90% of cases in patients over 50 Male:Female ratio of 1:3 70-98% of cases associated with gallstones 1% of cholecystectomy for gallstones 10% of porcelain gallbladders Approximately 2000 cases/ year
Gallbladder Cancer Histologic Subtypes Histologic Type Carriage and Hanson, Cancer, 1995 Fong et al., Ann Surg, 2000 Adenocarcinoma 89% 91% Papillary 6% 3% Mucinous 5% 2% Squamous 2% 2% Other 8% 7% Sarcoma 0.2% 0.2%
Gallbladder Cancer Symptoms Burdette (1957) Thorbjarnarson (1959) Perpetuo (1978) Chau (1991) Fong (2000) Pain 82% 86% 97% 54% 64% Jaundice 50% 23% 44% 46% 37% Weight loss 47% 35% 77% 28% 10%
Gallbladder Cancer Presentation RUQ discomfort RUQ mass c/w distended gallbladder
Gallbladder Cancer Radiologic Findings
Radiologic Presentation of Gallbladder Cancer
Gallbladder Cancer Questions What is the appropriate extent of resection? Is a radical resection necessary for early stage disease? Is a radical resection justified for advanced disease? When patients present after simple cholecystectomy, is a re-operative radical resection necessary and justified?
Gallbladder Cancer Surgical Options Simple cholecystectomy Extended cholecystectomy Extended hepatic resection Hepatic resection and pancreaticoduodenectomy
Gallbladder Cancer Major Hepatic Resection as Therapy Treated by right lobectomy,, node dissection Three cases: two after previous exploration One One patient died peri-operatively One One died of disseminated recurrence One One alive NED at two years Wound implantation noted in one case on re- exploration Pack et al., Ann. Surg., 142:6, 1955
Gallbladder Cancer Major Hepatic Resection as Therapy First to advocate right lobectomy, lymph node dissection First report of wound implantation of tumor Pack et al., Ann. Surg., 142:6, 1955
Gallbladder Cancer Presentation after Cholecystectomy T-stage GB involvement Tis T1 T2 T3 T4 In situ Mucosal Not through serosa Through serosa >2 cm beyond gallbladder
Gallbladder Cancer Simple Cholecystectomy for Stage I Author 5-yr Survival Donohue, 1990 100% Gall, 1991 86% Shirai, 1992 100% Yamaguchi, 1992 100% Shirai, 1992 100% Oertli, 1993 100%
Author Gallbladder Cancer Stage II Disease Source Shirai, 1992 Ann Surg, 216:565 40% Yamaguchi, 1992 Am J Surg, 163:382 36% Oertli, 1993 Eur J Surg, 159:415 24% Author Simple Cholecystectomy Extended Resection Source Matsumoto, 1992 Am J Surg, 163:239 100% Shirai, 1992 Ann Surg, 216:565 90% Bartlett, 1996 Ann Surg, 224:639 88% 5-yr Survival 5-yr Survival
Gallbladder Cancer Survival after Resection Author Source % Stage III/IV 5-yr Surv Nakamura, 1989 Surgery, 106:467 86 25% Donohue, 1990 Arch Surg, 125:237 78 33% Ogura, 1991 World J Surg, 15:337 48 51% Shirai, 1992 Ann Surg, 216:565 52 65% Ouchi, 1993 Surgery, 101:731 47 61% Bartlett, 1996 Ann Surg, 224:639 65 51% Fong, 2000 Ann Surg, 232:557 63 38% Behari, 2003 J Am Coll Surg, 196:82 45 49%
Gallbladder Cancer Goals of Resection Removal of gallbladder Removal of areas of liver invasion Portal lymph node dissection Remove and reconstruct areas of portal vein invasion Biliary reconstruction
Gallbladder Cancer Resection and Reconstruction
Gallbladder Cancer MSKCC Report July 1986 - March 2000 n=410 M:F = 137:273 Median age (range) = 65 (28-87) 162 presented without prior surgery 248 presented after surgery 127 open cholecystectomy 85 laparoscopic cholecystectomy
Gallbladder Cancer Surgical Therapy and Outcome 1.0.8 Survival.6.4 Resection.2 Cholecystectomy +/- bypass 0.0 0 None 12 24 36 48 60 P=0.0001 Months
Gallbladder Cancer Extent of Resection and Outcome for T2 Tumors 1.0.8 Radical Resection Survival.6.4.2 Cholecystectomy 0.0 0 12 24 36 48 60 P=0.04 Months
Gallbladder Cancer 1.0 T stage.8 T2 Survival.6.4 T3.2 T4 0.0 0 12 24 36 48 60 P=0.003 Months
Gallbladder Cancer Effect of Prior Exploration on Outcome 1.0 Survival.8.6.4.2 Previous exploration No previous exploration 0.0 0 12 24 36 48 60 P=NS Months
Gallbladder Cancer T-stage and Resectability Resected Lymph Node Metastases Peritoneal or Liver Metastases T2 58% 33% 16% T3 27% 58% 42% T4 13% 69% 79%
Gallbladder Cancer Node Status 1.0 Survival.8.6.4 Node negative.2 0.0 0 Node positive 12 24 36 48 60 P=0.002 Months
Gallbladder Cancer Laparoscopically-discovered 2616 2616 laparoscopic cholecystectomy 24 cancers found 3 3 cases of port site recurrence Yamaguchi et al., Arch Surg, 131:981, 1996
Gallbladder Cancer Laparoscopic Port Site Recurrence
Gallbladder Cancer Summary Unresected gallbladder cancer is a rapidly fatal disease Radical resection is indicated for T2-T4 T4 disease Long-term survival can result from resection of T4 cancer Patients presenting after prior non-curative cholecystectomy should be considered for radical re-resection resection
Peripheral Cholangiocarcinoma Location Hilar Distal GB CBD D PD 10 20% Large mass Unknown 1 o 40 60% Biliary confluence Most common 20 30% 10% of periampullary tumors
Cholangiocarcinoma Demographics Uncommon: 1.2/100,000 < 2% of all cancers Disease of elderly: 2/3 over 65 years. 10/100,000 in octogenarians Death results from hepatic failure or sepsis Carriaga and Henson. Cancer Suppl. 1995;75:171
Hilar Cholangiocarcinoma Gerald Klatskin, MD Thirteen cases reported in 1965 Adenocarcinoma at hepatic duct bifurcation Klatskin, G. American Journal of Medicine 1965;38:241-256.
Cholangiocarcinoma Anatomical Considerations Portal vein involvement Lobar atrophy Tumor contact w/ distortion, narrowing, encasement/occlusion. Small, hypoperfused lobe w/ crowded, dilated ducts. Lobar atrophy implies portal venous involvement Common 60% have one or both findings Mandate hepatic resection
Cholangiocarcinoma Anatomical Considerations Principal caudate duct enters LHD in most patients Additional drainage of the right portion of the caudate and caudate process is via the RHD
Cholangiocarcinoma Goals of Resection R0 resection Leaving a well-perfused liver remnant With adequate biliary drainage. Remove bile duct Remove involved liver Portal lymphadenectomy Remove/reconstruct areas of portal vein invasion Biliary reconstruction
Hilar Cholangiocarcinoma MSKCC Results 279 Patients 1/91 11/03 Unresectable at Presentation 64 patients, 23% (metastases in 26) Explored for Cure 215 Patients, 77% Unresectable 109 Patients, 51% (metastases in 90) Resected 106 Patients, 49%
Cholangiocarcinoma Operative Procedures and Operative Results All resections Complete gross resection 106 Concomitant liver resection 87 (82%) En bloc caudate resection 36 (41%) Vascular resection/reconstruction 11 (10%) Mortality 8 (7.5%)
1.0.75 Cholangiocarcinoma Survival after Resection Resection margin status R0, 43 months (n = 82) R1, 24 months (n = 24) Loc Adv, 16 months (n = 29) %.5 p<0.001.25 P=0.19 0.0 0 20 40 60 Time (months) 80 100
Cholangiocarcinoma Variables Associated with Survival after Resection p p (univariate) (multivariate) HR R0 Resection (82) 0.0003 0.006 2.27 Liver Resection (87) 0.021 0.003 2.69 Well-Differentiated (35) 0.0001 0.0001 3.62 Papillary Tumor (25) 0.013 0.015 2.49 Node (-)( 0.0007 0.64 1.15 Variables not significant: Age, gender, AJCC stage, tumor size, vascular resection, en bloc caudate lobectomy
Cholangiocarcinoma Hepatic Resection and Margin Status %Hepatic %neg Author Resection Margin Tsao 16 28 Cameron 20 15 Gerhards 29 14 Hadjis 60 56 Jarnagin 78 78 Klempnauer 79 79 Neuhaus 85 61 Nimura 98 83 % Liver Resection 100 75 50 25 0 R 2 = 0.9 0 25 50 75 100 % Negative Magins
Morbidity and Mortality Resected Author Years (N) Morbidity Mortality Iwatsuki ( 96) * 15 72-18% Klempnauer ( 97) * 24 147 30% 10% Gerhards ( 00) 15 112 65% 18% Tabata ( 00) 22 75 31% 12% Gazzaniga ( 00) 17 75-10% Neuhaus ( 00) * 10 95 59% 8% Nimura ( 00) 20 142 49% 9% Jarnagin ( 01) 9 80 64% 10% Nagino ( 01) 9 105 81% 10% * - includes OLT in some patients.
Cholangiocarcinoma Hepatic Resections and Operative Mortality 100 80 60 % 77% 78% 92% 40 Liver Resection Mortality 20 0 10% 10% 1991-95 (n = 30) 1996-99 (n = 40) 2000-03 (n = 36) 2.8%
Percutaneous Portal Vein Embolization
Pre-operative Biliary Drainage: Rationale Improve: Hepatic function Allow normal regeneration of liver remnant Decrease risk of post-operative hepatic failure Renal function, cell-mediated immunity, nutrition Indications: Sepsis Renal insufficiency Left dominant tumors Severe medical co-morbidity
Pre-operative Biliary Drainage Procedure-related complications Pancreatitis Biloma Biliary injury Hemorrhage Perforation
Summary Prolonged survival is possible after complete resection Advances in non-surgical therapy are needed Heightened awareness of intrahepatic cholangioca Hepatic resection required for hilar tumors Operative mortality has been high but is improving Points of ongoing debate: Pre-operative biliary drainage? Pre-operative portal vein embolization? Caudate resection for all patients? Extended lymphadenectomy?
Chemotherapy for Biliary Cancers Regimen Response Median Survival 5-FU 10% 6-7 m 5-FU/ cisplatin 20-40% 6-12 m Gemcitabine 20-30% 6-12 m Gemcitabine/ 5-FU 10-35% 9-14 m Gemcitabine/ Cisplatin 20-35% 9-11 m Gemcitabine/ Oxaliplatin 20-50% 11-15 m
Molecular Abnormalities in Biliary Cancers EGF/ EGFR HER-2 MAPK COX2 VEGF MUC-1/ MUC-4 K-RAS Cyclin-D1 TGF-b p53
Llovet and Bruix, Hepatology 2008
Targeted Agents In Development Hezel and Zhu, Oncologist 2008;13:415-423 Copyright 2008 AlphaMed Press
Incidence of Gallbladder Cancer Delhi: 22/100 K Quito: 13 Roi Et: 33 Cali: 10 N Mexico: 9
Etiology of Biliary Cancers Gallbladder Cancer Stones Environmental pathogens Cadmium, Chromium, Lead (Tanneries of Northern India) Infections Typhoid (Chile, Northern India, Scotland) Salmonella Helicobacter
Etiology of Biliary Cancers Meal of Koi-Pla: Fermented Uncooked Cyprinoid Fish Opisthorchis viverrini
Public Education Roi Et Province