Gallbladder cancer: Can newer insights improve the outcome?

Authors


Dr Usha Dutta, Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Email: ushadutta@gmail.com

Abstract

Gallbladder cancer (GBC) is the leading cause of cancer related mortality in certain geographic areas. Most of the patients with GBC have advanced disease at presentation, precluding curative resection resulting in a dismal prognosis. However, recent advances in the understanding of its epidemiology and pathogenesis coupled with development of newer diagnostic tools and therapeutic options, has resulted in enhanced optimism towards the management of the disease. The leading risk factors are gallstones, advancing age, female gender, anomalous pancreaticobiliary ductal junction, certain ethnic groups and geographic populations. Advances in radiological imaging and the advent of endoscopic ultrasound have facilitated early detection and accurate staging of the tumor. A high index of suspicion in high risk groups is necessary to pick up incidental and early GBC, as surgical resection is curative. In patients with suspected GBC, an open surgical resection that is appropriate for that stage is advocated. Adjuvant combination chemotherapy and molecular targeted therapy are emerging as effective therapeutic options in those with advanced GBC. Endoscopic palliation of biliary and gastric outlet obstruction with metallic stents has improved their quality of life. Prevention remains the hitherto less explored option to reduce GBC related mortality. Prophylactic cholecystectomy in high risk groups is a cost-effective option. A multi-disciplinary systematic global approach to initiate collaborative ventures to understand epidemiology, standardize management strategies, conduct multi-centric trials with newer therapeutic agents and initiate preventive measures, would pave way for the future conquest of the disease.

Introduction

Gallbladder cancer (GBC) originates from the mucosal epithelial lining of the gallbladder (GB) and the cystic duct. The GB is the most common site for biliary tract cancers.1 The incidence of GBC is characterized by marked geographic and ethnic variations.2 Curative resection provides the only hope of long-term cure and survival.3 However, most patients with GBC have advanced disease at presentation as they either present late or are detected late due to non-specific symptomatology.4 The aggressive biological behavior of the tumor results in its rapid spread in an anatomically “busy” area, rendering it unresectable.5 Therefore, historically, GBC has been considered an incurable disease with a dismal prognosis, spawning an attitude of nihilism. Long term survival is primarily seen in those detected incidentally during routine cholecystectomy for gallstones (GS). This fortunate scenario exists in only 2% of all cases with GBC. Poor understanding of the risk factors and molecular pathogenesis and absence of chemotherapeutic agents have hampered our ability to devise strategies to deal with this disease. Moreover, GBC affects certain pockets in the developing parts of the world, and thus has been an orphan disease. Literature on GBC primarily emanates from small underpowered studies and few institutional experiences, making it difficult for policy makers to formulate a strategy.4 Finally, management of biliary diseases has been at the interface of physicians and surgeons; hepatologists and gastroenterologists; endoscopists and non-procedurally orientated clinicians. This has hampered development of a consensus approach on the disease.

Fortunately, over the last decade, there have been significant advances in our understanding of the epidemiology and tumor biology of GBC. This has coincided with the development of better diagnostic tools, more effective drugs and strategies to combat this otherwise rapidly fatal disease. Also, with increasing global migration, the incidence of GBC in the west is increasing, making it a global disease. This review will cover pertinent developments in this area, so that it can pave the way for a better outcome in the future.

Anatomical considerations

The GB has a thin wall (< 3 mm) composed of a single layered columnar lining, a thin lamina propria, a thin muscle layer and serosa.5 The thin and discontinuous muscularis propria, in the absence of muscularis mucosae and submucosa allow early tumor invasion.6 The lack of the serosal layer, in the area where the GB is in direct contact with the liver, allows early hepatic invasion. Also, some of the cholecystic veins directly drain into the liver bed facilitating tumor metastasis.7 This forms the basis behind segments IV b and V resection, even in patients with early GBC. (Fig. 1) GB's lymphatic drainage is extensive and in multiple directions, facilitating early lymphatic spread. The lymphatic drainage follows four routes: cholecysto-retropancreatic to the retropancreatic group, cholecysto-celiac to the celiac group, cholecystomesenteric to the superior mesenteric group and the ascending lymphatics to the hilar group of lymph nodes.5 Understanding the anatomy of lymphatic drainage is crucial for accurately staging GBC and planning resection. The GB is in an anatomically “busy” area due to presence of adjoining bile duct, portal vein, liver, duodenum and colon, which become involved early, making surgical resection and radiotherapy difficult.5

Figure 1.

(a) On injection of Indocyanin green via the cystic artery, the diaphragmatic surface of the liver is also stained green. This indicates that the cholecystic veins drain also directly into the liver parenchyma. (b) Arrow indicates the stained area on the liver surface. This demarcation line on the visceral surface of the liver helps in delineating the part of the liver that needs to be resected during gallbladder cancer surgery. With permission from Hepaticopancreaticobiliary (Oxford publications).

Physiological considerations

Gallbladder is an out pouching from the gastrointestinal tract. It needs to empty itself regularly to prevent stagnation of bile. In contrast to the urinary bladder, it has to empty more viscous material against gravity. The GB mucosa is constantly exposed to various metabolites excreted by the liver in a conjugated form (less toxic form). In the presence of bacterial β-glucuronidase, these get deconjugated to form toxic substances.8 Progressive physiological concentration of the bile, leads to their increased levels, promoting chronic injury and mutagenesis. This has been shown experimentally for certain oxysterols.9 The fundus of the GB being most dependent in the erect position is most prone to stagnation. It is thus not surprising to note that the fundus is the commonest site for GBC.10

Epidemiology

One of the unique features of the global pattern GBC incidence is the striking variation on the basis of gender, geography and ethnicity. This suggests a strong influence of both genetic and environmental factors. The incidence of GBC is three times higher among women than men in almost all populations.2,11,12 (Table 1) Though it is common in the Indian Subcontinent (India, Pakistan), South America (Chile, Bolivia, Columbia), East Asia (Korea, Japan) and central Europe (Slovakia, Poland, and Czech Republic), it is relatively infrequent in most parts of Europe, North America and Australia/New Zealand2,11,13 Certain ethnic groups such as Hispanics, American Indians and Mexican Indians are identified as high risk groups for GBC.11

Table 1.  Risk factors identified for gallbladder cancer
FactorHigh risk subsetRemarks
  • Time period 1993–1997.

  • Summary relative risk (RR) is provided whenever available, otherwise RR of best available study quoted.

  • BMI, body mass index; CI, confidence interval; GB, gallbladder; GBC, gallbladder cancer; GS, gallstones; OR, odds ratio.

Geographical2,13 (Incidence in women per 100 000 population)Chile, Ecuador, Columbia, Bolivia15.5, 12.9, 9.5
North India, Pakistan21.5, 13.8
Korea, Japan10.5, 5.8
Slovakia, Poland, Czech republic∼10
Ethnicity2,13 (Incidence in women per 100 000 population)Hispanics8.2
American Indians7
Mexican Indians5.4
Chilean-Mapuche 
Age2,145th and 6th decadeYounger age if multiple risk factors and high incidence areas
Gender2,13Female versus males2–6 times
Pregnancy2,14,15Higher parity (> 5 vs≤ 5)RR 4.2 (95% CI: 1.5–12.8)
Family history of GBC2First degree relativesSummary RR 4.8 (95% CI:2.6–8.9)
Socioeconomic status14PoorOR 3 (95% CI: 0.9–10)
Gallstones (GS)2,12,14,16,17 Summary RR 4.9 (95% CI:3.3–7.4)
Large GS > 3 cm,RR 10.1
GS volume > 6 mLRR 5
Multiple GSHigher the number: higher the risk
Longstanding GSTime from stone to cancer: 20 years
Mirrizi's syndrome, Empyema GBIncreased likelihood of associated GBC
GB polyp18Single, sessile, > 1 cm size, echopenic, Age > 50 years, increasing size on FU, associated GSIncreasing size: higher risk
Porcelain GB17Associated chronic cholecystitis and gallstonesIncidence of GBC variable: 10–61%
Anomalous pancreaticobiliary junction2,19Common channel > 8 mm (especially type I) especially in Japan, Korea, ChinaYounger, no associated GS, papillary tumor, less invasive.
Salmonella carriers14,20Especially In Chile, IndiaSummary RR 10.2 (95% CI:2–51)
Helicobacter species2,21Few and small studies onlySummary RR
4.3 (95% CI:2.1–8.8) for H. bilis
RR 9.9 (95% CI:1.4–70.5) for H. pylori
Obesity2BMI > 30–35 versus BMI 18.5–25Summary RR 1.88 (95% CI: 1.66–2.13)
Smoking2> 10 cigarettes for 5 yearsRR 11 (CI: 1.7–71)
Dietary intake2,16Low in vegetable, fiber, fruit, vitamin B6, C and E; High in calorie, Carbohydrate, red meat, red chilli pepperIncreased risk
Serum lipids22High triglycerides and low LDLRR 1.9 (95% CI: 1.3–2.8)
Chemical exposure2,17Oil, chemical, miner, textile and paper industryIncreased risk
Medications2Methyldopa, IsoniazidIncreased risk
Oral contraceptivesSummary RR 0.9 (CI: 0.5–1.3)
Hormone replacement therapySummary RR 0.9 (CI: 0.3–3.3)

Gallbladder cancer has a high case fatality rate, and thus the mortality rates reflect incidence rates of this tumor. GBC is the leading cause of cancer death among women in Chile and in North Indian women.23,24 The time trend analysis shows that age-standardized mortality has decreased in the USA and European Union countries by 30% in women and 10% in men.11 However, it continues to be high in Chile, Japan, India, Algeria and certain eastern European countries. The decline in GBC incidence/mortality has been attributed to one or more of the following: increasing cholecystectomy rates; introduction of laparoscopic cholecystectyomy; increasing use of ultrasound for abdominal complaints; introduction of sophisticated diagnostic techniques like computerized tomography, endoscopic retrograde cholangiography, fine needle aspiration cytology; and introduction of prophylactic cholecystectomy in certain countries like Chile.25,26 Inadequate access to diagnostic ultrasound facilities to detect gallstones as well as facilities for cholecystectomy in rural/remote areas of South America and India influence the high mortality rates in these regions.25

Risk factors and their interplay

The various known risk factors of GBC have been summarized in Table 1.2,13,14,16,18,22,27 Factors that promote mutations, gallstone formation, GB dysfunction, chronic infection and inflammation are likely to be associated with increased risk of GBC. A significant number of patients have multiple risk factors. This may act in an additive manner to increase the risk for GBC and also promote earlier onset.14,27

Gallstones are present in 60–80% of patients with GBC.2,4,17 The larger number, larger size, higher GS volume, cholesterol/mixed stones and longer duration of stones have been documented to be risk factors.16,28 The incidence of GBC parallels the prevalence of GS. However, the incidence of GBC is out of proportion to the GS prevalence in India.14 In GS patients from North India and Chile there is a high prevalence of cofactors for GBC pathogenesis, such as higher parity, malnutrition, Salmonella typhi carrier state, Helicobacter infection, presence of environmental pollutants in the GB bile, poor socioeconomic status and GB stasis.14,21,23,29,30 Absence of these co-factors in the western populations possibly explains the lower incidence of GBC despite a high prevalence of GS.29

Gallbladders that harbor stones are more likely to become chronic carriers of Salmonella and Helicobacter resulting in chronic inflammation and mutagenesis. Patients with GS, who also had GB stasis, were found to have an increased prevalence of precancerous lesions of the GB mucosa.10,20,28,31 GS and GB stasis promote each other, with both acting as cofactors in the pathogenesis of GBC.

Pregnancy increases the risk for GB stasis and GS formation. Higher parity, hormone replacement therapy and oral contraceptive pills result in enhanced estrogen exposure.15 Though estrogen and progesterone receptors have been identified in the GB mucosa of patients with GBC, their roles need to be further delineated.32 Repeated pregnancies, especially if poorly spaced, may also result in chronic malnutrition in impoverished societies, thereby reducing immunological defenses against infection and cancer.33

Pathological aspects

Three pathways for the pathogenesis of GBC have been detailed in Figure 2.1,13,19,34 The commonest predisposing conditions in decreasing order are GS, anomalous pancreaticobiliary ductal junction and GB polyps.2,35,36 The adenoma-carcinoma sequences has been found in GB polyps and seen in < 1% of cases.37 Such cancers develop from a malignant focus within a GB polyp. However, most GB polyps (95%) are non-neoplastic in nature.8,16 GB polyps are likely to be malignant, if they are larger (> 1 cm), shows heterogenous echoes, have a height/width ratio of < 0.8, show a rapid growth, have irregular GB wall, show increased vascularity and are symptomatic.18

Figure 2.

Pathways for gallbladder cancer pathogenesis.

The most frequent histological type is adenocarcinoma. This accounts for 98% of all GB tumors, two-thirds of which are moderately or poorly differentiated.34 Infiltrative adenocarcinomas are seen in 65% of patients, papillary in 15% and colloidal in 10%. Most GB carcinomas originate in the fundus (60%), 30% in the body and 10% in the neck.38 Metaplasia, especially of the intestinal type, has been found to be the key precursor lesion in patients with gallstones and in those with anomalous pancreaticobiliary junction.1,19 Metaplasia increases steadily with age and is found to be present in 70% of patients undergoing routine cholecystectomy for symptomatic gallstones in high incidence areas.31 The time to progression from dysplasia to advanced GBC is around 15 years. Precursor lesions in the form of dysplasia or carcinoma-in-situ are found adjacent to the tumor in 80% of patients with GBC.31,34 We need to systematically evaluate for these precursor lesions at histology, as the mucosa is macroscopically normal.

Molecular aspects

Progressive accumulation of mutations results in development of frank malignancy. The common genetic alterations are in the oncogenes, tumor suppressor genes, microsatellite instability and methylation of gene promoter areas. The dominant mutation in patients with GBC is the p53 gene. In most studies, positive immunostaining for p53 is found in more than 50% of patients with GBC.34,39 Analysis of exon 5 to 8 of TP53 has demonstrated point mutations in 31% to 70% of GBC. In addition, deletions at 17p13 (the chromosomal location of p53) have been reported in 58% to 92% of GBC. However, the exact nature of the deletions may be different between different populations.

K-ras mutations are found in 40–50% of patients with GBC, especially among those with anomalous pancreaticobiliary junction.1 p21 mutations are seen in 28% of GBC and are associated with poorer prognosis, especially if there are co-existent p53 or p27 mutations.34 Inactivation of p16 has been observed in 41% of patients with GBC and is associated with poor outcome. Cyclooxygenease-2 (COX-2) enzyme promotes tumor growth, neovascularization and its presence is associated with poor prognosis. COX-2 expression is present in 70% and 73% of dysplastic tissue and frankly malignant tissue, respectively.34,40 Microsatellite instability is present in 10% of patients with GBC and has been identified in the dysplastic and metaplastic tissue adjacent to the tumor.41,42

Vascular endothelial growth factor (VGEF) and heparanase expression steadily increases as the tumor advances.40,43 Their presence promotes the neovascularization critical for tumor growth and metastasis. Together, p53 mutation and VGEF upregulation promote tumor vascularity. VGEF has also emerged as an important target for therapy in GBC. Microvascular density has been found to be an independent poor prognostic factor. Inducible nitric oxide synthase is expressed in the GB tissue in 88% of patients with chronic cholecystitis and 71% with adenocarcinoma. The loss of the fragile histidine triad gene is almost universal in GBC and is detected early in the sequential development of GBC.

Mutations in the hTERT/Telomerase region progressively increase with increasing degree of abnormality of the mucosa; 3% in normal tissue, 25% in low grade dysplasia, 82% in high grade dysplasia and 93% in adenocarcinomas.34,44 The c-erb-B2 oncogene is present in 10% to 46% of GBC tumor tissue but absent in dysplasia and is a marker for poor prognosis. Apart from these genetic alterations, decreased expression of adhesion molecules is associated with poor prognosis. Hypermethylation in gene promoter areas produces inactivation of tumor suppressor genes such as p73, MGMT, and DCL1, which are associated with poor survival.34

Advances in diagnostic modalities

The GB is an inaccessible organ from the perspective of histology. Imaging modalities therefore play an important role in diagnosis and staging, as well as follow up. The three common radiological patterns of GBC are GB fossa mass (40–65%); focal or diffuse wall thickening (20–30%) and polypoidal lesion (15–25%).45,46 The GB fossa mass often with entrapped GS represents a more advanced form of disease. GB wall thickening is most often missed or mistaken to be uncomplicated chronic cholecystitis. The polypoidal tumors are usually well differentiated, resectable and carry a better prognosis.

Ultrasound (US) evaluation has been the cornerstone for detecting GB pathology. It is particularly useful in detecting the presence of an obvious GB mass or GB wall thickening. In the setting of suspected GBC, it can also reveal the presence of gallstones, porcelain GB, and invasion of adjacent structures, vascular invasion, biliary dilatation, lymphadenopathies and ascites. In the presence of GS, acoustic shadowing is likely to pose serious problems to the radiologists. It is thus worthwhile for radiologists to focus on the GB wall to detect suspicious lesions, ignoring distractions from the luminal stones. Any GB wall thickness over 3 mm focally or diffusely with enhanced vascularity should alert the radiologist, especially in high incidence areas for GBC. Addition of high frequency probes, color Doppler and the use of contrast agents has enhanced the discriminative ability of US.45,47

Computerized tomography (CT) is an important tool to assess early lesions, assess disease extensions into adjacent structures (especially the portal vein and hepatic artery) and accurately stage disease. Use of spiral CT, multi-detector CT and assessment in dual phase has enhanced the ability of CT to delineate lesions (Fig. 3). However, CT scan is poor in detecting small metastases on the liver surface and peritoneal metastases.

Figure 3.

Computerized tomographic scan showing a focal irregular mass in the gallbladder wall which is enhancing with intravenous contrast (black arrow).

Magnetic resonance imaging (MRI) has been found to be very useful in detecting biliary, vascular and hepatic invasion. In combination with MR cholangiography and MR angiography, MRI may provide accurate information regarding resectability as a single investigation.

Positron emission tomography (PET) is an attractive imaging modality as the tumor cells show an avid uptake of fluorodeoxyglucose. It is useful in differentiating malignant from benign disease, in preoperative staging, and in detecting postoperative residual disease. PET is better than CT in detecting lymph nodal involvement and distant metastasis and can be combined with CT scan to provide structural and functional assessment in a single setting.47,48

Endoscopic ultrasound (EUS) has emerged as an important tool to diagnose early GBC, stage GBC more accurately than CT scan, and provide direct access to GB and lymph nodal tissue through fine needle aspiration.49 The accuracy of EUS staging is 100% for tumor in situ (Tis), 76% for T1, 85% for T2, and 93% for T3–4. EUS also provides clinicians with the ability to diagnose and manage associated biliary obstruction.47,50,51

Fine needle aspiration cytology is performed trans-abdominally through a trans-hepatic approach. Though safe, it has limited utility in obtaining diagnostic tumor tissue due to the fear of dissemination along the needle tract. It is useful in establishing the diagnosis in patients with unresectable GBC.

Bile obtained during endoscopic retrograde cholangiography can be centrifuged and analyzed for malignant cells as well as molecular markers such as K-ras, hTERT and others. Recently, an endoscopic transpapillary approach to obtain bile or GB tissue through a tube placed in the GB, has yielded promising results.52 However, the technical difficulties as well as low diagnostic yield have precluded their routine use.

Various GB tumor markers such as CEA, CA-19-9, CA-125 and CA-242 have been studied. CA 242 is particularly useful in differentiating malignant from benign biliary disorders with a specificity of 84%. It performed better than CA 19-9 or CEA.53,54 These markers may have a role in assessing tumor burden and response to therapy.

Staging

Nevin's staging system followed by the modified Nevin's system has been in use for many years.3,47,55 The Japanese Biliary Surgical Society staging system classified tumors into four stages: Stage I, confined to GB capsule; Stage II, positive N1 lymph nodes and/or minimal liver/bileduct invasion; Stage III, positive N2 lymph nodes and/or marked liver/bile duct invasion; Stage IV, distant metastases.56 In 2010, the seventh edition of the American Joint Committee on Cancer has published a simplified tumor node metastasis (TNM) classification (Table 2, Fig. 4).3 It is presently the most widely used system.

Table 2.  Adapted from the American Joint Committee on Cancer Staging for gallbladder cancer, 7th Edition3
  1. Cystic duct is included in this classification. Carcinoids and sarcomas are not included.

Primary tumor (T)
TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
TisCarcinoma in situ
T1aTumor invades lamina propria
T1bTumor invades muscle layer
T2Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver
T3Tumor perforates the serosa and/or directly invades liver and/or 1 adjacent organ/structure
T4Tumor invades main portal vein or hepatic artery or invades 2 or more extrahepatic organs
Regional lymph nodes (N)
N0No regional lymph node metastasis
N1Metastasis to nodes along cystic duct, common bile duct, hepatic artery and or portal vein
N2Metastasis to periaortic, pericaval, superior mesenteric artery and/or celiac artery lymph nodes
Distant metastasis (M)
M0No distant metastasis
M1Distant metastasis
Stage grouping
Stage 0TisN0M0
Stage IT1N0M0
Stage IIT2N0M0
Stage IIIAT3N0M0
Stage IIIBT1-3N1M0
Stage IV AT4N0-1M0
Stage IVBAny TN 2M0
Any TAny NM1
Figure 4.

Histologic depiction of the layers of the gallbladder wall with corresponding T stage for GBCA. HA, hepatic artery; PV, portal vein. (This figure was published in Jayaraman S, Jarnagin WR. Management of Gallbladder Cancer. Gastroenterol. Clin. N. Am. 2010; 39: 333. Copyright Elsevier, 2010, with permission from Elsevier). See Table 2 for details.

Early GBC refers to primary tumor confined to the GB wall (Tis, T1, T2 lesions) and advanced GBC to that which penetrates GB serosa (T3, T4 lesions). GBC categorized as stages I or II are potentially resectable with curative intent; stage III generally indicates locally unresectable disease as a consequence of vascular invasion or involvement of multiple adjacent organs; stage IV represents unresectability with distant metastases.3

Preoperative assessment in suspected cases of GBC

All patients should undergo detailed preoperative evaluation to stage the disease. This is usually done using a combination of US and CECT. PET scans and MRI may provide additional information in selected situations. Elevated tumor markers may aid the diagnosis when the radiological picture is not definitive. Preoperative assessment with laparoscopy and laparoscopic US has the potential benefit of identifying occult hepatic and peritoneal metastasis or major vascular invasion. This can avoid unnecessary laparotomy, postoperative morbidity, reduce hospital stay, decrease overall cost and help in early initiation of palliative therapy. Laparoscopic staging helps in avoiding futile open laparotomy in 36–56% of cases.47 Contraindications to surgery include hepatic metastases, encasement of main portal vein or proper hepatic artery, gross para-aortic adenopathy or malignant ascites. Other factors, such as cirrhosis and insufficient future liver remnant, may also contraindicate surgery in some patients.

Surgical therapy

Surgical resection remains the mainstay of therapy for GBC. The approach depends on the stage of the disease, the availability of local expertise, patient's performance status and whether preoperative diagnosis was suspected or not. There has been increasing emphasis on aggressive surgery for patients with GBC.3,47,57,58 This approach has overall efficacy only in those in whom curative resection could be achieved. Appropriate patient selection cannot be over-emphasized to prevent unnecessary ineffective surgical explorations. An optimal surgical approach balancing the risk of surgery and outcome (short and long term) of the patient should be considered. Patients should be referred to a major centre experienced with this condition when appropriate expertise is not available locally.

Histological T stage is the single most important determinant of the required extent of resection.59 It correlates directly with extent of lymph nodal involvement and distant metastasis. For T1a lesions, simple cholecystectomy alone is adequate; it has a cure rate of 85–100%. As these lesions are usually discovered after the cholecystectomy, no further intervention is necessary. However, a careful re-evaluation by a pathologist for assessing the maximum depth of invasion is important to stage the disease accurately, thereby providing an opportunity to completely cure the disease. For T1b lesions, radical cholecystectomy is required because 1-year survival after simple cholecystectomy is only 50%. With radical cholecystectomy, apart from removal of the GB, wedge resection of the GB bed (including segments IV and V) and portal lymphadenectomy is undertaken.58,60

For T2 lesions, more extensive surgical resection includes standard radical cholecystectomy with more extensive liver resection and hepato-duodenal lymphadenectomy.

T3 lesions pose challenging problems for the surgeons, in view of the need for en-bloc resection of surrounding organs, bile duct resection, extensive lymph nodal dissection and surgical reconstruction. The definitive indication for bile duct resection is whenever the margin of the cystic duct is positive for malignant cells, or performance of an extended right hemi-hepatectomy. Some Japanese surgeons prefer removal of the bile duct to facilitate lymph nodal dissection. This aggressive approach should only be undertaken if there is a possibility of potentially curative R0 resection. The 5-year survival after radical surgery with complete resections is 30–50%.3,17 T4 lesions are unlikely to be resectable with a curative intent. Patients should therefore undergo palliative treatment.

Tumors discovered at the time of surgery

If a tumor is suspected during laparoscopic dissection, the procedure should be converted into open cholecystectomy.61–63 Frozen section should be obtained; if malignancy is confirmed, radical cholecystectomy with port-site excision should be performed. Precautions should be taken to avoid bile leaks and GB perforations, both of which are associated with increased risk of dissemination. All routine cholecystectomy specimens should be carefully examined for mucosal thickening, mass, and areas of induration or ulceration as these may indicate unsuspected malignancy.

Tumors discovered after surgery

Tumors diagnosed histologically after cholecystectomy are known as incidental GBC. All GBs should be examined for any occult malignancy especially in high incidence areas, notwithstanding additional costs. A high index of suspicion is necessary on the part of radiologists, surgeons, and pathologists to detect incidental tumors. In the author's centre, among 300 patients with GBC referred to the hospital, in 7% of the patients, the diagnosis of GBC has been missed at the time of routine cholecystectomy for gallstones. They presented a few months later to us with features of local recurrence of the tumor. These cases were missed at the preoperative radiological assessment, at surgery and at histology. On retrospective review, the commonest clue was a preoperative US showing a thickened GB wall, mistaken to have been indicative of uncomplicated chronic cholecystitis. These incidental GBC were possibly missed due to low index of suspicion for lurking GBC.

If the tumor is Tis or T1a and the resection margins are clear, no further intervention is needed. In case of a T1b lesion, a radical second operation should also be offered to improve survival. For T2 or other advanced lesions, radical second surgery should be undertaken at the earliest feasible time. Before undertaking such a surgery, patients should be counseled regarding the further treatment options, prognosis, reassessed for fitness and appropriate imaging modality used to stage the disease.

Adjuvant chemotherapy

Gallbladder cancer is likely to have spread to loco-regional sites at the time of diagnosis. It is therefore necessary to administer adjuvant chemotherapy in all patients with advanced GBC. It is especially necessary in those in whom R0 resection is not achievable. However, data are limited from few phase II trials.64–67 Moreover, most of these studies have lumped GBC with cholangiocarcinoma, making data interpretation difficult. The three classes of cytotoxic agents used are gemcitabine, fluropyrimidines and platinum compounds (Table 3). 5-Fluorouracil when used as a single agent, had only 20% response rate. Gemcitabine alone is safe but has a limited response rate of 36%.

Table 3.  Trials with chemotherapeutic agents in biliary cancer64–67
DrugSingle/combinationTrial phaseNo. patientsTumor siteResponse rateMedian survival (in months)
  1. BTC, biliary tract cancer; GBC, gallbladder cancer.

5-Fluorouracil+ LeucovorinII28BTC32%6
 + CisplatinII25BTC24%10
Capecitabine+ CisplatinII32BTC40.6%12.4
GemcitabineSingleII26GBC36%7
 + CapecitabineII44BTC32%14
 + OxaliplatinII24BTC50%14
 + CisplatinII42GBC48%7
 + Cisplatin versus Gemcitabine aloneIII204 versus 206BTC81% versus 72% (P = 0.049)11.7 versus 8.1 (P < 0.001)

A recent landmark study established the combination of gemcitabine and cisplatinum as the standard of care for GBC.64 Among 204 patients in the cisplatin–gemcitabine group, median overall survival was 11.7 months, compared with 8.1 months among 206 patients in the gemcitabine group (hazard ratio, 0.64; 95% CI 0.52–0.80; P < 0.001). The median progression-free survival was 8.0 months in the cisplatin–gemcitabine group and 5.0 months with gemcitabine only (P < 0.001). Adverse events were similar with the exception of higher incidence of neutropenia in the cisplatin–gemcitabine group.

Recently many phase II trials are have been completed with varying combinations of gemcitabine, capecitabine, cisplatinum and irinotecan.58 The results have varied. However, patients who had undergone complete resection did not benefit from additional chemotherapy. Also, the gain in overall survival is minimal and the response to these agents may show individual variation. Further studies are needed to identify markers of response and define stopping rules.

Radiotherapy

There is paucity of quality data regarding the role of adjuvant radiotherapy in GBC. Analysis of pooled data by Mojica et al. showed that the median survival with versus without adjuvant radiation therapy was 14 months compared to 8 months (P < 0.001). Survival benefit was observed only among those with regional spread (P = 0.001) and hepatic infiltration (P = 0.011).68

Molecular targeted therapy

Recent understanding of intracellular events involved in tumor cell proliferation and growth has paved the way for development of therapeutic agents that target crucial molecular sites. Drugs targeting epidermal growth factor receptors, anti-angiogenic agents and MEK inhibitors have been particularly promising (Table 4).40,42,58,65 A multi-targeted approach has synergistic anti-tumor effects and has been found to be more efficacious, as well as better tolerated, than monotherapies. Molecular targeted therapy when combined with chemotherapy has been shown to confer greater benefit than chemotherapy alone.

Table 4.  Trials with drugs against molecular targets in biliary cancers65–67
DrugAgentsTargetTrialSingle/combinationResponse rateRemarks
  1. CA4P, combretastatin A-4 phosphate; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor receptor -2; MEK, mitogen activated protein kinase; VGEF, vascular endothelial growth factor; VGEF-R, vascular endothelial growth factor receptor.

Tyrosine kinase inhibitorsErlotinibEGFRApprovedSingle7% 
+ Bevacizumab12% 
 GefitinibEGFRApprovedIn vitro studies suggest important role when combined with radiotherapy
 LapatinibEGFR/HER-2IIISingle0%Overall survival 5.2 months
Monoclonal antibodiesCetuximabEGFRII+ Gemcitabine and oxaliplatin63%Overall survival 12.7 months
 TrastuzumabHER-2Approved   
Antiangiogenic factorsBevacizumabVEGF-AApproved+ Gemcitabine and oxaliplatin40% 
 SorafenibMultikinase inhibitorSingle 6% 
 AfliberceptVEGFIII   
 VatalanibVEGFR-1,-2,-3.III   
Vascular disrupting agents (Inhibits tumor vessels)CA4PTubulinII   
 DMXAACytokine reductionII   
MEK inhibitorSelumetinibInhibits mitogen activate protein kinasesIISingle14% 

Palliative therapy

Most patients with symptomatic GBC present with advanced, incurable disease.4 Symptoms requiring palliation include pruritus, cholangitis, pain, and gastrointestinal obstruction. In patients with extra-hepatic bile duct obstruction, the site and nature of obstruction need to be assessed, together with the severity of cholestasis and presence or absence of cholangitis. Radiological assessment of the biliary tract aids in assessing feasibility and planning the most appropriate mode of biliary drainage. Presence of confluence block, duodenal obstruction, lack of advanced expertise in endoscopic retrograde cholangiopancreatiography (ERCP) all favor percutaneous biliary drainage over ERCP. A recent study has shown that percutaneous trans-hepatic biliary drainage provides better biliary drainage and has lower complication rates in GBC patients with hilar block.69 Usually one or two 10 French straight plastic stents are placed beyond the site of obstruction. Metallic stents offer better palliation in those with expected survival of > 3 months.70 If unresectable disease is discovered at the time of surgery, a segment III bypass can be performed to relieve the biliary obstruction.

Gastric outlet obstruction is palliated by placing a metallic duodenal stent or a feeding nasojejunal tube. Through duodenal metallic stents, biliary interventions are feasible if required. Rapidly re-accumulating ascites requires repeated paracentesis and intra-peritoneal administration of cytotoxic agents. Pain palliation requires referral to a specialized pain management team if available. Decompression of the biliary tree in itself results in significant pain relief in those with a distended duct system.

Prognosis

The prognosis is dismal if the patient presents due to the symptoms of GBC per se. Pain, jaundice, anorexia, weight loss or GB mass are features of advanced disease.3,4,47 In contrast, incidental detection of GBC at the time of routine cholecystectomy for gallstones carries a good prognosis. Tumor size, depth of invasion and lymph node involvement are associated with poor prognosis.17 Tumor size and depth show a very high degree of correlation with the other prognostic factors.60 Destructive pattern of invasion has been shown to have a poorer outcome compared with infiltrative pattern.71 At histology, poorly differentiated malignancy, presence of perineural and perivascular invasion, GLUT-1 expression, mutations in p53, p21, p16 and p27 gene are associated with poorer survival. Papillary carcinomas are associated with a better prognosis.34

Prevention and screening

Gallstones are the most attractive target for prevention as they are found in 80% of patients with GBC, they are easily detected by ultrasound examination, the lead time to development of GBC is long (20 years), the GB wall can be non-invasively monitored using ultrasound at regular intervals and removal of the GB completely abrogates the risk of GBC. It is the standard of care to advise cholecystectomy for all patients with symptomatic GS even if they are not presently symptomatic, as this not only eliminates the risk of GBC, but it also decreases morbidity and mortality due to other complications of GS disease.

However, the debate regarding the role of prophylactic cholecystectomy for asymptomatic gallstones has not been completely resolved.72,73 In North India, a significant number of patients with unresectable GBC were harboring asymptomatic stones for prolonged periods of time. These gallstones were incidentally detected and no particular treatment advised as they were asymptomatic. Prophylactic cholecystectomy for these stones could have avoided this unfavorable outcome. It is neither feasible nor necessary to subject all patients with asymptomatic stones to cholecystectomy. However, a targeted approach for high risk groups with gallstones may be worthwhile in high incidence areas.73 The identified high risk groups are patients with large GS (> 2 cm), associated GB polyps, non-functioning GB, porcelain GB and young patients who are expected to live another 20 years or more. Cost-effectiveness analysis of screening and treating Chilean women under 40 years old with asymptomatic stones showed that prophylactic laparoscopic cholecystectomy could significantly benefit the population at a low incremental cost.74 In order to prevent one GBC, 67 cholecystectomies would need to be performed in high risk areas, in contrast to 769 cholecystectomies in low risk areas. Availability of laparoscopic cholecystectomy worldwide has made the process of cholecystectomy in experienced hands a simple procedure with only minimal morbidity.

Detection rate for GBC in mass screening of general population comprising 1 306 947 persons in Japan, yielded only 143 cases (0.011%); most of whom had advanced GBC.75 Thus, mass screening for GBC is an ineffective approach. However, screening high risk groups may yield more rewarding results. Red flags for possible presence of GBC should be actively looked for in all patients with gallstones (Table 5). Importantly, patients with biliary diseases at risk for malignancy should be counseled regarding the need for routinely surveillance or cholecystectomy.

Table 5.  Red flag alerts for presence of gallbladder cancer (GBC) in patients with gallstones (GS)13,14,73
Age> 40 years in high incidence areas
> 60 years in low incidence areas
GenderFemale : Male (3 : 1)
High incidence areasIndia, Pakistan, Chile, Bolivia, Japan, Korea, East European countries
High risk ethnicityAmerican Indians, Pima Indians, Chilean-Mapuche, Mexican Indians
High risk GSMultiple GS, GS > 3 cm, GS volume > 6 mL, duration > 20 years
Family historyGBC
ClinicalRight upper abdominal persistent pain, recent change in character of the pain
 Anorexia, weight loss
 GB lump
 Jaundice
RadiologyHypoechoic enhancing mass
 Diffuse gallbladder (GB) wall thickening (> 3 mm)
 Biliary dilatation
 Lymph nodes
 Porcelain GB
 Mirrizi syndrome
Non-functioning GB
Ascites
At surgeryThickened GB wall
 Induration, ulceration, focal mass, elevated mucosa
 Lymph node enlargement
 Difficult dissection
On histologyDysplasia, metaplasia: Look for gallbladder cancer foci in adjacent areas

Future directions

Gastroenterologists, radiologists, surgeons, pathologists and molecular biologists need to work together in tandem to unravel the unresolved issues in GB cancer. We need to initiate global collaborative ventures to understand its pathogenesis, explore therapeutic options, standardize terminology and formulate management strategies. Long term cohort studies are required in high risk areas to prospectively evaluate the role of risk factors. Determining the prevalence and predictors of pre-malignant lesions in the GB would provide valuable insight into the pathogenesis of GBC. Public health programs to sensitize the lay public regarding preventive and screening strategies for GS/GBC could be valuable. Molecular targeted therapy has shown some promise in patients with advanced GBC. We need to now adopt an optimistic systematic approach to close the gaps in our understanding of the disease to pave the way for a better future.

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