Carcinoma of Gallbladder -Carcinoma of Gallbladder -an update on surgical an update on surgical managementmanagement

Dr Alfred C C Wong,Dr Alfred C C Wong,

Department of Surgery,Department of Surgery,

Ruttonjee & Tang Shiu Kin Ruttonjee & Tang Shiu Kin Hospital.Hospital.

TSKH

IntroductionIntroduction

gallbladder carcinoma is a gallbladder carcinoma is a relatively rare diseaserelatively rare disease

in the United States, in the United States, approximately 1.2 cases/100,000 approximately 1.2 cases/100,000 population per yearpopulation per year

worldwide it is the most common worldwide it is the most common cancer of the biliary tractcancer of the biliary tract

5th most common malignancy of 5th most common malignancy of the GI Tractthe GI Tract

IntroductionIntroduction

5836 cases in world’s literature from 5836 cases in world’s literature from 1960-19781960-1978

outcome of gallbladder cancer was outcome of gallbladder cancer was poor, 5 years survival rate less than 5%poor, 5 years survival rate less than 5%

median survival 5 – 8 monthsmedian survival 5 – 8 months 25% treated by surgery with curative 25% treated by surgery with curative

intent, only 16.5% survived 5 yearsintent, only 16.5% survived 5 years

Piehler & Crichlow Piehler & Crichlow Surg Gynecol Surg Gynecol ObstetObstet 1978 1978

(Germany)(Germany)

IntroductionIntroduction

median survival 3-5 monthsmedian 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 ratestage I & II: 12% 5-year survival rate Stage III & IV: median survival was Stage III & IV: median survival was

only 46 daysonly 46 days without surgery without surgery

Perpetuo et alPerpetuo et al Cancer Cancer 1978 (USA)1978 (USA)Cubertafond et alCubertafond et al Ann Surg Ann Surg 1994 (France)1994 (France)Wilkinson Wilkinson Aust N Z J Surg Aust N Z J Surg 1995 1995

(Australia)(Australia)

IntroductionIntroduction

surgery is the only hope of cure / surgery is the only hope of cure / prolonged survivalprolonged survival

chemotherapy / radiotherapy: chemotherapy / radiotherapy: unequivocal resultsunequivocal results

Morbidity & mortality of resection of gallbladderMorbidity & mortality of resection of gallbladder

AuthorAuthor YearYear No. of No. of casescases

ProcedureProcedure Morbidity Morbidity (%)(%)

Mortality Mortality (%)(%)

OuchiOuchi 19871987 1212 Extended Extended procedureprocedure

-- 2121

NakamuraNakamura 19891989 1313 Extended Extended procedureprocedure

4646 00

DonohueDonohue 19901990 1717 Extended Extended procedureprocedure

55 00

TodorokiTodoroki 19911991 2727 Extended Extended procedure + IORTprocedure + IORT

-- 77

NimuraNimura 19911991 1414 HepatopancreatioHepatopancreatioc-duodenectomyc-duodenectomy

-- 2121

GallGall 19911991 88 Extended Extended procedureprocedure

-- 00

OguraOgura 19911991 695695 Extended Extended procedureprocedure

2222 22

302302 Hepatic Hepatic lobectomylobectomy

4848 1818

150150 HepatopancreatioHepatopancreatioc-duodenectomyc-duodenectomy

5454 1515

De De AretxabalaAretxabala

19921992 2525 Extended Extended procedureprocedure

-- 00

MatsumotoMatsumoto 19921992 3535 Extended Extended procedureprocedure

1515 44

ChijiiwaChijiiwa 19941994 3030 Extended Extended procedureprocedure

-- 33

BartlettBartlett 19961996 2323 Extended Extended procedureprocedure

2626 00

morbidity and mortality rates of major morbidity and mortality rates of major liver resections have decreased in recent liver resections have decreased in recent reports, even in the aged populationreports, even in the aged population

most recent series report a mortality most recent series report a mortality rate of 5% or less even with extensive rate of 5% or less even with extensive liver resectionsliver resections

Matsumato et al Matsumato et al Am J SurgAm J Surg 1992 1992de Aretxabala et al de Aretxabala et al CancerCancer 1992 1992Tsau et al Tsau et al Ann Surg Ann Surg 19931993Fong et al Fong et al Ann SurgAnn Surg 1995 1995Bartlett et al Bartlett et al Ann SurgAnn Surg 1996 1996Fong et al Fong et al Ann SurgAnn Surg 2000 2000

Incidental gallbladder Incidental gallbladder carcinomacarcinoma long term survivors after radical long term survivors after radical

surgery from incidental surgery from incidental carcinoma of gallbladdercarcinoma of gallbladder

defines as carcinoma of defines as carcinoma of gallbladder first diagnosed at the gallbladder first diagnosed at the histological examination of the histological examination of the resected gallbladderresected gallbladder

Incidental gallbladder Incidental gallbladder carcinomacarcinoma 1-2% operation for biliary tract1-2% operation for biliary tract 0.35% of cholecystectomy for benign 0.35% of cholecystectomy for benign

diseasedisease Affects <0.5% of patients with Affects <0.5% of patients with

gallstonesgallstones 90% of gallbladder are removed by 90% of gallbladder are removed by

laparoscopic cholecystectomylaparoscopic cholecystectomy new entity “laparoscopic discovered new entity “laparoscopic discovered

gallbladder carcinoma”gallbladder carcinoma”

How to handle How to handle gallbladder cancer in gallbladder cancer in laparoscopic era?laparoscopic era? tumor seedings? port site tumor seedings? port site

metastasis?metastasis? incidental cancer warrants second incidental cancer warrants second

radical operations?radical operations? advanced disease justifies radical advanced disease justifies radical

operations?operations? choice of radical operations?choice of radical operations?

Tumor seedings & port Tumor seedings & port site metatstasissite metatstasis laparoscopic cholecystectomy is laparoscopic cholecystectomy is

associated with dissemination of associated with dissemination of tumor cells when an incidental tumor cells when an incidental gallbladder cancer is removedgallbladder cancer is removed

Fong et al Arch Surg 1993Fong et al Arch Surg 1993

Ndaka et al Br J Surg 1994Ndaka et al Br J Surg 1994

Paolucci et al World J Surg Paolucci et al World J Surg 19991999

Tumor seedings & port Tumor seedings & port site metatstasissite metatstasis 70/409 (17.1%) cases with incidental 70/409 (17.1%) cases with incidental

gallbladder cancer over a median of gallbladder cancer over a median of 180 days following laparoscopic 180 days following laparoscopic cholecystectomycholecystectomy

8 out 0f 70 using plastic bag8 out 0f 70 using plastic bag only 49 from extraction siteonly 49 from extraction site 6/409 (1.5%) carcinomatosis 6/409 (1.5%) carcinomatosis

peritoneiperitonei

Paolucci et al World J Surg 1999Paolucci et al World J Surg 1999

Tumor seedings & port Tumor seedings & port site metatstasissite metatstasis 174 cases of port site metastasis of 174 cases of port site metastasis of

malignancy after laparoscopic malignancy after laparoscopic cholecystectomycholecystectomy

12 cases of recurrence in surgical scar 12 cases of recurrence in surgical scar after converted or open cholecystectomyafter converted or open cholecystectomy

14% of port site metastasis 7 months after 14% of port site metastasis 7 months after laparoscopic cholecystectomy for cancerlaparoscopic cholecystectomy for cancer

similar incidence for open cholecystectomysimilar incidence for open cholecystectomy

PaolucciPaolucci J Hepatobiliary Pancreat Surg J Hepatobiliary Pancreat Surg 2001 2001

Tumor seedings & port Tumor seedings & port site metatstasissite metatstasis perforation of gallbladder during perforation of gallbladder during

laparoscopic cholecystectomy laparoscopic cholecystectomy worsens survivalworsens survival

Yoshida et al J Am Coll Surg 2000Yoshida et al J Am Coll Surg 2000

Ouchi et al Ouchi et al J Hepatobiliary Pancreat SurgJ Hepatobiliary Pancreat Surg 20022002

RecommendationsRecommendations

port sites excision in second port sites excision in second radical procedureradical procedure

open cholecystectomy if pre-open cholecystectomy if pre-operatively suspected carcinoma operatively suspected carcinoma of gallbladderof gallbladder

avoid bile spillageavoid bile spillage

Surgical ManagementSurgical Management

controversy exists regarding the controversy exists regarding the extent of surgical resectionextent of surgical resection

T-stage is most important prognostic T-stage is most important prognostic factorfactor

simple cholecystectomy to ultra-simple cholecystectomy to ultra-aggressive resections consisting of aggressive resections consisting of combined major liver resection and combined major liver resection and pancreaticoduodenectomy +/- pancreaticoduodenectomy +/- adjacet organ resectionadjacet organ resection

StagingStaging

multiple staging systemsmultiple staging systems– American Joint Committee on Cancer American Joint Committee on Cancer

–Union Internationale Contre le –Union Internationale Contre le Cancer TNM staging systemCancer TNM staging system

– modified Nevin systemmodified Nevin system– Japanese Biliary Surgical Society Japanese Biliary Surgical Society

systemsystem

AJCC-UICCAJCC-UICC TNM staging TNM staging systemsystem

AJCC-UICC TMN stagingAJCC-UICC TMN staging

Primary tumor (T)Primary tumor (T)– Tx: cannot be assessedTx: cannot be assessed– T0: no evidence of primary tumorT0: no evidence of primary tumor– Tis: carcinoma in situTis: carcinoma in situ– T1: 1a invades mucosaT1: 1a invades mucosa 1b invades muscle layers1b invades muscle layers– T2: invades peri-muscular connective T2: invades peri-muscular connective

tissue; not beyond serosa or into livertissue; not beyond serosa or into liver– T3: perforates serosa or invades into liver T3: perforates serosa or invades into liver

(<2cm) and/or adjacent organ(<2cm) and/or adjacent organ– T4: invades liver >2cm and/or into 2 or T4: invades liver >2cm and/or into 2 or

more adjacent organsmore adjacent organs

T1 diseaseT1 disease

StudyStudy YearYear No. of No. of casescases

ProcedureProcedure 3-Y survival 3-Y survival (%)(%)

5-Y survival 5-Y survival (%)(%)

OuchiOuchi 19871987 1414 Not specifiedNot specified 7878 71.471.4

YamaguchiYamaguchi 19881988 1111 Not specifiedNot specified 100100 NRNR

DonohueDonohue 19901990 66 83% simple 83% simple cholecystectomycholecystectomy

100100 100100

GallGall 19911991 77 Simple Simple cholecystectomycholecystectomy

8686 8686

OguraOgura 19911991 366366 Not specifiedNot specified 8787 7878

YamaguchiYamaguchi 19921992 66 Simple Simple cholecystectomycholecystectomy

100100 100100

ShiraiShirai 19921992 5656 Simple Simple cholecystectomycholecystectomy

100100 100100

3838 Extended Extended cholecystectomycholecystectomy

100100 100100

MatsumotoMatsumoto 19921992 44 Extended Extended cholecystectomycholecystectomy

100100 100100

OertliOertli 19931993 66 Simple Simple cholecystectomycholecystectomy

100100 100100

De De AretxabalaAretxabala

19971997 3232 69% simple 69% simple cholecystectomycholecystectomy

9494 9494

Survival after resection of Stage I carcinoma of gallbladder

T1 diseaseT1 disease

cured by simple cholecystectomy alonecured by simple cholecystectomy alone 5-year survival rate: 85-year survival rate: 866% to 100%% to 100% importance of cystic duct marginimportance of cystic duct margin if all margins are negative if all margins are negative no therapy no therapy

necessarynecessary if the cystic duct margin is positive if the cystic duct margin is positive

consider common bile duct excision and consider common bile duct excision and biliary reconstruction to improve survivalbiliary reconstruction to improve survival

no benefit of second radical no benefit of second radical operation for early incidental operation for early incidental gallbladder carcinoma if the gallbladder carcinoma if the surgical margins were tumor freesurgical margins were tumor free

Shirai et al Eu J Surg 1992Shirai et al Eu J Surg 1992

Wakai et al Br J Surg 2001Wakai et al Br J Surg 2001

T2 diseaseT2 disease

StudyStudy YearYear No. of No. of casescases

ProcedureProcedure 3-Y survival 3-Y survival (%)(%)

5-Y survival 5-Y survival (%)(%)

ShiraiShirai 19921992 3535 Simple Simple cholecystectomycholecystectomy

5757 40.540.5

1010 extended extended cholecystectomycholecystectomy

9090 9090

YamaguchiYamaguchi 19921992 2525 Simple Simple cholecystectomycholecystectomy

3636 3636

MatasumotoMatasumoto 19921992 99 extended extended cholecystectomycholecystectomy

100100 100100

OerttliOerttli 19931993 1313 simple simple cholecystectomycholecystectomy

2929 2424

BartlettBartlett 19961996 88 extended extended cholecystectomycholecystectomy

100100 8888

PaquetPaquet 19981998 55 extended extended cholecystectomycholecystectomy

100100 8080

De AretxabalaDe Aretxabala 19971997 1818 Simple Simple cholecystectomycholecystectomy

NRNR 2020

2020 extended extended cholecystectomycholecystectomy

NRNR 7070

FongFong 20002000 3737 extended extended cholecystectomycholecystectomy

6868 5959

Survival after Resection of Stage II (T2) Gallbladder Cancers

T2 diseaseT2 disease

tumor remains sub-serosaltumor remains sub-serosal recommends second radical surgeryrecommends second radical surgery

– plane between liver & gallbladderplane between liver & gallbladder– high incidence of regional LN metastasishigh incidence of regional LN metastasis

Radical cholecystectomy: Radical cholecystectomy: – wedge resection of gallbladder bed / wedge resection of gallbladder bed /

segmentectomy segmentectomy – regional lymphadenopathyregional lymphadenopathy– +/- CBD resection for better lymphatic +/- CBD resection for better lymphatic

clearenceclearence

T3 & T4 diseaseT3 & T4 disease

StudyStudy YearYear No. of No. of casescases

StageStage 3-Y 3-Y Survival Survival

(%)(%)

5-Y 5-Y Survival Survival

(%)(%)

DonohueDonohue 19901990 1717 III/IVIII/IV 5050 2929

OguraOgura 19911991 453453 IVIV 1818 88

TodorokiTodoroki 19911991 2727 IVIV 77 --

GallGall 19911991 88 III/IVIII/IV 5050 --

NimuraNimura 19911991 1414 IVIV 1010 --

MatsumotoMatsumoto 19921992 88 IIIIII 3838 --

2727 IVIV 2525 --

ShiraiShirai 19921992 2020 III/IVIII/IV -- 4545

OnoyamaOnoyama 19951995 1212 IIIIII 4444 4444

1414 IVIV 88 88

BartlettBartlett 19961996 88 IIIIII 6363 6363

77 IVIV 2525 2525

FongFong 20002000 3636 IIIIII -- 2121

2727 IVIV -- 2828

Survival after resection of Stage III & IV carcinoma of gallbladder

T3 and T4 diseaseT3 and T4 disease

area of great controversyarea of great controversy perceived poor long term perceived poor long term

prognosisprognosis literature provides support for literature provides support for

aggressive approach aggressive approach by by confirming a possibility for long-confirming a possibility for long-term survival after resection of term survival after resection of locally advanced diseaselocally advanced disease

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

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

Effect of clinical and pathologic parameter on long-term outcome after resection.

Fong et al Ann Surg 2000

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

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

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

Multivariate analysis for predictors of long-term outcome for resected patients

Fong et al Ann Surg 2000

Radical operative procedureRadical operative procedure

Wedge liver resectionWedge liver resection 88

Wedge liver, LNDWedge liver, LND 2323

Wedge liver, LND, CBD resection & reconstructionWedge liver, LND, CBD resection & reconstruction 88

Segment 4/5, LNDSegment 4/5, LND 33

Segment 4/5, LND, CBD resection & reconstructionSegment 4/5, LND, CBD resection & reconstruction 1616

Rt lobectomy, LNDRt lobectomy, LND 22

Rt lobectomy, LND, CBD resection & reconstructionRt lobectomy, LND, CBD resection & reconstruction 66

Rt trisegmentectomy, LNDRt trisegmentectomy, LND 22

Rt trisegmentectomy, LND, CBD resection & Rt trisegmentectomy, LND, CBD resection & reconstructionreconstruction

3131

Lt trisegmentectomy, caudate, LND, CBD resection & Lt trisegmentectomy, caudate, LND, CBD resection & reconstructionreconstruction

11

TotalTotal 100100Fong et al Ann Surg 2000

ConclusionConclusion

T1: simple cholecystectomyT1: simple cholecystectomy T2: recommends second radical T2: recommends second radical

operation + excision of port sitesoperation + excision of port sites T3/4: may prolonged survival with T3/4: may prolonged survival with

radical operationradical operation

Importance of tertiary referral centreImportance of tertiary referral centre

Risk factorsRisk factors

female sexfemale sex high parityhigh parity increasing ageincreasing age gallstonesgallstones anomalous pancreatico-biliary duct anomalous pancreatico-biliary duct

junctionjunction chronic typhoid infectionchronic typhoid infection inflammatory bowel diseaseinflammatory bowel disease porcelain gallbladderporcelain gallbladder single, sessile polyp >10mm in sizesingle, sessile polyp >10mm in size Methyldopa, oral contraceptives, isoniazid, Methyldopa, oral contraceptives, isoniazid,

chemicals used in the rubber industrychemicals used in the rubber industry

StageStage TMNTMN Modified Modified Nevin SystemNevin System

Japanese Biliary Japanese Biliary Surgical Society Surgical Society

SystemSystem

II Mucosal or muscular Mucosal or muscular invasion (T1N0M0)invasion (T1N0M0)

In situIn situ carcinomacarcinoma

Confined to Confined to gallbladder gallbladder capsulecapsule

IIII Transmural invasion Transmural invasion (T2N0M0)(T2N0M0)

Mucosal or Mucosal or muscular muscular invasioninvasion

N1 lymph nodes; N1 lymph nodes; minimal liver or minimal liver or bile duct invasionbile duct invasion

IIIIII Liver invasion <2 cm; Liver invasion <2 cm; lymph node lymph node metastases (T3N1M0)metastases (T3N1M0)

Transmural Transmural direct liver direct liver invasioninvasion

N2 lymph nodes; N2 lymph nodes; marked liver or marked liver or bile duct invasionbile duct invasion

IVIV A: liver invasion >2 A: liver invasion >2 cm (T4N0M0, cm (T4N0M0,

TXN1M0)TXN1M0)

Lymph node Lymph node metastasismetastasis

Distant metastasisDistant metastasis

B: distant metastasis B: distant metastasis

(TXN2M0, TXNXM1)(TXN2M0, TXNXM1)

VV Distant Distant metastasismetastasis

Fong et al Ann Surg 2000

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

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