at SciVerse ScienceDirect

Surgical Oncology 21 (2012) e183ee191

Contents lists available

Surgical Oncology

journal homepage: www.elsevier .com/locate/suronc

Review

Gallbladder cancer: Past, present and an uncertain future

C. Boutros a, M. Gary b, K. Baldwin b, P. Somasundar b,*aUniversity of Maryland School of Medicine, Division of Surgical Oncology, Baltimore, MD, USAbRoger Williams Outcomes Research Program, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908, USA

a r t i c l e i n f o

Article history:Accepted 28 August 2012

Keywords:Gallbladder cancerEpidemiologyTreatment

* Corresponding author. Tel.: þ1 401 456 4897; faxE-mail address: psomasun@chartercare.org (P. Som

0960-7404/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.suronc.2012.08.002

a b s t r a c t

Although gallbladder cancer (GBC) is the most common malignancy of the biliary tract, its relatively lowincidence and confounding symptomatology result in advanced disease at the time presentation,contributing to the poor prognosis and decreased survival associated with this disease. It is thereforeincreasingly important to understand its pathogenesis and risk factors to allow for the earliest possiblediagnosis. To date, gallbladder cancer is poorly understood compared to other malignancies, and is stillmost commonly discovered incidentally after cholecystectomy. Moreover, while much is known aboutbiliary neoplasms as a whole, understanding the clinical and molecular nuances of GBC as a separatedisease process will prove a cornerstone in the development of early intervention, potential screeningand overall more effective treatment strategies.

The present work reviews the most current understanding of the pathogenesis, diagnosis, staging andnatural history of GBC, with additional focus on surgical treatment. Further, review of current adjuvanttherapies for unresectable and advanced disease as well as prognostic factors provide fertile ground forthe development of future studies which will hopefully improve treatment outcomes and affect overallsurvival for this highly morbid, poorly understood malignancy.

� 2012 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e184Epidemiology and pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e184Chronic inflammation and GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e184Gallstones and risk of GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e184Infection, chronic inflammation and GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e184Chemical and environmental (causes of chronic inflammation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e184Autoimmune and hereditary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e185Gallbladder polyps and risk of GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e185

Radiological evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e185Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e185Surgical options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e185Surgical options for T1 GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e186Surgical options for T2 GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e186Surgical options for T3eT4 GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e187Role of surgery in locally invasive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e187

The role of chemotherapy and radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e187Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e188Long term result after surgical resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e188Multimodal management and potential for new therapeutic options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e188

: þ1 401 456 6708.asundar).

All rights reserved.

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191e184

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e189Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e189References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e189

Introduction volume, not just size, were significantly higher in patients with

Gallbladder cancer (GBC) was first described by Maximillian deStoll in two autopsy cases in 1777, with the first documented cancerresection performed by Keen in 1891 [1].. In the 21st century GBC isthe fifth most commonly occurring gastrointestinal cancer in theUS. According to data from the Surveillance, Epidemiology, and EndResults (SEER) program (1992e2000) the incidence of GBC is esti-mated at 2.5 per 100,000 persons; it is the most common primarybiliary tract malignancy, representing 46% of all such malignancies.

The pathogenesis of GBC is poorly understood compared toother neoplasms [2]. Diagnosis of GBC commonly occurs as anincidental finding in the setting of operative intervention forcholelithiasis, resulting in advanced disease at the time of initialdiagnosis [3]. In addition, symptoms associated with GBC can bevague and nonspecific, further complicating early detection. Finally,symptoms of GBC mirror those due to cholelithiasis and cholecys-titis, making it difficult to differentiate (in the absence of familyhistory) from benign pathology.

Several risk factors have been associated with GBC includingage, sex, parity, race/ethnicity, and obesity. In one retrospectiveseries, the majority of GBC patients were of low socioeconomicstatus and rural background [4].

Epidemiology and pathogenesis

Chronic inflammation and GBC

Chronic inflammation may result from a wide and multifactorialrange of etiologies: mechanical obstruction via gallstones, infectiousand environmental exposure, polyps and adenomas, autoimmunedisease, as well as anatomic variations including pancreatobiliarymaljunction. Studies implicate each of these as a contributing factorto the development of GBC [4e6]. The exact role of inflammation inthe molecular progression leading to the development of GBC hasbeen poorly understood. However, recent studies may elucidatepotential mechanisms and provide targets for therapeutic inter-vention. These will be discussed in further detail later in this work.

Gallstones and risk of GBC

Gallstones are present in about 80% of patients with GBC. Stonescan lead to chronic inflammation, promoting metaplasia andadenocarcinoma by either mechanical irritation of the gallbladdermucosa or mechanical obstruction of the gallbladder leading tocholestasis [2]. The presence of stones alone is insufficient; gall-stones remain asymptomatic in 66e77% of the general population[7]. Freidman et al. [8] reported that only 1e2% of patients withgallstones become symptomatic per year to warrant a cholecystec-tomy, and over a 20 year period 2/3 of asymptomatic patients withgallstones remain symptom free. The study reported as well thatthe longer the stones remain quiescent, the less likely they are toproduce symptoms. As with nonmalignant cholecystic disease,cholesterol is the predominant component of gallstones, withgreater than 75% being cholesterol [9].

The relationship between gallstone size and the risk of GBC hasbeen studied. The relative risk of gallbladder carcinoma rises from2.4� for stones size of 2e2.9 cm, to 10� for stones larger than 3 cm[10]. However, another study reported that gallstone weight and

gallbladder carcinoma. In their study a total stone volume greaterthan 10 mL had an odds ratio 11 times higher than the controlgroup for the development of GBC [11].

The associated increase in number and size of gallstones inpatients with GBC could be simply an effect of aging, or a reflectionof the long term presence of the stones on the gallbladder ratherthan a chemical or physical influence [12].

Other gallstone-associated patient factors may act asconfounding variables as well. One prospective caseecontrol studyof 37 patients with GBC identified typhoid carrier state, age, andsmoking as three independent risk factors for the development ofGBC in patients with concomitant gallstones [13].

Infection, chronic inflammation and GBC

The relationship between bacterial infection and oncogenesishas been characterized for many different types of cancers.Exploring the contribution of infection to the development of thismalignancy continues to be an area of ongoing investigation,particularly in endemic regions where GBC is more prevalent. Theproposedmechanism of action involves persistent infection leadingto chronic inflammation, along with production of toxins andmetabolites which may result in malignant transformation ofgallbladder epithelium [14].

Chronic bacterial infection has also been associated with GBC,and even specific pathogens have been implicated [15,16]. Organ-isms recovered from bile are typically concomitantly present inlarge bowel flora; these include Escherichia coli, streptococcus,klebsiella and enterobacter. Anaerobic colonization by clostridiumand bacteroides is observed in 48% of gallbladder specimenscollected in one series [17,18]. Bacterial DNAwere isolated in 78% ofGBC tissue specimens using only a single round of amplification,however the causal association between bacterial presence andgallbladder carcinogenesis needs to be evaluated in depth.

Salmonella typhi has become a model for understanding thisrelationship. The first report of carcinoma of the gallbladder asso-ciated with typhoid carriagewas in 1971 by Axelrod et al. [19]. Longterm cohort studies after the Aberdeen typhoid outbreak in 1964and from Central American typhoid patients, report a 6% lifetimerisk of developing GBC and a 12-fold increase in this population,respectively [20,21].

Chemical and environmental (causes of chronic inflammation)

Exposure to carcinogenic agents represents a contributoryetiology to the development of many types of cancers. Historicalstudies have shown that chemical pollution via pesticides, exces-sive exposure to heavy metals, radiation and vinyl chloride, as wellas industrial/occupational exposures (e.g. rubber, textile, petro-leum, and shoe factories) increase the risk of gallbladder cancer. ACalifornia Tumor Registry review of 1808 cases of gallbladder andbile duct cancers found a significant association between GBC andworkers in rubber, automobile, wood furnishing and metal fabri-cating industries [22]. Interestingly, results from a study of biliarytract cancers in Akron, Ohio, a site of four major rubbermanufacturing companies in the US demonstrated that 27.6percent of the patients with GBC in their study were employed byrubber industries [23]. Clearly validation studies are necessary to

Table 1Nevin’s staging for gall bladder carcinoma [51].

Stage I Intramucosal tumorStage II Tumor extends to the muscularisStage III Tumor extends to the serosaStage IV Transmural involvement and cystic lymph node involvementStage V Direct extension to the liver and or distant metastasis

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191 e185

corroborate these epidemiologic findings and validate the associ-ation between caustic agents and GBC; indeed, population, in vivoand in vitro studies are ongoing.

Increased risk for the development of GBC has also been associ-ated with ingestion of some medications (e.g., isoniazid and oralcontraceptives) [24]. In a population-based caseecontrol study inShanghai, China examined the role of oral contraceptives. A groupconsisting of 411 biliary tract cancer patients, 893 biliary stonepatients and 786 healthy Shanghai residents, were evaluated foreighteen single-nucleotide polymorphisms (SNPs) in 9 genesinvolved in steroid hormone synthesis. Among women taking oralcontraceptives, polymorphisms present in this cohort possessedhormone related gene alterations linked to increased risk of biliarytract cancers [25]. Increased estrogen levels have been implicated inbiliary tract neoplasia by multiple mechanisms including decreasedgallbladder motility, thereby increasing the formation of gallstonesand the risk of infection and inflammation in the biliary tract [26,27].

Autoimmune and hereditary syndromes

The association between ulcerative colitis (UC) and biliarydiseasedbenign and malignant, has been well documented. Lessclear is the more specific role of UC in the development of GBC,specifically, However, beginning in the 1950s there have been severalreports ofGBCarising inpatientswithbothUCandprimarysclerosingcholangitis (PSC), and the suggestion has beenmade that UC confersan increased risk in the development of GBCup to 10 times that of thegeneral population [28,29]. Though still an area of interest andcontroversy, review of the available literature suggests that length ofsymptomatic colitis plays an active role in the development, furtherfueling the discussion of inflammation as an important etiologicfactor in the progression of malignancy within the gallbladder [30].

Gallbladder polyps and risk of GBC

Gallbladder polyps are not an infrequent finding; ranging from0.3% to 12.3% in healthy adults [31e34], several studies reported therelationship of gallbladder polyp size and the risk of GBC. All foundthat approximately 45% and 67% of polyps larger than 10 and15 mm, respectively, harbored malignancy [35e38], supporting thecurrent recommendation for cholecystectomy for polyps largerthan 10 mm. In addition to polyp size, advanced age [36,37,39,40],sessile polyps [41], concurrent gallstones [42] and the presence ofsymptoms [42] have all been implicated as factors associated withan increased risk of malignancy in the polyp.

The exact sequence of molecular events taking place during thepathogenesis of GBC within polyps remains to be elucidated. K-rasand p53 alterations are likely to take part in the de novo pathway ofgallbladder carcinogenesis [43].

A recent Cochrane review of the role of cholecystectomy in themanagement of gallbladder polyps was unable to identify anyrandomized clinical trial comparing cholecystectomy with obser-vation; thus the management of gallbladder polyps remainscontroversial [23].

Radiological evaluation

Ultrasound (US) can detect suspicious lesions for GBC; con-cerning characteristics include a wide polyp base and irregularborders. US accuracy to determine the non resectability of a gall-bladder carcinoma is between 63% [44] and 38% [45]. However, thedepth of the invasion is better appreciated with an endoscopicultrasound (EUS) than with trans-abdominal ultrasound.

Fujita et al. [46] studied 39 GBC patients with preoperative EUSand classified the tumor morphology into four categories. Type A

implied a pedunculated mass with a fine-nodular surface and intactneighboring wall. Type B was a broad-based mass with an irregularsurface and intactouterhyperechoic layerof theadjacentwall. In typeC, the outerhyperechoic layerwas irregulardue to themass,whereas,in typeD, the outerhyperechoic layerwas completely disrupted. Eachof the four categories of EUS images correlated well with the histo-logic depth of invasion and was found to be useful to T staging.

Endoscopic retrograde cholangiopancreatography (ERCP) hasutility when bile can be retreived for cytological examination.Although the yield for biliary cytologies is notoriously low, if theyare positive in the setting of suspicion for GBC, the likelihood of thediagnosis is high as 73% in one study [47].

Computed tomography scan (CT) is valuable because of itsability to detect local invasion of the liver, lymph nodes, and thepresence of hepatic and peritoneal metastasis [48]. Spiral CT scanwith thin slices has up to 93% accuracy for determining resectabilityof gallbladder carcinoma [49].

The roleofpositronemission tomography (PET) inGBC is still to bedetermined. Since most patients are diagnosed with after cholecys-tectomy,postoperative inflammation limits thevalueof PETscan [50].The potential use of PET scan will be to preoperatively identifypatients with advanced locoregional or metastatic disease, who willnot benefit from any surgical exploration. In a recent series, PET hadthe sensitivity to detect primary tumor, residual disease and meta-static disease of 86%, 86% and 87% respectively. Corvera et al. [50].

Magnetic resonant imaging (MRI) may be helpful in identifyingbile duct invasion and vascular invasion. A small cohort study(n ¼ 18) utilizing magnetic resonant imaging, angiography andcholangiography reported a combined sensitivity of 100% fordetecting biliary and vascular invasion [32]. However, the sensi-tivity for detecting lymph node metastasis was only 56%.

Staging

The staging of GBC is based on the depth of penetration andextent of spread. In 1976, Nevin et al. [51] reported a series of 66patients with GBC and described a method combining staging andhistological grading of this cancer (Table 1). Currently the stagingsystem of the American Joint Committee on Cancer (AJCC), is themost widely used (Table 2).

The most important prognostic factor is depth of invasion. Fonget al. [52] reported a progressive increase of distant and nodalmetastasis from 16% to 79% and from 33% to 69%, respectively ingoing from T2 to T4 tumors.

Histologically, GBC is graded according to its cellular differen-tiation into four grades. Henson et al. [53] found that themajority ofGBC patients presented with grade 3, poorly differentiated tumors.

Surgical options

The goal of surgical resection is to achieve a complete resectionand obtain negative margins (R0 resection); unfortunately this canonly be achieved in about half of cases. In one series, R0 status wasobtained inonly43%ofpatientsevenwithanextended resection [37].

The extent of the required surgical resection varies from simplecholecystectomy to a more complex surgery that may involve liver,bile duct and pancreatic resections.

Table 2AJCC staging classification of gallbladder carcinoma, 7th edition [104].

Primary tumor (T)TX Primary tumor can not be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor invades lamina propria or muscle layerT1a Tumor invades lamina propriaT1b Tumor invades muscle layer

T2 Tumor invades perimuscular connective tissue,no extension beyond the serosa or into the liver

T3 Tumor perforates the serosa and/or directlyinvades the liver and/or one other adjacent organ or structure

T4 Tumor invades main portal vein or hepatic artery orinvade two or more extrahepatic organs or structures

Regional Lymph nodes (N)NX Regional lymph nodes ca not be assessedN0 No regional lymph node metastasesN1 Metastases to nodes along the cystic duct, common bile duct,

hepatic artery, and or portal veinN2 Metastases to periarotic,pericaval,and/or celiac artery lymph nodes

Distant metastasis (M)M0 No distant metastasisM1 Distant metastasis

Stage 0 Tis N0 M0Stage I T1 N0 M0Stage II T2 N0 M0Stage IIIA T3 N0 M0Stage IIIB T1-3 N1 M0Stage IVA T4 N0-1 M0Stage IVB Any T N2 M0

Any T Any N M1

Table 3Likelihood of lymph node metastasis (LNM), and lymphatic invasion (LI) in pT1blesion.

Study Number ofpatientswith PT1b

% LNM/LI Locoregionalrecurrence

Survival

You et al. [105](2008)

25 3.8% LNM e 96% 5-yearsurvival afterextendedcholecystectomy

1.9% LI

Wagholikaret al. [106] (2002)

12 e 50% e

De Aretxaballaet al. [80] (1992)

9 20% LNM 11% 100% 5-yearsurvival afterextendedcholecystectomy

Ogura et al. [79](1991)

165 15.6% LNM e 72.5% 5-yearsurvival (45% ofpatients hadsimplecholecystectomy)

18.2% LI

Ouchi et al. [107](1987)

7 28% LNM 60% e

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191e186

The only role of laparoscopic surgery in a case of known orsuspected gallbladder carcinoma is to determine resectability.Laparoscopy can detect unresectabe disease in 39e48% of patients,sparing them an unnecessary laparotomy [38,39]. Aside fromstaging, laparoscopic surgery is felt to have no role in the definitiveresection due to the risk of dissemination.

Lymphatic route of spread is defined by different stations,starting with the primary cystic lymph node and pericholedochalnodes to the secondary group of regional lymph nodes, includingthe common hepatic and pancreatico-duodenal nodes. Metastasisto these lymph nodes are currently considered N1 disease accord-ing to the 7th edition of the AJCC classification.

Lymph node metastases in the celiac, superior mesenteric andpara-aortic lymph nodes (N2) represent unresectable disease [54].Unfortunately, the lymphatic drainage frequently does not followpredictable patterns [55] as some patients with T2 tumors havepositive para-aortic lymph nodes [56].

Surgical options for a curative resection of GBC includes a simplecholecystectomy, extended cholecystectomy (including 2 cm livermargin/segmental liver resection and station N1 lymph nodedissection) and radical excision of the gallbladder with lobar liverresection, and/or resection of other adjacent organs.

Most GBC is diagnosed after laparoscopic cholecystectomy inwhich a suspected gallbladder is opened on-table and sent forfrozen section pathological evaluation. After pathological confir-mation, and assessment of the tumor depth further tissue excisionmay be needed.

There is general acceptance that a surgeon without sufficienthepatobiliary experience can safely close the patient and refer toa hepatobiliary center for a second opinion [35]. It has becomeacceptable practice that patients with incidentally discovered GBCat laparoscopic cholecystectomy need not be converted immedi-ately to an open resection and should be referred to a tertiary carecenter for further exploration [57].

Surgical options for T1 GBC

Curative resection can be generally obtained for T1 lesion bysimple cholecystectomy. In a series of 39 patients with T1a disease,a 100% 5-year survival was reported after simple cholecystectomy[44]. The management of T1b lesions is still controversial. Thesetumors have positive nodes in 3e28% of cases, potentially leadingto locoregional failure after simple cholecystectomy [84,86]. Resultsfrom selected studies are reported on Table 3, suggesting that anextended cholecystectomy could be beneficial in patients with T1blesions.

Extended liver wedge resection for early gall bladder cancer hasbeen studied. In one series, there was no statistically significantdifference in survival after extended or simple cholecystectomy instage I disease; however, local recurrence was less after extendedthan after simple cholecystectomy (7% versus 17%) [58].

Surgical options for T2 GBC

Extended cholecystectomy is required for tumors invading theperimuscluar connective tissue (pT2) since the subserosal dissec-tion in routine laparoscopic cholecystectomy results positivemargins.

Extended cholecystectomy is defined as wedge resection ofa two cm liver margin at the gall bladder bed (segment 4/5) as wellas N1 lymphadenectomy. The lymphadenectomy is performed byskeletonizing the portal vein, hepatic artery and the porta hepatiswith excision all lymphatic tissue surrounding these structures. InJapan this dissection also includes the nodes behind the head of thepancreas, the second part of the duodenum, and celiac axis.

There is definitely a survival benefit in favor of extendedcholecystectomy for pT2 lesions over simple cholecystectomy, with5-year survivals of 90% and 40%, respectively [44]. Other series haveconfirmed this observation. Muratore et al. [59] reported a 5 yearsurvival of 60e80% for T2 gallbladder carcinoma with extendedcholecystectomy.

Various other approaches and opinions exist regarding the roleof extended cholecystectomy. Bartlett et al. reported 3 year survivalof 90e100% for patients with T2 tumors after resection of segmentsIVb and V with aggressive lymph node dissection including N2aortocaval lymph nodes [55]. On the other end of the spectrum,a Japanese report found that the long term survival benefit of the

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191 e187

extended cholecystectomy in T2 lesions applied only to patients inwhom a positive margin was obtained during the initial surgery[46]. General consensus at this time is that patients with T2 GBCbenefit from an extended cholecystectomy.

The overall extent of hepatic resection still remains controver-sial. Yoshikawa et al. [60], in a retrospective clinicopathologicalstudy of 201 patients operated for advanced GBC, suggested thatsegmental hepatic resectionmay be beneficial in patients with liverbed type invasion >20 mm in depth.

In a study comparing simple vs. extended cholecystectomy forall stages of GBC, stage II patients with extended cholecystectomy(with 2 cm liver wedge resection) had a longer postoperativesurvival. There was no difference between extended and simplecholecystectomy in stage III and IV disease [48].

Though lymph node metastasis to N2 lymph nodes (para-aortic)is present in 19e25% of patients with locally advanced disease [59];there is no survival benefit for N2 dissection for these patients.Surgical morbidity after an extended cholecystectomy ranges from5 to 26% and surgical mortality ranges from 0% to 4% [61e63].

Surgical options for T3eT4 GBC

For more advanced disease (T3 and T4) the Japanese have re-ported extended hepatectomy, and pancreatoduodenectomy[64,65].

Since the 5-year survival of non-surgically treated locallyadvanced GBC is generally 0% (median survival 8 months), room forimprovement exists. One Japanese study reported a 5-year survivalof 50% (median survival 58.5 months) in those undergoinga potentially curative resection with non anatomic hepatectomy orpancreatoduoedenectomy [52]. Another group compared theoutcomes of patients undergoing radical hep-atopancreatectoduodenoectomy (HPD) vs no surgery. The HPDgroup had 1- and 2-year survival rates of 57% and 28.6%, respec-tively, with a median survival time of 12 months. In contrast, the 1-year survival rate of non-surgically treated patients was 5.8%, witha median survival of 2 months [66].

In the western world the management of advanced GBC iscontroversial. Some series suggest that aggressive surgery withhepatic resection prolongs survival even in the >70 year old pop-ulation provided that an R0 resection is performed [55,56]. A seriesof patients with T4, N0 tumors reported long term survival with nosurgical mortality [51]. Aggressive resection in this subset withadvanced T-stage and negative nodes is almost certainly justified.

The opposing view is that though radical cholecystectomy maybenefit individual patients and can be accomplished with lowmorbidity, theremaybenooverall survival advantage comparedwithsimple cholecystectomy (5-year survival rate 33% versus 32%) [61].

The role of lymph dissection has been debated, with varyinglevels of aggressiveness being practiced throughout the world.Dixon et al. [67] described a skeletonization of the portal structuresincluding suprapyloric lymph node overlying the hepatic-gastroduodenal junction. A more aggressive lymph node dissec-tion is described in the Japanese literature where the node baringadipose tissue located within the hepatoduodenal ligament, post-erosuperior to the head of pancreas, and around the portal vein andcommon hepatic artery is removed en bloc with the gall bladderand adjacent liver tissue [68]. However, there has also been anabsence of randomized controlled studies showing benefit forextended lymph node dissection [69].

Role of surgery in locally invasive disease

Advanced GBC can infiltrate as well surrounding structures suchas the omentum, colon, stomach and abdominal wall. In general the

prognosis of these patients is better than thosewith hepatic or hilarinvasion [70]. hepatopancreatectoduodenectomy though techni-cally feasible carry a high morbidity and mortality and should bereserved to selected cases [65,71].

Although bile duct infiltration can be present in up to 54.2% ofpatients with GBC, [72], a routine bile duct resection in patientswith advanced GBC is not recommended. Kosuge et al. [73] re-ported that bile duct resection did not confer any survival advan-tage in stages I, II, and III, and only a survival benefit was noted instage IV where bile duct resection improve resection of nodal tissueor connective tissue deposits in the hepatoduodenal ligament. Incase of cancer involving the neck of the gallbladder frozen sectionof the bile duct should be obtained to assure a negative resectionmargin.

Vascular involvement of the right hepatic artery should beincluded with right or extended right hepatectomy, whileinvolvement of the left hepatic artery is considered a marker ofunresectability [74].

Portal vein involvement is usually managed by either segmentalresection or wedge resection of the wall with reconstruction.Though technically feasible, portal vein resection does not affectlong-term survival. It should be only selectively used in few cases toachieve R0 resection [71,75].

In locally advanced disease where gall bladder cancer invadesthe duodenum and cause gastric outlet obstruction, a gastro-jejunostomy, or gastroduodenal stenting may be applied as a palli-ative treatment [76], to be noted that malignant gastroparesiswithout real obstruction will not be relieved by these measures[77]. For unresectable cases based on radiological preoperativetests, a tissue diagnosis can be obtained by percutaneous biopsy[78] prior to chemotherapy.

Surgical morbidity for radical cholecystectomy (including hep-atopancreatectomy, hepatic lobectomy, and or other major liverresection) ranges from 22% to 100% and themortality ranges from 2to 28% [65,71,79,80].

The role of chemotherapy and radiation

There is no reported benefit of neoadjuvant therapy foradvanced GBC, and to date, only few published studies haveassessed its role in long term survival. Most of these studies werenot sufficiently powered to show any statistically significant benefit[81,82]. One study found that combining neoadjuvant 5- flurouracilcontinuous infusion and radiation (4500 cGy) did not improvesurvival [72].

Studies examining the benefit of adjuvant upon GBC specificallyare inconclusive and often underpowered. Most published seriesare a heterogeneousmix of all cholangiocarcinomas including smallcohorts of GBC pts, and are unable to take into account the variableresponse to chemoradiotherapy due to differences in tumorbiology. A recent review of the genetic alterations in gallbladdercancer [83] has provided insight into the molecular mechanismsassociated with the pathogenesis of GBC, to hopefully providepromising targets for therapeutic chemo-intervention.

Systemic chemotherapy has been shown to have (albeitmarginal) superior impact on survival, versus supportive carealone. Gemcitabine and 5-FU asmonotherapy or in combination arefirst line therapy for treatment of unresectable GBC. As a singleagent, the clinical benefit of gemcitabine ranges from 15 to 60percent, and median survival averages 11 months. Data from clin-ical trials combining gemcitabine with capecitabine reportincreased survival times of 13e16 months [84e86].

There is Grade 2B evidence that combination therapy usinggemcitabine and cisplatin has (albeit marginally) superior impacton disease progression, resulting in prolonged survival when

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191e188

compared with basic supportive care alone. In a randomized trial of81 pts with unresectable GBC, gemcitabine plus oxaliplatin(GEMOX), 5-FU/leucovorin and supportive measures werecompared; median overall survival of GEMOX was approximatelytwice that of supportive care at 9.5 and 4.5 months, respectively. 5-FU gave no survival advantage [87].

Other studies evaluating the effects of 5-FU on survival forpatients with GBC show better overall averages, although still lessthan one year [88e91]. When infusional 5-FU was combined withcisplatin in two clinical trials, median survival ranged from 10 to11.5 months [88e91]. The ECF regimen (epirubicin cisplatin and 5-FU) was shown to confer remission in some patients, with amediansurvival time of 11.5 months [88]. In a phase III trial of ECF versus 5-FU, leucovorin and etoposide, the median overall survival wastwelvemonths with ECF infusion compared with 9months, and hadless associated toxicity [92].

Adjuvant chemoradiotherapy results are mixed and includea number of underpowered series. Kresl et al. [93] reported that 21patientswithR0 resection ofGBC followedbyadjuvant radiotherapy(median dose of 54 Gy in 1.8e2.0-Gy fractions) plus 5-FU had 5-yearsurvival rate of 64% compared to 33% with surgical resection only.

Another study examined 5-year overall survival, disease-freesurvival, and local-regional control in 22 patients with primaryGBC treated with radiation therapy after surgical resection as 37%,33%, and 59%, respectively. The patients received a median radia-tion dose of 45 Gy. Eighteen patients received concurrent 5-fluorouracil (5-FU) chemotherapy [94].

Currently there are no published studies examining the benefitof radiofrequency ablation (RFA) or transarterial chemo-embolization (TACE) for unresectable GBC.

Prognostic factors

Several factors influence the prognosis of GBC that can besummarized into the ability to perform a curative resection. Themost important of these factors are the depth of the invasion, whichis directly proportional with the odds of lymphatic invasion, andthe histological grade [95].

Pardeep et al. [96] in analyzing prognostic factors in 87 patientswith GBC found that the presence of palpable mass, the type ofsurgical treatment, and age were also a significant predictor ofsurvival by multivariate analysis. Interestingly, they reported thatmultivariate analysis of patients with Stage IV disease revealed thesame three factors to be significant. These findings suggested thatresectional surgery was associated with better survival comparedwith biliary and/or gastric bypass or laparotomy alone for patientswith all stages of the disease, including those with advancedcarcinoma of the gallbladder. Other studies failed to identify age asa risk factors, as well as serum bilirubin [63,97,98].

Long term result after surgical resection

GBC was usually considered a deadly disease, with poor five yearsurvival that spreads between 0% and 10% in most studies [99]. Thisdismal picture partially changed inmore recent studies probably dueto the advance of the diagnostic tools allowing detection of thedisease at early stageswhere a surgical cure can be achieved, and themore aggressive surgical approach adopted bymany surgical centers.

Gagner et al. [100] reviewed the American experience with theuse of radical operations for carcinoma of the gallbladder. The fiveyear survival rate for patients was 59%, 40%, 9%, 7% and 1% withNevin stage I, II, III, IV, and V disease, respectively. Other studiesreported almost similar results [95].

Cubertafond et al. [101] reported the results of the Frenchsurgical association survey on 724 patients surgically treated for

gallbladder carcinoma. The overall median survival was 3 months,and long term survival correlated with cancer stage, >60 months,>22 months, and 8 months for Tis, T1e2, and T3e4 tumors,respectively. Five year survival for cancer limited to the gallbladderand treated with simple cholecystectomy was 93%, 18%, and 10% forTis, T1 and T2 respectively. For T3 lesions and above no differencewas observed among different surgical procedures.

The Japanese literature reported better long term results.Tashiro et al. [102] reported a large series including 2269 patientssurgically treated out of 2567 patients with gallbladder carcinoma.The five year survival was 97%, 58%, 25% and 20% for Nevin stage I,II, III and IV, respectively.

Ogura et al. [79] reported similar results in a multicentricJapanese study including 1686 patients treated surgically for gall-bladder carcinoma. The five year survival was 82.6% for tumorslimited to the gallbladder mucosa, 72.5% for tumors involving thelamina propria. These numbers dropped significantly with tumorinvasion being 37% with extension to the subserosal layer, 14.7%with serosal invasion, and only 7.5% when the tumors invadedadjacent organs.

The primary cause of death from GBC is the local progression ofthe disease. Perputeo et al. [103] found in reviewing GBC patient atthe time of their death, that most of these patients have peritonealcarcinomatosis, one third of them had lung metastasis, and onlyfew (5%) had brain metastasis.

Multimodal management and potential for new therapeuticoptions

Similar to other malignant process, modern practice manage-ment of GBC relies on multidisciplinary approach. Though the onlyhope for cure is surgical resection of early disease, a large group ofpatients are diagnosed with advanced disease beyond surgicalresection. As previously discussed there are limited studiesreporting the role of neoadjuvant or adjuvant chemotherapy orradiation therapy for GBC. The main limitation of these studies arebeing underpowered as per the low number of patients and thepotential beneficial effect of the chemotherapeutic managementcaries a high risk for toxicity.

New chemotherapy molecules or treatment strategy may carrya potential role, however, to date very few studies discussed thesepotentials.

Expression of EGFR is increased in a majority of gallbladder andbile duct cancers and may be associated with a worse outcome.Unlike other GI malignancies, there is very limited experience withthe use of monoclonal antibodies in GBC. Given the popularity ofthe double pathway blocking approach, early results of thecombination of bevacizumab and erlotinib in previously untreatedadvanced gallbladder cancer or cholangiocarcinoma are interesting.The preliminary data were presented at the 2008 ASCO annualmeeting and showed that bevacizumab and erlotinib producedpartial response (PR) in 3 out of 17 (17.6%) evaluable patients [108].

This was followed by a full report in a recently published phase IImulti-institutional trial of bevacizumab and erlotinib combinationtherapy for patients with advanced biliary cancers. In this study 53patients were included including 10 patients with GBC. The resultsof this report showed that the combination of bevacizumab anderlotinib produced nine PRs in patients with biliary tract cancers,six of which were sustained (12%; 95% CI, 6%e27%). The confirmedPR plus stable disease rate of 64% (31 of 49) is comparable with thatfor gemcitabine plus capecitabine, gemcitabine plus oxaliplatin,and gemcitabine plus cisplatin. From the safety analysis, themajority of adverse effects were grade 1 or 2. While there weretwo deaths on study and four patients with grade 4 toxicity, the

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191 e189

regimen was not associated with prolonged neutropenia or GIadverse effects [109].

In a different track, liver targeted therapy using internal radia-tion therapy using. 90 yttrium (Y90) had evolved as a safe andeffective alternative or adjunct to systemic therapy for unre-dresectable liver and biliary cancer. Y90 radioembolization hasbeen investigatedmainly for treatment of hepatocellular carcinomaand secondary liver tumors. So far, little is known on treatment oftumors originating from the gallbladder with radioembolization. Asingle published case report suggested that Y90 radioembolizationcan be a feasible palliative treatment option for patients withlocally advanced gallbladder carcinoma [110]. As per the increasingexperience of the use of radioembolization as liver targeted therapyfor different primary and secondary hepatic malignancies, webelieve that this modality merits more investigation for patientswith unresectable GBC.

Summary

GBC is a rare but challenging disease. The most important prog-nostic factor is the depth of tumor invasion. Most cancers arediscovered incidentally after cholecystectomy, which is consideredcurative treatment for early stage cancer limited only to the laminapropria (pT1a). For tumors that infiltrate the gallbladdermuscle layer(pT1b), theremaybenefit in selectedpatients to performanextendedcholecystectomy. For more advanced disease extended or radicalcholecystectomy is needed to achieve negative margins. The classi-cally dismal prognosis of GBC has only partially improved in morerecent years due to earlier detection and a more aggressive surgicalapproach adopted by many surgical centers for advanced disease.Although adjuvant therapy is prolonging life, much work remains tobe done to develop solidly efficacious regimens. Given that theprimary cause of death is mainly local progression of the disease,surgical resection remains the mainstay of treatment for GBC.

Conflict of interest statement

All authors have no conflict of interest to disclose.

References

[1] Sheinfeld W. Cholecystectomy and partial hepatectomy for carcinoma of thegall bladder with local liver extension. Surgery 1947;22(1):48e58.

[2] Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. NatRev Cancer 2004;4(9):695e706.

[3] Yamaguchi K, Chijiiwa K, Saiki S, Nishihara K, Takashima M, Kawakami K,et al. Retrospective analysis of 70 operations for gallbladder carcinoma. Br JSurg 1997;84(2):200e4.

[4] Kumar JR, Tewari M, Rai A, Sinha R, Mohapatra SC, Shukla HS. An objectiveassessment of demography of gallbladder cancer. J SurgOncol 2006;93(8):610e4.

[5] Enomoto M, Naoe S, Harada M, Miyata K, Saito M, Noguchi Y. Carcinogenesisin extrahepatic bile duct and gallbladderecarcinogenic effect of N-hydroxy-2-acetamidofluorene in mice fed a “gallstone-inducing” diet. Jpn J Exp Med1974;44(1):37e54.

[6] Misra S, Chaturvedi A, Misra NC. Gallbladder cancer. Curr Treat OptionsGastroenterol 2006;9(2):95e106.

[7] Spina GP, Pagani M. Prophylactic cholecystectomy for gallbladder calculosis.Ann Ital Chir 1998;69(6):713e7.

[8] Friedman GD. Natural history of asymptomatic and symptomatic gallstones.Am J Surg 1993;165(4):399e404.

[9] Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet2006;368(9531):230e9.

[10] Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA 1983;250(17):2323e6.

[11] Roa I, Ibacache G, Roa J, Araya J, de Aretxabala X, Munoz S. Gallstones andgallbladder cancer-volume and weight of gallstones are associated withgallbladder cancer: a case-control study. J Surg Oncol 2006;93(8):624e8.

[12] Csendes A, Becerra M, Rojas J, Medina E. Number and size of stones inpatients with asymptomatic and symptomatic gallstones and gallbladdercarcinoma: a prospective study of 592 cases. J Gastrointest Surg 2000;4(5):481e5.

[13] Dutta U, Garg PK, Kumar R, Tandon RK. Typhoid carriers among patients withgallstones are at increased risk for carcinoma of the gallbladder. Am J Gas-troenterol 2000;95(3):784e7.

[14] Kumar S. Infection as a risk factor for gallbladder cancer. J Surg Oncol 2006;93(8):633e9.

[15] Samaras V, Rafailidis PI, Mourtzoukou EG, Peppas G, Falagas ME. Chronicbacterial and parasitic infections and cancer: a review. J Infect Dev Ctries;4(5): 267e81.

[16] Mishra RR, Tewari M, Shukla HS. Helicobacter species and pathogenesis ofgallbladder cancer. Hepatobiliary Pancreat Dis Int; 9(2): 129e34.

[17] Brook I. Aerobic and anaerobic microbiology of biliary tract disease. J ClinMicrobiol 1989;27(10):2373e5.

[18] Nath G, Gulati AK, Shukla VK. Role of bacteria in carcinogenesis, with specialreference to carcinoma of the gallbladder. World J Gastroenterol; 16(43):5395e404.

[19] Axelrod L, Munster AM, O’Brien TF. Typhoid cholecystitis and gallbladdercarcinoma after interval of 67 years. JAMA 1971;217(1):83.

[20] Caygill CP, Hill MJ, Braddick M, Sharp JC. Cancer mortality in chronic typhoidand paratyphoid carriers. Lancet 1994;343(8889):83e4.

[21] Strom BL, Soloway RD, Rios-Dalenz JL, Rodriguez-Martinez HA, West SL,Kinman JL, et al. Risk factors for gallbladder cancer. An internationalcollaborative case-control study. Cancer 1995;76(10):1747e56.

[22] Fever, hepatic lesions and ascites. Am J Med 1979;67(1):105e12.[23] Kelly TR, Chamberlain TR. Carcinoma of the gallbladder. Am J Surg 1982;

143(6):737e41.[24] Sataline L, Pelliccia O. Inflammatory oncotaxis. JAMA 1978;240(22):2434.[25] Park SK, Andreotti G, Sakoda LC, Gao YT, Rashid A, Chen J, et al. Variants in

hormone-related genes and the risk of biliary tract cancers and stones:a population-based study in China. Carcinogenesis 2009;30(4):606e14.

[26] Kritz-Silverstein D, Barrett-Connor E, Wingard DL. The relationship betweenreproductive history and cholecystectomy in older women. J Clin Epidemiol1990;43(7):687e92.

[27] Everson GT, McKinley C, Kern Jr F. Mechanisms of gallstone formation inwomen. Effects of exogenous estrogen (Premarin) and dietary cholesterol onhepatic lipid metabolism. J Clin Invest 1991;87(1):237e46.

[28] Parker RG, Kendall EJ. The liver in ulcerative colitis. Br Med J 1954;2(4845):1030e2.

[29] Ritchie JK, Allan RN, Macartney J, Thompson H, Hawley PR, Cooke WT. Biliarytract carcinoma associated with ulcerative colitis. Q J Med 1974;43(170):263e79.

[30] Pandey M. Risk factors for gallbladder cancer: a reappraisal. Eur J Cancer Prev2003;12(1):15e24.

[31] Hayashi Y, Liu JH, Moriguchi H, Takenawa H, Tazawa J, Nakayama E, et al.Prevalence of polypoid lesions of the gallbladder in urban and rural areas ofJapan: comparison between 1988 and 1993. J Clin Gastroenterol 1996;23(2):158e9.

[32] Pandey M, Khatri AK, Sood BP, Shukla RC, Shukla VK. Cholecystosonographicevaluation of the prevalence of gallbladder diseases. A university hospitalexperience. Clin Imaging 1996;20(4):269e72.

[33] Okamoto M, Okamoto H, Kitahara F, Kobayashi K, Karikome K, Miura K, et al.Ultrasonographic evidence of association of polyps and stones with gall-bladder cancer. Am J Gastroenterol 1999;94(2):446e50.

[34] Lin WR, Lin DY, Tai DI, Hsieh SY, Lin CY, Sheen IS, et al. Prevalence of and riskfactors for gallbladder polyps detected by ultrasonography among healthyChinese: analysis of 34 669 cases. J Gastroenterol Hepatol 2008;23(6):965e9.

[35] Mainprize KS, Gould SW, Gilbert JM. Surgical management of polypoidlesions of the gallbladder. Br J Surg 2000;87(4):414e7.

[36] Terzi C, Sokmen S, Seckin S, Albayrak L, Ugurlu M. Polypoid lesions of thegallbladder: report of 100 cases with special reference to operative indica-tions. Surgery 2000;127(6):622e7.

[37] Yeh CN, Jan YY, Chao TC, Chen MF. Laparoscopic cholecystectomy forpolypoid lesions of the gallbladder: a clinicopathologic study. Surg LaparoscEndosc Percutan Tech 2001;11(3):176e81.

[38] Chattopadhyay D, Lochan R, Balupuri S, Gopinath BR, Wynne KS. Outcome ofgall bladder polypoidal lesions detected by transabdominal ultrasoundscanning: a nine year experience. World J Gastroenterol 2005;11(14):2171e3.

[39] Huang CS, Lien HH, Jeng JY, Huang SH. Role of laparoscopic cholecystectomyin the management of polypoid lesions of the gallbladder. Surg LaparoscEndosc Percutan Tech 2001;11(4):242e7.

[40] Sun XJ, Shi JS, Han Y, Wang JS, Ren H. Diagnosis and treatment of polypoidlesions of the gallbladder: report of 194 cases. Hepatobiliary Pancreat Dis Int2004;3(4):591e4.

[41] Sugiyama M, Xie XY, Atomi Y, Saito M. Differential diagnosis of smallpolypoid lesions of the gallbladder: the value of endoscopic ultrasonography.Ann Surg 1999;229(4):498e504.

[42] Lee KF, Wong J, Li JC, Lai PB. Polypoid lesions of the gallbladder. Am J Surg2004;188(2):186e90.

[43] Saetta A, Lazaris AC, Michalopoulos NV, Davaris PS. Genetic alterationsinvolved in the development of gallbladder carcinomas from Greek patients.Hepatogastroenterology 2001;48(41):1284e8.

[44] Bach AM, Loring LA, Hann LE, Illescas FF, Fong Y, Blumgart LH. Gallbladdercancer: can ultrasonography evaluate extent of disease? J Ultrasound Med1998;17(5):303e9.

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191e190

[45] Haribhakti SP, Kapoor VK, Gujral RB, Kaushik SP. Staging of carcinoma of thegallbladderean ultrasonographic evaluation. Hepatogastroenterology 1997;44(17):1240e5.

[46] Fujita N, Noda Y, Kobayashi G, Kimura K, Yago A. Diagnosis of the depth ofinvasion of gallbladder carcinoma by EUS. Gastrointest Endosc 1999;50(5):659e63.

[47] Mohandas KM, Swaroop VS, Gullar SU, Dave UR, Jagannath P, DeSouza LJ.Diagnosis of malignant obstructive jaundice by bile cytology: resultsimproved by dilating the bile duct strictures. Gastrointest Endosc 1994;40(2Pt 1):150e4.

[48] Levy AD, Murakata LA, Rohrmann Jr CA. Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics 2001;21(2):295e314 [questionnaire,549e55].

[49] Kumaran V, Gulati S, Paul B, Pande K, Sahni P, Chattopadhyay K. The role ofdual-phase helical CT in assessing resectability of carcinoma of the gall-bladder. Eur Radiol 2002;12(8):1993e9.

[50] Corvera CU, Blumgart LH, Akhurst T, DeMatteo RP, D’Angelica M, Fong Y,et al. 18F-fluorodeoxyglucose positron emission tomography influencesmanagement decisions in patients with biliary cancer. J Am Coll Surg 2008;206(1):57e65.

[51] Nevin JE, Moran TJ, Kay S, King R. Carcinoma of the gallbladder: staging,treatment, and prognosis. Cancer 1976;37(1):141e8.

[52] Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patientspresenting initially for definitive operation with those presenting after priornoncurative intervention. Ann Surg 2000;232(4):557e69.

[53] Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the gallbladder.Histologic types, stage of disease, grade, and survival rates. Cancer 1992;70(6):1493e7.

[54] Kaushik SP. Current perspectives in gallbladder carcinoma. J GastroenterolHepatol 2001;16(8):848e54.

[55] Bartlett DL. Gallbladder cancer. Semin Surg Oncol 2000;19(2):145e55.[56] Kondo S, Nimura Y, Hayakawa N, Kamiya J, Nagino M, Uesaka K. Regional and

para-aortic lymphadenectomy in radical surgery for advanced gallbladdercarcinoma. Br J Surg 2000;87(4):418e22.

[57] Shih SP, Schulick RD, Cameron JL, Lillemoe KD, Pitt HA, Choti MA, et al.Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg2007;245(6):893e901.

[58] Kapoor VK, Haribhakti SP. Extended cholecystectomy for carcinoma of thegall bladder. Trop Gastroenterol 1995;16(4):74e5.

[59] Muratore A, Polastri R, Capussotti L. Radical surgery for gallbladder cancer:current options. Eur J Surg Oncol 2000;26(5):438e43.

[60] Yoshikawa T, Araida T, Azuma T, Takasaki K. Bisubsegmental liver resectionfor gallbladder cancer. Hepatogastroenterology 1998;45(19):14e9.

[61] Donohue JH, Nagorney DM, Grant CS, Tsushima K, Ilstrup DM, Adson MA.Carcinoma of the gallbladder. Does radical resection improve outcome? ArchSurg 1990;125(2):237e41.

[62] Matsumoto Y, Fujii H, Aoyama H, Yamamoto M, Sugahara K, Suda K. Surgicaltreatment of primary carcinoma of the gallbladder based on the histologicanalysis of 48 surgical specimens. Am J Surg 1992;163(2):239e45.

[63] Bartlett DL, Fong Y, Fortner JG, Brennan MF, Blumgart LH. Long-term resultsafter resection for gallbladder cancer. Implications for staging and manage-ment. Ann Surg 1996;224(5):639e46.

[64] Shirai Y, Ohtani T, Tsukada K, Hatakeyama K. Combined pan-creaticoduodenectomy and hepatectomy for patients with locallyadvanced gallbladder carcinoma: long term results. Cancer 1997;80(10):1904e9.

[65] Tsukada K, Yoshida K, Aono T, Koyama S, Shirai Y, Uchida K, et al. Majorhepatectomy and pancreatoduodenectomy for advanced carcinoma of thebiliary tract. Br J Surg 1994;81(1):108e10.

[66] Nakamura S, Nishiyama R, Yokoi Y, Serizawa A, Nishiwaki Y, Konno H, et al.Hepatopancreatoduodenectomy for advanced gallbladder carcinoma. ArchSurg 1994;129(6):625e9.

[67] Dixon E, Vollmer Jr CM, Sahajpal A, Cattral M, Grant D, Doig C, et al. Anaggressive surgical approach leads to improved survival in patients withgallbladder cancer: a 12-year study at a North American Center. Ann Surg2005;241(3):385e94.

[68] Shirai Y, Wakai T, Hatakeyama K. Radical lymph node dissection for gall-bladder cancer: indications and limitations. Surg Oncol Clin N Am 2007;16(1):221e32.

[69] Pitt HA. Gallbladder cancer: what is an aggressive approach? Ann Surg 2005;241(3):395e6.

[70] Miyazaki M, Itoh H, Ambiru S, Shimizu H, Togawa A, Gohchi E, et al. Radicalsurgery for advanced gallbladder carcinoma. Br J Surg 1996;83(4):478e81.

[71] Nimura Y, Hayakawa N, Kamiya J, Maeda S, Kondo S, Yasui A, et al. Combinedportal vein and liver resection for carcinoma of the biliary tract. Br J Surg1991;78(6):727e31.

[72] Kaneoka Y, Yamaguchi A, Isogai M, Harada T, Suzuki M. Hepatoduodenalligament invasion by gallbladder carcinoma: histologic patterns and surgicalrecommendation. World J Surg 2003;27(3):260e5.

[73] Kosuge T, Sano K, Shimada K, Yamamoto J, Yamasaki S, Makuuchi M. Shouldthe bile duct be preserved or removed in radical surgery for gallbladdercancer? Hepatogastroenterology 1999;46(28):2133e7.

[74] Gall FP, Kockerling F, Scheele J, Schneider C, Hohenberger W. Radical oper-ations for carcinoma of the gallbladder: present status in Germany. World JSurg 1991;15(3):328e36.

[75] Kondo S, Nimura Y, Hayakawa N, Kamiya J, Nagino M, Uesaka K. Extensivesurgery for carcinoma of the gallbladder. Br J Surg 2002;89(2):179e84.

[76] Sikora SS, Kapoor R, Pradeep R, Kapoor VK, Saxena R, Kaushik SP. Palliativesurgical treatment of malignant obstructive jaundice. Eur J Surg Oncol 1994;20(5):580e4.

[77] Singh B, Kapoor VK, Sikora SS, Kalawat TC, Das BK, Kaushik SP. Malignantgastroparesis and outlet obstruction in carcinoma gall bladder. Trop Gas-troenterol 1998;19(1):37e9.

[78] Akosa AB, Barker F, Desa L, Benjamin I, Krausz T. Cytologic diagnosis in themanagement of gallbladder carcinoma. Acta Cytol 1995;39(3):494e8.

[79] Ogura Y, Mizumoto R, Isaji S, Kusuda T, Matsuda S, Tabata M. Radical oper-ations for carcinoma of the gallbladder: present status in Japan. World J Surg1991;15(3):337e43.

[80] de Aretxabala X, Roa I, Burgos L, Araya JC, Fonseca L, Wistuba I, et al. Gall-bladder cancer in Chile. A report on 54 potentially resectable tumors. Cancer1992;69(1):60e5.

[81] Lin LL, Picus J, Drebin JA, Linehan DC, Solis J, Strasberg SM, et al. A phase IIstudy of alternating cycles of split course radiation therapy and gemcitabinechemotherapy for inoperable pancreatic or biliary tract carcinoma. Am J ClinOncol 2005;28(3):234e41.

[82] Ammori JB, Colletti LM, Zalupski MM, Eckhauser FE, Greenson JK, Dimick J,et al. Surgical resection following radiation therapy with concurrent gem-citabine in patients with previously unresectable adenocarcinoma of thepancreas. J Gastrointest Surg 2003;7(6):766e72.

[83] Maurya SK, Tewari M, Mishra RR, Shukla HS. Genetic aberrations in gall-bladder cancer. Surg Oncol; 21(1): 37e43.

[84] Cho JY, Nam JS, Park MS, Yu JS, Paik YH, Lee SJ, et al. A Phase II study ofcapecitabine combined with gemcitabine in patients with advanced gall-bladder carcinoma. Yonsei Med J 2005;46(4):526e31.

[85] Riechelmann RP, Townsley CA, Chin SN, Pond GR, Knox JJ. Expanded phase IItrial of gemcitabine and capecitabine for advanced biliary cancer. Cancer2007;110(6):1307e12.

[86] Iyer RV, Gibbs J, Kuvshinoff B, Fakih M, Kepner J, Soehnlein N, et al. A phase IIstudy of gemcitabine and capecitabine in advanced cholangiocarcinoma andcarcinoma of the gallbladder: a single-institution prospective study. AnnSurg Oncol 2007;14(11):3202e9.

[87] Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, et al. Bestsupportive care compared with chemotherapy for unresectable gall bladdercancer: a randomized controlled study. J Clin Oncol; 28(30): 4581e86.

[88] Ducreux M, Rougier P, Fandi A, Clavero-Fabri MC, Villing AL, Fassone F, et al.Effective treatment of advanced biliary tract carcinoma using 5-fluorouracilcontinuous infusion with cisplatin. Ann Oncol 1998;9(6):653e6.

[89] Sanz-Altamira PM, Ferrante K, Jenkins RL, Lewis WD, Huberman MS,Stuart KE. A phase II trial of 5-fluorouracil, leucovorin, and carboplatin inpatients with unresectable biliary tree carcinoma. Cancer 1998;82(12):2321e5.

[90] Patt YZ, Jones Jr DV, Hoque A, Lozano R, Markowitz A, Raijman I, et al. PhaseII trial of intravenous flourouracil and subcutaneous interferon alfa-2b forbiliary tract cancer. J Clin Oncol 1996;14(8):2311e5.

[91] Choi CW, Choi IK, Seo JH, Kim BS, Kim JS, Kim CD, et al. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tractadenocarcinomas. Am J Clin Oncol 2000;23(4):425e8.

[92] Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, et al. Phase IIIstudy of 5FU, etoposide and leucovorin (FELV) compared to epirubicin,cisplatin and 5FU (ECF) in previously untreated patients with advancedbiliary cancer. Br J Cancer 2005;92(9):1650e4.

[93] Kresl JJ, Schild SE, Henning GT, Gunderson LL, Donohue J, Pitot H, et al.Adjuvant external beam radiation therapy with concurrent chemotherapy inthe management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys 2002;52(1):167e75.

[94] Czito BG, Hurwitz HI, Clough RW, Tyler DS, Morse MA, Clary BM, et al.Adjuvant external-beam radiotherapy with concurrent chemotherapy afterresection of primary gallbladder carcinoma: a 23-year experience. Int JRadiat Oncol Biol Phys 2005;62(4):1030e4.

[95] Wanebo HJ, Vezeridis MP. Carcinoma of the gallbladder. J Surg Oncol Suppl1993;3:134e9.

[96] Pradeep R, Kaushik SP, Sikora SS, Bhattacharya BN, Pandey CM, Kapoor VK.Predictors of survival in patients with carcinoma of the gallbladder. Cancer1995;76(7):1145e9.

[97] Schauer RJ, Meyer G, Baretton G, Schildberg FW, Rau HG. Prognostic factorsand long-term results after surgery for gallbladder carcinoma: a retrospec-tive study of 127 patients. Langenbecks Arch Surg 2001;386(2):110e7.

[98] Todoroki T, Kawamoto T, Otsuka M, Koike N, Yoshida S, Takada Y, et al.Benefits of combining radiotherapy with aggressive resection for stage IVgallbladder cancer. Hepatogastroenterology 1999;46(27):1585e91.

[99] Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg GynecolObstet 1978;147(6):929e42.

[100] Gagner M, Rossi RL. Radical operations for carcinoma of the gallbladder:present status in North America. World J Surg 1991;15(3):344e7.

[101] Cubertafond P, Mathonnet M, Gainant A, Launois B. Radical surgery forgallbladder cancer. Results of the French Surgical Association Survey. Hep-atogastroenterology 1999;46(27):1567e71.

[102] Tashiro S, Konno T, Mochinaga M, Nakakuma K, Murata E, Yokoyama I.Treatment of carcinoma of the gallbladder in Japan. Jpn J Surg 1982;12(2):98e104.

C. Boutros et al. / Surgical Oncology 21 (2012) e183ee191 e191

[103] Perpetuo MD, Valdivieso M, Heilbrun LK, Nelson RS, Connor T, Bodey GP.Natural history study of gallbladder cancer: a review of 36 years experienceat M. D. Anderson Hospital and Tumor Institute. Cancer 1978;42(1):330e5.

[104] Gallbladder cancer. AJCC Cancer staging manual. 6th ed. New York: Springer;2010.

[105] You DD, Lee HG, Paik KY, Heo JS, Choi SH, Choi DW. What is an adequateextent of resection for T1 gallbladder cancers? Ann Surg 2008;247(5):835e8.

[106] Wagholikar GD, Behari A, Krishnani N, Kumar A, Sikora SS, Saxena R, et al.Early gallbladder cancer. J Am Coll Surg 2002;194(2):137e41.

[107] Ouchi K, Owada Y, Matsuno S, Sato T. Prognostic factors in the surgicaltreatment of gallbladder carcinoma. Surgery 1987;101(6):731e7.

[108] Holen KD, Mahoney MR, LoConte NK, Szydlo DW, Picus J, Maples WJ, et al.Efficacy report of amulticenter phase II trial testing a biologic-only combi-nation of biweekly bevacizumab and daily erlotinib in patientswith unre-sectable biliary cancer (BC): a Phase II Consortium (P2C) study. J Clin Oncol2008;26 [Meeting Abstracts: Abstract 4522].

[109] Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, et al.Report of a multicenter phase II trial testing a combination of biweeklybevacizumab and daily erlotinib in patients with unresectable biliary cancer:a phase II Consortium study. J Clin Oncol 2010 Jul 20;28(21):3491e7.

[110] Wijlemans JW, Van ErpecumKJ, LamMG, Seinstra BA, Smits ML, Zonnenberg BA,et al. Trans-arterial (90)yttrium radioembolization for patients with unresectabletumorsoriginating fromthebiliary tree.AnnHepatol 2011 Jul-Sep;10(3):349e54.