Gallbladder Gallbladder CancerCancer

Manuel Molina, MDManuel Molina, MDLutheran Medical CenterLutheran Medical Center

Gallbladder CarcinomaGallbladder Carcinoma

EpidemiologyEpidemiology

Most common malignancy of the Most common malignancy of the biliarybiliary system.system.55thth most common tumor of the GI tractmost common tumor of the GI tractMost common in the seventh or eighth decades Most common in the seventh or eighth decades of life.of life.Females to males: 3Females to males: 3--4:14:11.2 cases per 100,0001.2 cases per 100,000Highest rates in Native Americans and South Highest rates in Native Americans and South Americans, Polish and North IndiansAmericans, Polish and North Indians

PathogenesisPathogenesis

Relationship between Relationship between cholelithiasischolelithiasis and GB and GB cancer. 80% of patients with GB cancer have cancer. 80% of patients with GB cancer have gallstones, 60% located in the gallstones, 60% located in the fundusfundus..Multistage process:Multistage process:

Mucosal inflammationMucosal inflammationHyperplasiaHyperplasiaMetaplasiaMetaplasiaDysplasiaDysplasiaCarcinoma. Invades surrounding structuresCarcinoma. Invades surrounding structuresHematogenousHematogenous or lymphatic spread (cystic node)or lymphatic spread (cystic node)

PathogenesisPathogenesis

Risk increases in direct proportion to gallstone Risk increases in direct proportion to gallstone size. RR is 2.4 if gallstones are 2 to 2.9 cm, and size. RR is 2.4 if gallstones are 2 to 2.9 cm, and 10.1 if >3.0cm10.1 if >3.0cm.(A.K. Diehl et al, JAMA 250, 1983.).(A.K. Diehl et al, JAMA 250, 1983.)

Porcelain Gallbladder has been associated with Porcelain Gallbladder has been associated with GB cancer in 12.5GB cancer in 12.5--62%. Higher in selective 62%. Higher in selective mucosal calcification.mucosal calcification. (A.E. Stephen et al.,. Surgery 129, 2001).(A.E. Stephen et al.,. Surgery 129, 2001).

Polyps greater than 10mm in diameter have the Polyps greater than 10mm in diameter have the greatest malignant potential. greatest malignant potential. ((M.C.AldridgeM.C.Aldridge et al., Br J et al., Br J SurgSurg &&, &&, 1990).1990).

PathogenesisPathogenesis

Anomalous Anomalous pancreaticobiliarypancreaticobiliary duct junction is duct junction is associated with GB cancer; found in 17% of patients. associated with GB cancer; found in 17% of patients. This causes free back flow of pancreatic juice into the This causes free back flow of pancreatic juice into the gallbladder causing bile stasis in patients with normal gallbladder causing bile stasis in patients with normal CBD. These patients are younger and have lower CBD. These patients are younger and have lower incidence of gallstones. incidence of gallstones. (K. (K. ChijiiwaChijiiwa et al., et al., IntInt SurgSurg 80,1995)80,1995)

Carcinogens like Carcinogens like methylcholanthrenemethylcholanthrene, , OO--aminoazotoluleneaminoazotolulene, nitrosamines are associated with , nitrosamines are associated with GB cancer in experimental GB cancer in experimental animals.animals.(K(K. . KowalewskiKowalewski et al, Proc Soc Exp et al, Proc Soc Exp Bio Med 136, 1971.)Bio Med 136, 1971.)

PathogenesisPathogenesis

Other risk factors include obesity, estrogens, Other risk factors include obesity, estrogens, thyphoidthyphoid infection, segmental infection, segmental adenomyomatosisadenomyomatosis, chronic inflammatory bowel , chronic inflammatory bowel disease and disease and polyposispolyposis coli.coli.

PathologyPathology

DysplasiaDysplasia to invasive carcinoma takes over 15 years.to invasive carcinoma takes over 15 years.Macroscopically is divided into papillary, tubular or Macroscopically is divided into papillary, tubular or nodular. Papillary less invasion to the liver and lymph nodular. Papillary less invasion to the liver and lymph nodes.nodes.Most carcinomas are Most carcinomas are adenocarcinomasadenocarcinomas 8080--95%, and 95%, and can be papillary, tubular, can be papillary, tubular, mucinousmucinous or signet cells.or signet cells.Less common types include: Less common types include: anaplasicanaplasic (2(2--7%), 7%), squamoussquamous cell (1cell (1--6%), and 6%), and adenosquamousadenosquamous (1(1--4%). 4%). CarcinoidCarcinoid, small, small--cell, malignant melanoma, lymphoma cell, malignant melanoma, lymphoma and sarcomas are particularly rare.and sarcomas are particularly rare.

GeneticsGenetics

KK--rasras mutations in 39mutations in 39--59%. Increases to 5059%. Increases to 50--83% in patients with abnormal 83% in patients with abnormal pancreaticobiliarypancreaticobiliary duct junction.duct junction.P53 abnormalities are seen in 35P53 abnormalities are seen in 35--92% of GB 92% of GB cancers.cancers.(S(S. . MisraMisra et al, et al, EurEur J J SurgSurg OncolOncol 26, 2000). 26, 2000).

OverOver--expression of p53 is associated with grade, expression of p53 is associated with grade, stage and presence of gallstones.stage and presence of gallstones.

Clinical PresentationClinical PresentationSymptomsSymptoms Proportion of patientsProportion of patients

RUQ pain RUQ pain 82%82%Weight lossWeight loss 72%72%AnorexiaAnorexia 74%74%Nausea and vomitingNausea and vomiting 68%68%RUQ massRUQ mass 65%65%JaundiceJaundice 44%44%Abdominal distentionAbdominal distention 30%30%PruritusPruritus 20%20%HematemesisHematemesis 2%2%MelenaMelena 1%1%

DiagnosisDiagnosis

Only 8Only 8--10% are diagnosed preoperatively.10% are diagnosed preoperatively.Diagnosis is often challenging, no signs and Diagnosis is often challenging, no signs and symptoms specific to gallbladder cancer.symptoms specific to gallbladder cancer.Most are incidental discovery during the OR.Most are incidental discovery during the OR.

DiagnosisDiagnosisUltrasonographyUltrasonography: 80% accurate; part of the : 80% accurate; part of the initial assessment. Demonstrates initial assessment. Demonstrates polypoidalpolypoidalmass without acoustic shadow with localized mass without acoustic shadow with localized thickening. Loss of GB/liver interface found in thickening. Loss of GB/liver interface found in advance cancer.advance cancer.Limitation in diagnosis of involved nodes and Limitation in diagnosis of involved nodes and staging of the diseasestaging of the diseaseEndoscopicEndoscopic ultrasound improves diagnosis of ultrasound improves diagnosis of GB cancer and predicts depth of tumor. GB cancer and predicts depth of tumor. Helpful for differential diagnosis of Helpful for differential diagnosis of polypoidpolypoidlesions.lesions.

DiagnosisDiagnosis

CT Scan accurately detects GB abnormalities CT Scan accurately detects GB abnormalities and the extent of disease, direct infiltration into and the extent of disease, direct infiltration into adjacent tissues or vessels, nodal or distant adjacent tissues or vessels, nodal or distant metastasis. metastasis. MRI: tumors are MRI: tumors are hypodensehypodense in T1 images and in T1 images and hyperdensehyperdense in T2 images. Particularly useful for in T2 images. Particularly useful for visualizing invasion of the visualizing invasion of the hepatoduodenalhepatoduodenalligament, portal vein encasement and lymph ligament, portal vein encasement and lymph node involvement.node involvement.

DiagnosisDiagnosis

Selective angiography is very accurate for Selective angiography is very accurate for detection of vessel encasement or detection of vessel encasement or neovascularizationneovascularization..ERCP is helpful in planning surgery, because it ERCP is helpful in planning surgery, because it can show tumor growth in the can show tumor growth in the intrahepaticintrahepatic ducts ducts or CBD.or CBD.HIDA can show CBD obstruction or cystic duct HIDA can show CBD obstruction or cystic duct obstruction (rare in GB cancer).obstruction (rare in GB cancer).FNA ultrasound or CT guided most frequently FNA ultrasound or CT guided most frequently used for used for preoppreop cytodiagnosiscytodiagnosis, has a sensitivity of , has a sensitivity of 88%.88%.

DiagnosisDiagnosis

Laparoscopy and biopsy are extremely useful for Laparoscopy and biopsy are extremely useful for assessment of peritoneal metastasis, extend of assessment of peritoneal metastasis, extend of the disease and suitability of surgery in patients the disease and suitability of surgery in patients with locally advanced disease.with locally advanced disease.Markers as CA 19Markers as CA 19--9 >20U/ml have 79.4% 9 >20U/ml have 79.4% sensitivity and 79.2% specific. CEA >4mcg/L sensitivity and 79.2% specific. CEA >4mcg/L is 93% specific but only 50% sensitive.is 93% specific but only 50% sensitive.

StagingStaging UICC/AJCC TNMUICC/AJCC TNMPrimary tumorPrimary tumorTxTx Primary tumor cannot be assessed.Primary tumor cannot be assessed.T0 No evidence of primary tumorT0 No evidence of primary tumorTisTis Carcinoma in situCarcinoma in situT1a Tumor invade lamina T1a Tumor invade lamina propriapropriaTibTib tumor tumor invadesmuscleinvadesmuscle layerlayerT2 Tumor invades T2 Tumor invades perimuscularperimuscular connective tissue, no extension connective tissue, no extension beyongbeyong serosaserosa or into or into

liver.liver.T3 Tumor perforates T3 Tumor perforates serosaserosa or directly invades the liver or other adjacent organs or or directly invades the liver or other adjacent organs or

structure (stomach, duodenum, colon, pancreas, structure (stomach, duodenum, colon, pancreas, omentumomentum, , extrhepaticextrhepatic bile bile ducrsducrs))T4 Tumor invades main portal vein or hepatic artery or invades tT4 Tumor invades main portal vein or hepatic artery or invades two or more wo or more extrahepaticextrahepatic

organs or structures.organs or structures.Regional NodesRegional NodesNxNx Regional nodes cannot be assessedRegional nodes cannot be assessedN0 No regional lymph no metastasisN0 No regional lymph no metastasisN1 Regional Lymph nodes metastasisN1 Regional Lymph nodes metastasisDistant metastasisDistant metastasisMxMx distant metastasis cannot be assesseddistant metastasis cannot be assessedM0 no distant metastasisM0 no distant metastasisM1 distant metastasisM1 distant metastasis

Stage UICC/AJCC TNMStage UICC/AJCC TNM

Staging groupStaging groupStage 0 Stage 0 TisTis N0m0N0m0Stage IA T1N0M0Stage IA T1N0M0Stage IB T2N0M0Stage IB T2N0M0Stage IIA T3N0M0Stage IIA T3N0M0Stage IIB T1,T2,T3 N1M0Stage IIB T1,T2,T3 N1M0Stage III T4 Any N M0Stage III T4 Any N M0SatgeSatge IV Any T Any N M1IV Any T Any N M1

StagingStaging

NevinNevin’’ss classification:classification:Stage I: mucosa only (45% 2yr survival)Stage I: mucosa only (45% 2yr survival)Stage II: Stage II: muscularismuscularis (15%)(15%)Stage III: all layers (4%)Stage III: all layers (4%)Stage IV: lymph nodes (2%)Stage IV: lymph nodes (2%)Stage V: liver invasion, adjacent organs, distant Stage V: liver invasion, adjacent organs, distant metastasis metastasis

Survival by Tumor TypeSurvival by Tumor Type

Histology 2yr Histology 2yr survsurv. Median . Median survsurv..AdenocarcinomaAdenocarcinoma 14%14% 4 months4 months

Papillary variantPapillary variant 47%47% 20 months20 monthsMucinousMucinous Variant 12%Variant 12% 4 months4 months

SquamousSquamous cellcell 9%9% 4 months4 months

AdenosquamousAdenosquamous 8%8% 3 months3 months

UndifferentiatedUndifferentiated 0%0% 2 months2 months

Surgical managementSurgical managementThe only potentially curative therapyThe only potentially curative therapySurgical options:Surgical options:

Simple Simple cholecystectomycholecystectomyRadical or extended Radical or extended cholecystectomycholecystectomyRadical Radical cholecystectomycholecystectomy with liver with liver resection(segementalresection(segemental or or lobar)lobar)Radical Radical cholecystectomycholecystectomy with extensive lymphwith extensive lymph--node node dissectiondissectionRadical Radical cholecystectomycholecystectomy with bile duct resection or with bile duct resection or pancreaticoduodenectomypancreaticoduodenectomyBilioBilio--enteric bypassenteric bypassResection of port sites after laparoscopic Resection of port sites after laparoscopic cholecystectomycholecystectomy

Surgical managementSurgical management

Stage I: simple Stage I: simple cholecystectomycholecystectomyStage II: radical Stage II: radical cholecystectomycholecystectomy (2(2--5cm wedge 5cm wedge resection of GB resection of GB fossafossa and regional lymph node and regional lymph node dissectiondissectionStage III and above: controversial ( liver resection or Stage III and above: controversial ( liver resection or palliative palliative bilioentericbilioenteric bypass bypass vsvs adjuvant adjuvant chemo/radiotherapy)chemo/radiotherapy)If GB cancer is suspected during laparoscopic If GB cancer is suspected during laparoscopic cholecystectomycholecystectomy, recommend , recommend convertionconvertion to open to open procedure.procedure.GB cancer suspected before surgery, laparoscopic GB cancer suspected before surgery, laparoscopic cholecystectomycholecystectomy should not be considered. should not be considered.

Surgical managementSurgical management

8080--96% 5yr survival for T1 lesions with simple 96% 5yr survival for T1 lesions with simple cholecystectomycholecystectomy..15% lymph node metastasis in T1b lesions. 15% lymph node metastasis in T1b lesions. 87% 10 yr survival with simple 87% 10 yr survival with simple cholecystectomy.cholecystectomy.(T(T. . WakaiWakai et al, Br J et al, Br J SurgSurg 88, 2001).88, 2001).

3030--40% 5 yr survival for T2 lesions treated with 40% 5 yr survival for T2 lesions treated with simple simple cholecystectomycholecystectomy(D.L.Barlett(D.L.Barlett, et al, Ann , et al, Ann SurgSurg 224, 1996)224, 1996)

8080--90% 5yr survival for T2 and T3 lesions 90% 5yr survival for T2 and T3 lesions treated with radical treated with radical cholecystectomy.cholecystectomy.(Y.shirai(Y.shirai et al, Ann et al, Ann SurgSurg 215, 1992).215, 1992).

ReRe--exploration reveals residual tumor in 40exploration reveals residual tumor in 40--76% 76% of casesof cases

Surgical managementSurgical management

Palliation for advance GB cancer:Palliation for advance GB cancer:Segment II duct Segment II duct biliobilio--enteric bypassenteric bypassEndoscopicEndoscopic stentingstentingRadiological Radiological stentingstentingDuodenal or intestinal bypass for gastric outlet or Duodenal or intestinal bypass for gastric outlet or intestinal obstruction.intestinal obstruction.

RadiotherapyRadiotherapy

Stage IV tumors treated with resection and Stage IV tumors treated with resection and radiotherapy, 3yr survival of 10%.radiotherapy, 3yr survival of 10%.(Todoroki et al, World J (Todoroki et al, World J surgsurg 15, 1991).15, 1991).

Tumor control is rarely achieved by radiotherapy Tumor control is rarely achieved by radiotherapy alone.alone.BrachytherapyBrachytherapy via via percutaneouspercutaneous transhepatictranshepaticapproach is used for palliation of obstructive approach is used for palliation of obstructive jaundice due to bile duct obstruction.jaundice due to bile duct obstruction.

ChemotherapyChemotherapy

34% response rate and 7 months response 34% response rate and 7 months response duration with intraduration with intra--arterial infusion of 5arterial infusion of 5--FU and FU and mitomycinmitomycin c.c.(Misra(Misra, et al, , et al, RegReg Cancer Treat 5 ,1992).Cancer Treat 5 ,1992).

61% response rate with 61% response rate with GemcitabineGemcitabine and and CisplatinumCisplatinum. Needs further studying. . Needs further studying.