Gallbladder Cancer

Cancers of the biliary tract include cholangiocarcinoma (cancers arising from the bile duct epithelium), ampulla of Vater cancer, and gallbladder cancer. All subtypes of biliary tract cancers are rare and have an overall poor prognosis. They are also difficult to diagnose. These diseases are often discussed together and are mingled in therapeutic trials. However, this leads to significant confusion.

Gallbladder cancer is the fifth most common gastrointestinal (GI) cancer in the United States.[5] Worldwide, it is the sixth most common GI cancer and the most common biliary tract malignancy, accounting for 80%–95% of biliary tract cancers.[6] About 20% arise from the extrahepatic biliary tract and 20% arise from the ampulla of Vater.[7] Despite some similarities with other biliary tract malignancies, gallbladder cancer is a distinct clinical entity and will be discussed exclusively in this article.

Gallbladder cancer typically arises in the setting of chronic inflammation. In the vast majority of patients (>75%), the source of this chronic inflammation is cholesterol gallstones. The presence of gallstones increases the risk of gallbladder cancer 4- to 5-fold.[8] Other more unusual causes of chronic inflammation are also associated with gallbladder cancer. These causes include primary sclerosing cholangitis, inflammatory bowel disease,[9] liver fluke infestation, chronic Salmonella typhi and paratyphi infections,[10] and Helicobacter infection.[11]

However, chronic gallbladder inflammation is likely only part of the cause of the malignant transformation seen in gallbladder cancer. Many other factors have been identified. Ingestion of certain medications (eg, oral contraceptives, isoniazid, methyldopa) can increase the risk of gallbladder cancer. Likewise, certain chemical exposures (eg, pesticides, rubber, vinyl chloride) and occupational exposures associated with working in the textile, petroleum, paper mill, and shoemaking industries increase the risk of gallbladder cancer.

In addition, exposures through water pollution (organopesticides, eg, dichlorodiphenyltrichloroethane and benzene hexachloride); heavy metals (eg, cadmium, chromium, lead); and radiation exposure (eg, radon in miners) are associated with gallbladder cancer. Obesity[12] may contribute to gallbladder cancer through its association with gallstones, its association with increased endogenous estrogens, or through the ability of fat cells to secrete a large number of inflammatory mediators.[7]

An increased incidence of gallbladder cancer also occurs in hereditary syndromes, including the following[7] :

• Gardner syndrome
• Neurofibromatosis type I
• Hereditary nonpolyposis colon cancer

The role of various oncogenic mutations in gallbladder cancer is an area of active research. For example, a small study of gallbladder cancer from Japan reported an excess risk associated with polymorphism of the cytochrome P450 1A1 gene (CYP1A1), which encodes a protein involved in catalyzing the synthesis of cholesterol and other lipids.[13] Another study looked at polymorphisms within the apolipoprotein B gene.[14]

A case-control genome-wide association study from India identified common genetic variations that confer gallbladder cancer risk at genome-wide significance. Substantial variation in risk was associated with single-nucleotide polymorphisms involving the hepatobiliary phospholipid transporter genes ABCB1 and ABCB4, suggesting a role for those genes in the pathology of gallbladder cancer.[15]

Wu et al retrospectively analyzed surgical specimens from 97 consecutive gallbladder cancer patients treated in Taiwan between 1993 and 2005 at 2 tertiary medical centers for alpha-methylacyl coenzyme A racemase (AMACR) expression. The authors found that overexpression of this enzyme in gallbladder cancer was associated with a more advanced T stage, a higher histologic grade and vascular invasion. Overexpression of AMACR was also found to be an independent predictor of decreased disease-specific survival in this group of patients.[16]

Abnormal anatomy such as congenital defects with anomalous pancreaticobiliary duct junctions and choledochal cysts increase the risk of gallbladder cancer.[17, 18] The tumor is usually located in the fundus of the gallbladder. Local spread through the gallbladder wall can lead to direct liver invasion, or, if in the opposite direction, leads to transperitoneal spread (20% of patients at presentation), with implants on the liver, on the bowel, and in the pelvis. Tumor may also directly invade other adjacent organs such as the stomach, duodenum, colon, pancreas, and extrahepatic bile duct.

At diagnosis, the gallbladder is often replaced or destroyed by the cancer. In addition, approximately 50% of patients have regional lymph node metastases.

See the Gallbladder and Biliary Disease Resource Center for more information about related conditions.

United States

Gallbladder cancer incidence increases with age and is more common in women. Approximately 11,980 new cases—5730 in men and 6250 in women—of cancer of the gallbladder and nearby large bile ducts are predicted for 2021, with about 4 in 10 of them gallbladder cancers, according to the American Cancer Society. Approximately 4310 deaths are projected for 2021, 1770 in men and 2540 in women.[1]

In the United States, incidence varies substantially with racial and ethnic group and sex. Gallbladder cancer rates are the highest among American Indians/Alaska Natives and among white Hispanic peoples. Within both groups, incidence of gallbladder cancer is significantly higher in women.[7] The white Hispanic female incidence rate is 4.2 per 100,000 person-years. The American Indian/Alaskan Native female incidence rate is 4.1 per 100,000 person-years. The corresponding male rates are 1.4 and 3,3 per 100,000 person-years, respectively. The lowest incidence rate for gallbladder cancer is among non-Hispanic white males and is 0.7 per 100,000 person-years.

The incidence of gallbladder cancer rises with age; 75% of patients with gallbladder cancer are older than 64 years.[1] In non-Hispanic Whites and Blacks, the rate of gallbladder cancer rises more slowly than among Hispanic whites and American Indian/Alaskan Natives. The rates for gallbladder cancer are higher among women than men in all age groups.[7]

Overall, the incidence (cases per year) has been decreasing over the last three decades for males. In females, the incidence rate decreased from 1973 to mid‐90s but then stabilized.[19]

International

Considerable variation exists in the incidence of gallbladder cancer throughout the world. Areas with the highest incidence rates include India, Korea, Japan, Czech Republic, Slovakia, Spain, Columbia, Chile, Peru, Bolivia, and Ecuador. The high incidence rates reported in Peru and Chile are thought to reflect the Hispanic populations with Indian heritage. Women from India have the highest international rate of gallbladder cancer, at between 8.8 per 100,000 person-years and 21.2 per 100,000 person-years.[7, 10] The United Kingdom, Denmark, and Norway have the lowest international incidence rates. Gallbladder cancer is the most common cancer affecting women in Chile.

Survival is correlated with staging based on the American Joint Committee on Cancer (AJCC) tumor, node, metastases (TNM) staging system.[20] Most patients have regional disease or distant metastases at presentation. Therefore, the prognosis in gallbladder disease is poor, with 5-year survival rates of 15-20%.[7]

Patients with stage IA disease (T1N0M0) should be cured with a simple cholecystectomy. In selected surgical series, patients with stage IB (T2N0M0) disease treated with extended cholecystectomy have a 5-year survival rate of 70-90%, and patients with stage IIB (T1-3N1M0) treated with extended cholecystectomy have a 5-year survival of 45-60%. Stage III (T4, any N, M0) gallbladder cancer is generally not surgically curable. The 1-year survival rate for advanced gallbladder cancer is less than 5%. The median survival is 2-4 months.

The SEER registry from 1995-2001 shows 5-year survival rates for localized gallbladder cancer of approximately 40%. The 5-year survival rate for regional disease is listed at approximately 15%, and the 5-year survival rate for distant metastatic disease is reported at less than 10%.[6] However, survival data are variable from institution to institution for each stage.

Unfortunately, only about 10-20% of patients present with tumor confined to the gallbladder wall. At diagnosis, 40-60% of patients have lesions that perforate the gallbladder wall and invade adjacent organs (T3) and 45% of patients have regional lymph node involvement (N1). Approximately 30% of patients present with metastatic disease.

Race-, sex-, and age-related demographics

The highest rates of gallbladder cancer in the US are found in the US Native American and Hispanic, especially Mexican, populations. A substantial female predominance exists in the US and worldwide, with female-to-male ratios of approximately 2.5:1 to 3:1. Gallbladder cancer is most typically diagnosed in the seventh decade of life, with a median age of 62-66 years.

The symptoms of gallbladder cancer overlap with the symptoms of gallstones and biliary colic. Abdominal pain may be of a more diffuse and persistent nature than the classic right upper quadrant pain of gallstone disease. Jaundice, anorexia, and weight loss often indicate more advanced disease.[21]

Findings on physical examination may include the following:

• Jaundice
• Palpable mass in the right upper quadrant (Courvoisier sign, if this is due to a palpable gallbladder)
• Periumbilical lymphadenopathy (Sister Mary Joseph nodes)
• Left supraclavicular adenopathy (Virchow node)
• Pelvic seeding: Palpable mass on digital rectal examination (Blumer shelf).

See Pathophysiology. Associated conditions include the following:

• Chronic gallstones
• Calcification of the gallbladder (porcelain gallbladder) - 10-25% incidence of gallbladder cancer
• Crohn ileocolitis
• Ulcerative colitis
• Occupational chemical exposure
• Estrogens
• Typhoid carriage
• Anomalous pancreatobiliary duct junction
• Gallbladder polyps

Measurement of tumor marker CA 19-9 may be helpful in the appropriate situation if the clinical suspicion for gallbladder cancer is high. CA 19-9  levels may be significantly elevated in both cholangiocarcinoma and gallbladder cancer. CA 19-9 measurement can also be useful in conjunction with carcinoembryonic antigen (CEA) assays. These markers are not specific for gallbladder cancer, however, and could be elevated because of other conditions.

The relevance of other laboratory tests is as follows:

• Liver function tests: Elevated alkaline phosphatase and bilirubin levels are often found with more advanced disease.
• Blood urea nitrogen (BUN), creatinine, urinalysis: Assess kidney function prior to performing an enhanced CT scan.
• Complete blood cell count (CBC): Anemia may be an indicator of more advanced disease.

Ultrasonography (US) is a standard initial study in patients with right upper quadrant pain. A mass can be identified in 50-75% of patients with gallbladder cancer. It also can delineate metastatic lesions in the liver.

Computed tomography (CT) scans also may be useful in patients with upper abdominal pain and can demonstrate tumor invasion outside of the gallbladder and identify metastatic disease elsewhere in the abdomen or pelvis. Liver invasion occurs in 60% of cases, and the combination of CT scan and US provides accurate details of disease extension. However, a study of multi-detector CT (MDCT) found that MDCT has moderate sensitivity, poor specificity, and moderate-to-substantial inter-rater repeatability for differentia ting gallbladder cancer from acute and xanthogranulomatous cholecystitis.[22]

Magnetic resonance imaging (MRI) has been useful in examining this region for disease extension into other tissues or metastatic disease in the liver. It can provide details of the vasculature for preoperative planning via magnetic resonance angiogram (MRA) and bile duct passages via magnetic resonance cholangiogram (MRCP).

A systematic review and meta-analysis of diffusion-weighted MRI reported a pooled sensitivity of 91% and a pooled specificity of 87% for differentiating benign from malignant gallbladder lesions. The authors recommended obtaining thinner image slices (≤5 mm) with 3T field strength and performing qualitative assessment in order to enhance the diagnostic ability of diffusion-weighted imaging.[23]

Cholangiography, via a percutaneous route, or endoscopic retrograde cholangiography (ERCP) may establish the diagnosis of gallbladder cancer by bile cytology.

Endoscopic ultrasonography can be useful to assess regional lymphadenopathy and depth of tumor invasion into the wall of the gallbladder. In conjunction with other studies, it also can provide a means of obtaining bile for cytologic analysis, which has a sensitivity of 73% for the diagnosis of gallbladder cancer.[24]

Angiography may be used to confirm encasement of the portal vein or hepatic artery and may assist in preoperative planning for definitive resection.

A routine chest radiograph should also be obtained.

The role of positron emission tomography (PET) scanning in the evaluation of patients wtih gallbladder cancer has not been established. Emerging evidence suggests that PET may be useful for the detecting radiologically occult regional lymph node and distant metastatic disease in patients with otherwise potentially resectable disease. However, the accuracy of PET is limited by false positives in patients with an inflamed gallbladder.[25] European Society for Medical Oncology guidelines note that 18F-fluorodeoxyglucose (FDG)-PET has a sensitivity and specificity of ∼80-90% for the diagnosis of gallbladder cancer, but do not recommend FDG-PET for primary diagnosis. However, FDG-PET may allow identification of nodal metastases and distant metastases, and may identify disease recurrence.[26]

See the list below:

• Endoscopic retrograde cholangiopancreatography (ERCP) can demonstrate the site of the obstruction by direct retrograde dye injection, as well as exclude ampullary pathology by endoscopic evaluation. Brush cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide material for histology. Palliative stenting to relieve biliary obstruction can be performed at the time of the evaluation.

• Percutaneous transhepatic cholangiography (PTC) may allow access to the proximal biliary tree that has become obstructed by extensive tumor growth from the gallbladder. Material for cytology can be obtained and drainage performed as well.

• Other methods to obtain tissue include CT- or endoscopic ultrasonographic (EUS)–guided fine-needle aspiration if a mass lesion is present.

Adenocarcinoma is the primary histologic finding in 80-85% of gallbladder carcinomas, with several histologic subtypes, including papillary, nodular, and infiltrative. The papillary type appears to be less aggressive and more often localized and has a better prognosis than the other forms. Additional rare histologic types of gallbladder cancer exist. These include squamous cell cancer, sarcomas, carcinoid, lymphoma, and melanoma.

Grade is also important, with poorly differentiated tumors associated with a poorer prognosis than the typically less infiltrative, better differentiated tumors with metaplasia.

Staging of tumor extent is essential in selection of the appropriate treatment approach.

Gallbladder cancer is staged using the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system, with depth of tumor penetration and regional spread defined pathologically.[20] Survival is correlated directly with stage of disease.

Tumor (T) classification is as follows:

• TX - Primary tumor cannot be assessed
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ
• T1 - Tumor invades lamina propria or muscle layer
• T1b - Tumor invades muscle layer
• T1a - Tumor invades lamina propria
• T2 - Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver
• T2b - Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver
• T2a - Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum)
• T3 - Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts
• T4 - Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

Regional lymph node (N) classification is as follows:

• NX - Regional lymph nodes cannot be assessed
• N0 - No metastases in regional lymph nodes
• N1 - Metastases to regional lymph nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein
• N2 - Metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes

Distant metastasis (M) classification is as follows:

• MX - Presence of metastases cannot be assessed
• M0 - No distant metastases
• M1 - Distant metastases

TNM groupings by stage are are shown in the table below

Table. Gallbladder Cancer Anatomic Stage/Prognostic Groups (Open Table in a new window)

Although complete surgical resection is the only therapy to afford a chance of cure for gallbladder cancer, en bloc resections of the gallbladder and portal lymph nodes carry a high morbidity and mortality (similar to bile duct carcinoma). Adequate surgical margins may be difficult to achieve.

The role of adjuvant radiation therapy is to control microscopic residual deposits of carcinoma in the tumor bed and regional lymph nodes.[27] The rationale for radiation therapy with or without concurrent chemotherapy in patients with unresectable disease is to provide palliation of symptoms. Rarely, it may increase survival.

The role of radiotherapy for carcinoma of the gallbladder is unclear because the available literature is derived from small, single-institutional experiences over many years, with a variety of treatment methods used. Complicating this is the fact that only approximately 25% of patients with carcinoma of the gallbladder can undergo curative surgery.

Even large institutions do not accrue more than single-digit numbers of patients per year, and many are not on protocol. Available reports contain small numbers of patients with incomplete reporting of technical treatment data, histological grading, and tumor extent. The literature is strongly biased by patient selection, and interpretation of the reports is difficult. Given these difficulties, the data support the following statements:

Radiotherapy has been delivered in a variety of situations, including after curative resections with close or positive microscopic margins, gross macroscopic residual disease, and palliative debulking with bypass.

Significant increases in survival rates have been reported after curative surgery is attempted and only microscopic residual disease remains. Survival in these patients after surgery alone ranges from 6-7 months and can be prolonged to longer than 12 months with adjuvant external beam radiotherapy. This excludes patients with T1 or stage I disease confined to the mucosa of the gallbladder, whose survival rates are extremely high and who are at very low risk for lymph node metastases.

All patients with tumors beyond the mucosa are candidates for external beam radiotherapy. Patients with curative resection and AJCC stages T2-T4 who have had complete resection who receive radiation have a mean survival of over 16 months. This compares with less than 6 months mean survival with surgery alone.

Combination chemotherapy with gemcitabine plus cisplatin is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer.[28] The multicenter, phase III randomized ABC-02 study, which included 149 patients with gallbladder cancer, established gemcitabine plus cisplatin as the standard of care in this setting. In ABC-02, the median overall survival was 11.7 months for those receiving gemcitabine plus cisplatin compared with 8.1 months for those receiving gemcitabine alone; progression-free survival was 8 months in the group receiving gemcitabine plus cisplatin compared with 5 months in those receiving only gemcitabine.[29]

Simiarly, a randomized, controlled, single-institution study in 81 patients with unresectable gallbladder cancer by Sharma et al found that gemcitabine plus oxaliplatin provided statistically superior rates of overall response, median overall survival, and progression-free survival, compared with best supportive care or 5-fluorouracil plus folinic acid.[30]

However, the TOPAZ-1 trial demonstrated that the addition of the programmed death–ligand 1 (PD-L1) inhibitor durvalumab to the gemcitabine/cisplatin regimen improved  In the trial—a double-blind, placebo-controlled, phase 3 study in 685 patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease—24-month overall survival was 24.9% (95% CI, 17.9 to 32.5) in the durvalumab group, versus 10.4% (95% CI, 4.7 to 18.8) in the placebo group. The hazard ratio for progression-free survival (PFS) with durvalumab was 0.75. Objective response rates were 26.7% with durvalumab and 18.7% with placebo.[3] Real-world experience has largely confirmed the TOPAZ-1 results.[31] Current National Comprehensive Cancer Network guidelines recommend durvalumab/gemcitabine/cisplatin as the preferred regimen for unresectable and metastatic disease.[25]

For the most part, randomized studies of the addition of biological therapies (EGFR or VEGF inhibitors) to treatment for gallbladder cancer have failed to show an improvement in survival.[28] For example, the BINGO trial concluded that the addition of cetuximab did not seem to enhance the activity of gemcitabine and oxaliplatin in patients with advanced biliary cancer.[32] However, an open-label, single-arm, phase II trial found that treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival versus the rates reported for historical controls.[33]

For patients with gallbladder cancer that progresses despite treatment with cisplatin and gemcitabine, the phase III ABC-06 study demonstrated a role for second-line therapy with FOLFOX (folinic acid, fluorouracil, and oxaliplatin). In ABC-06, median overall survival with FOLFOX plus active symptom control versus symptom control only was 6.2 versus 5.3 months, respectively (adjusted hazard ratio 0.69 [95% CI 0.50–0.97]; P=0.031). FOLFOX had an acceptable toxicity profile.[28]

Because some patients are not able to receive platinum-based chemotherapy, Iqbal et al explored gemcitabine plus capecitabine as a possible treatment option in a phase II study of 57 patients with advanced or metastatic biliary cancer. This study included both patients with cholangiocarcinoma (67%) and patients with gallbladder cancer (33%). No complete responses were seen. Of the 52 patients who were able to continue the study, a confirmed partial response was seen in 7 patients, and an unconfirmed partial response was seen in 6 patients. Stable disease was seen in 12 patients. Six-month overall survival was 55%, and median survival was 7 months. Of the 51 patients available for toxicity assessment, 6 had grade 4 toxicities. The study concluded that the combination of gemcitabine and capecitabine was well tolerated.[34]

Targeted therapy for gallbladder canceris is an area of active investigation.[35, 4] For patients with unresectable or metastatic disease, current National Comprehensive Cancer Network guidelines recommend entrectinib or larotrectinib for NTRK gene fusion–positive tumors and pembrolizumab for tumors with high microsatellite instability or deficient mismatch repair.[25]

Selected patients with initially unresectable disease may be considered for surgical resection after response to chemotherapy. This is based on a retrospective study showing markedly improved survival in a small number of patients who received gemcitabine and cisplatin followed by surgery.[36] More trials are needed to evaluate this benefit.

Patients with a good performance status should be considered for treatment with the regimens described in this section, or for participation in a clinical trial. Patients with a poor performance status may be best treated with supportive care.

Complete surgical resection is the only therapy to offer a chance of cure in this disease. Unfortunately, only a minority of patients present with early-stage disease and are, therefore, considered for curative resection.

Optimistically, 5 year survival rates for gallbladder cancer have increased 5-12% up to 38%. This increase is felt to be related to a trend in standardizing aggressive approaches to locally confined disease.[37] Studies evaluating the significance of tumor involvement of the liver in early T-stage tumors and lymph node metastases on outcomes suggest that a need to standardize minimum requirements for adequate surgical resection and pathological examination of gallbladder cancer resections.[38]

Patients who present with a gallbladder mass or jaundice are evaluated preoperatively for resectability, including chest imaging, abdominal/ pelvic CT scan, or MRI and possibly a staging laparoscopy. Nodal metastases outside of the regional area (ie, porta hepatis, gastrohepatic ligament, retroduodenal area) are not resectable. If the tumor is resectable, the patient should undergo a cholecystectomy, hepatic resection, and regional lymphadenectomy (see the image below).

The necessary extent of hepatic resection is currently undefined. However, approximately 25% of T2 tumors have liver involvement. Liver involvement is a prognostic indicator of worse outcome.[38] Bile duct excision may also be necessary, especially if jaundice is present. The operative morbidity and mortality rate increases with the complexity of the operative procedure.

A schematic drawing of the extent of lymphadenectomy for gallbladder cancer, especially when the extrahepatic biliary tree is resected.

Gallbladder cancer is sometimes an incidental pathology finding after a cholecystectomy is performed for reasons other than cancer. If the tumor is carcinoma in situ (Tis) or only invades the lamina propria (T1a) and the margins of resection are negative, then postoperative observation alone is acceptable. If the tumor is T1b or greater or the margins of resection are positive and if no metastatic disease is present on evaluation (CT or MRI scan and chest radiograph), then a second surgical resection is required. This additional surgery should include partial hepatic resection and regional lymphadenectomy (porta hepatis, gastrohepatic ligament, and retroduodenal lymph nodes). A bile duct resection may also be necessary, depending on tumor size and location.

If the original surgery was performed via a laparoscopic approach, then the port sites should also be resected to avoid tumor seeding. However, several studies have found that port site resection does not improve survival in patients with incidentally discovered gallbladder cancer.[39]

Because of the high incidence of gallbladder cancer in a calcified (porcelain) gallbladder, patients with this finding should be strongly considered for an open cholecystectomy, even if they are asymptomatic. Avoid a laparoscopic cholecystectomy in this setting to avoid the risk of peritoneal seeding if, indeed, gallbladder cancer is present.

Lymph node evaluation is a critical component of radical resections for gallbladder cancer and has been shown to improve survival in a retrospective trial.[40] Although no consensus has been reached on the minimum number of lymph nodes required for evaluation for accurate staging, one study demonstrated that resection and histologic evaluation of at least 6 lymph nodes improves risk stratification.[38] This underscores the importance of a thorough lymphadenectomy of the porta hepatis and complete review of the pathological specimens in patients with gallbladder cancer.[38]

The surgical role in treatment of unresectable disease is usually limited to biopsy of the tumor for diagnosis and possible biliary decompression procedures.

A radiation oncologist and medical oncologist should be part of the multidisciplinary team participating in the treatment of patients with gallbladder cancer.

Guidelines Contributor:  Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

Diagnosis

National Comprehensive Cancer Network (NCCN) guidelines offer different algorithms for the following presentations of gallbladder cancer[25] :

• Incidental finding of suspicious mass at surgery
• Incidental on pathologic review of cholecystectomy specimen
• Mass on imaging study
• Jaundice

When a suspicious gallbladder mass is an incidental finding during surgery and hepatobiliary surgery expertise is available, the NCCN recommends intraoperative staging with or without biopsy, and resection if possible. Postoperatively, imaging studies are performed for staging. If hepatobiliary surgery expertise is unavailable or the tumor is unresectable, the NCCN recommends biopsy and molecular testing. The postoperative workup in those cases and in cases that present as a mass on an imaging study should include the following:

• History and physical examination
• Multiphasic abdominal/pelvic CT/MRI with IV contrast and chest CT ± contrast
• Liver function tests (LFTs) and assessment of hepatic reserve
• Consideration of CEA and CA 19-9
• Surgical consultation

For  the recommended workup includes the following:

• History and physical examination
• Multiphasic abdominal/pelvic CT/MRI with IV contrast
• Chest CT with or without contrast
• LFTs and assessment of hepatic reserve
• Consider CEA and CA 19-9 testing
• Surgical consultation

For patients who present with jaundice, the recommended workup includes all of the above, as well as the following:

• Cholangiography (preferably magnetic resonance cholangiopancreatography [MRCP])
• Consider staging laparoscopy
• Consider biliary drainage

The European Society for Medical Oncology (ESMO) clinical practice guidelines for biliary cancer, updated in 2023, recommend the following diagnostic and staging investigations[26] :

• Perform LFTs and other blood tests to identify underlying liver or biliary tract disease (eg, hepatitis B and C, steatohepatitis, primary cholangitis)
• Obtain a core biopsy for diagnostic pathology and molecular profiling before providing any nonsurgical treatment.
• Depending on tumor location, endoscopic ultrasound (EUS)–guided fine needle aspiration (FNA) or biopsy may be an option to obtain biopsies of enlarged regional nodes and to obtain a tumor biopsy if endoscopic retrograde cholangiopancreatography (ERCP)–guided biopsies are negative or inconclusive.
• Perform CT of chest and abdomen ± pelvis for staging; positron emission tomography (PET/CT, if available, may allow identification of nodal metastases, distant metastases, and disease recurrence
• Molecular analysis is recommended in advanced disease considered suitable for systemic treatment.
• Elevated CA 19-9 is associated with poorer prognosis and can be useful for assessing response to treatment

In 2013, the American Society for Gastrointestinal Endoscopy (ASGE) released guidelines for the use of endoscopy in the evaluation of biliary neoplasia. The recommendations for gallbladder polyps included the following[41] :

• EUS or FNA if the results would change the management
• Cholecystectomy for symptomatic patients with gallbladder polyps, asymptomatic patients with gallbladder polyps > 10 mm, and any patient with gallbladder polyps and primary sclerosing cholangitis
• Asymptomatic patients with gallbladder polyps 6-10 mm but no other risk factors for gallbladder cancer should receive annual transabdominal ultrasound screening

Staging

Gallbladder cancer staging follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) and is classified into four stages based on the depth of invasion into the gallbladder wall and the extent of spread to surrounding organs and lymph nodes.[20]

TNM groupings by stage are as follows:

• Stage 0- Tis N0 M0
• Stage I - T1 N0 M0
• Stage IIA - T2a N0 M0
• Stage IIB - T2b N0 M0
• Stage IIIA - T3 N0 M0
• Stage IIIB - T1-3 N1 M0
• Stage IVA - T4 N0-1 M0
• Stage IVB - Any T Any N M1

Treatment

The NCCN guidelines include the following recommendations for treatment of gallbladder cancer discovered as an incidental finding during surgery[25] :

• If hepatobiliary surgery expertise is available and there is convincing clinical evidence of cancer, a definitive resection can be performed. If the diagnosis is not clear, frozen section biopsies can be considered in selected cases before proceeding with definitive resection. If malignancy is suspected or confirmed after cholecystectomy has been initiated and expertise is available, then definitive resection should be undertaken.
• If malignancy is suspected before cholecystectomy has begun and there is a question of resectability (eg, locally advanced, possible metastatic disease), then definitive resection can be postponed, regardless of available expertise, until complete staging and evaluation has been performed. Consider biopsy if chemotherapy is anticipated.
•  Definitive resection consists of radical cholecystectomy including segments IV B and V and lymphadenectomy and extended hepatic or biliary resection as necessary to obtain a negative margin.

NCCN recommendations for gallbladder cancer discovered as an incidental finding on pathologic review include the following[25] :

• Consider pathologic re-review by a hepatobiliary pathology expert and/or speak to surgeon to check for completeness of cholecystectomy, signs of disseminated disease, location of tumor, and any other pertinent information. Review the pathology report for T stage, cystic duct margin status, and other margins.
• Diagnostic laparoscopy can be performed but is of relatively low yield. Higher yields may be seen in patients with T3 or higher tumors, poorly differentiated tumors, or with a margin-positive cholecystectomy. Diagnostic laparoscopy should also be considered in patients with any suspicion of metastatic disease on imaging that is not amenable to percutaneous biopsy.
• Repeat cross-sectional imaging of the chest, abdomen, and pelvis should be performed prior to definitive resection.
• Initial exploration should rule out distant lymph node metastases in the celiac axis or aorto-caval groove, as these contraindicate further resection.
• Hepatic resection should be performed to obtain clear margins, which usually consists of segments IV B and V. Extended resections beyond segments IV B and V may be needed in some patients to obtain negative margins.
• Lymphadenectomy should be performed to clear all lymph nodes in the porta hepatis.
• Routine resection of the bile duct for lymphadenectomy is not recommended, as it increases morbidity and may not improve survival, but in some cases resection may be needed to obtain negative margins.
• Port site resection has not been shown to improve outcome, as the presence of implanted disease at a port site is a surrogate marker of underlying disseminated disease.

NCCN recommendations for gallbladder cancer discovered as an incidental finding on an imaging study include the following[25] :

• Biopsy is not necessary
• Diagnostic laparoscopy is recommended prior to definitive resection.
• In selected cases where the diagnosis is not clear, a reasonable approach may be to perform a cholecystectomy (including intraoperative frozen section) followed by definitive resection during the same setting if pathology confirms cancer.
• Definitive resection consists of radical cholecystectomy including segments IV B and V and lymphadenectomy and extended hepatic or biliary resection as necessary to obtain a negative margin.

The NCCN notes that the presence of jaundice in gallbladder cancer usually portends a poor prognosis, and curative-intent resection is usualy contraindicated. However, in selected patients with resectable disease curative-intent resection can be attempted in centers with expertise.

For management of patients with unresectable or metastatic disease, NCCN makes the following category 1 recommendations[25] :

• Durvalumab plus gemcitabine plus cisplatin (preferred)
• Gemcitabine plus cisplatin

For targeted therapy in unresectable or metastatic disease NCCN recommendations are as follows[25] :

• NTRK gene fusion–positive tumors: Entrectinib, larotrectinib
• High microsatellite instability/deficient mismatch repair (MSI-H/dMMR) tumors: Pembrolizumab
• High tumor metastatic burden (TMB-H) tumors: Nivolumab plus ipilimumab
• RET gene fusion–positive tumors: Pralsetinib
• BRAF V600Emutated tumors: Dabrafenib plus trametinib (subsequent-line therapy for progressive disease)

NCCN recommendations for second-line therapy in unresectable or metastatic disease are as follows[25] :

European Society for Medical Oncology

ESMO recommendations for local and locoregional disease include the following[26] :

• Radical surgery, which includes lymphadenectomy, is the only curative-intent treatment. The exact nature and extent of surgery will depend on tumor subtype and location and should be determined by a specialist hepatobiliary multidisciplinary tumor board.

• Radiologic imaging should be carried out before ERCP or percutaneous transhepatic cholangiography in patients with jaundice.

• Consideration of non-tumor-related factors (eg, performance status [PS], comorbidities) is important, as resection carries a significant risk of mortality.

• In incidentally diagnosed gallbladder (after cholecystectomy), re-operation with radical intent should be offered to sufficiently fit patients with stage ≥T1b disease, provided there is no metastatic spread. Resection of some or all of segment IVb/V of the liver is carried out together with a lymphadenectomy of the hepatoduodenal ligament.

• If the gallbladder was not removed with a bag during laparoscopic resection or the gallbladder was perforated, resection of the port sites may also be considered.

• Adjuvant chemotherapy with capecitabine should be considered following resection.

• Radiation therapy, after completion of adjuvant capecitabine, might be considered in selected patients (eg, R1 resection).

• In case of response following locoregional or systemic treatment of locally advanced tumors, patients should be re-assessed by the multidisciplinary team to discuss surgery.

• Curative-intent resection of tumors located at the infundibulum requires resection of the bile duct, the duodenal bulb and, potentially, the pancreatic head.

ESMO recommendations for management of advanced and metastatic disease are as follows[26] :

• Cisplatin–gemcitabine is recommended as the first-line standard of care for patients with a PS of 0-1
• The combination of cisplatin–gemcitabine with durvalumab should be considered as first-line treatment.
• Oxaliplatin may be substituted for cisplatin when kidney function is of concern.
• Gemcitabine monotherapy may be used in patients with a PS of 2.
• FOLFOX is the standard of care in the second-line setting after cisplatin–gemcitabine.
• FGFR inhibitors are recommended for the treatment of patients with FGFR2 fusions whose disease has progressed after ≥1 prior line of systemic therapy.
• Pembrolizumab is recommended in patients with MSI-H/dMMR disease that has progressed on or are intolerant to prior treatment.
• Dabrafenib–trametinib is recommended for the treatment of patients with BRAF V600E mutations whose disease has progressed after ≥1 prior line of systemic therapy.
• Patients with BRCA1/2 or PALB2 mutations responding to platinum-based therapy can be considered for treatment with PARP inhibitors.
• NTRK inhibitors are recommended in patients with NTRK fusions who have progressed on or are intolerant to prior treatment.
• HER2-directed therapies can be considered in patients with the respective genetic alterations who have progressed on or are intolerant to prior treatment.
• During systemic and locoregional therapy for advanced disease, conduct follow-up every 8-12 weeks. In addition to imaging with CT or MRI, CA 19-9 or CEA levels may be used to monitor the course of the disease if one or both are known to be secreted.

Historically, chemotherapy has not shown significant activity in gallbladder carcinoma. Typically, 5-fluorouracil (5-FU) has been used with response rates of 10-24% in advanced disease. Often 5-FU is administered either as a bolus or as a prolonged infusion regimen with radiation. Capecitabine is a currently available oral alternative to a prolonged 5-FU infusion.

More recently, gemcitabine has shown activity in gallbladder cancer. Early-phase studies show an increased response rate with gemcitabine combination therapy over historical treatment response rates with 5-FU alone. Gemcitabine has been studied in combination with cis-platinum and capecitabine.

The programmed death ligand (PD-L) inhibitor pembrolizumab has demonstrated benefit in tumors with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR).[42] The tyrosine kinase inhibitor entrectinib may be useful in NTRK gene fusion–positive tumors.[25]

Currently, no clearly defined standard exists for chemotherapy in gallbladder cancer. Patients should be encouraged to participate in clinical trials.

Class Summary

These agents inhibit cell growth and proliferation.

Gemcitabine (Gemzar)

Cytidine analog, after intracellular metabolism to active nucleotide, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Cell cycle-specific for S phase.

This drug has been shown to have activity in a phase-2 trial against relapsed germ cell tumors.

Cisplatin (Platinol)

Platinum-containing compound that exerts antineoplastic effect by covalently binding to DNA with preferential binding to N-7 position of guanine and adenosine. Can react with 2 different sites on DNA to cause cross-links. Platinum complex also can bind to nucleus and cytoplasmic protein. A bifunctional alkylating agent, once activated to aquated form in cell, binds to DNA, resulting in interstrand and intrastrand cross-linking and denaturation of double helix.

Modify dose on basis of CrCl. Avoid use if CrCl < 60 mL/min.

Capecitabine (Xeloda)

Prodrug of fluorouracil that undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA, and to a lesser degree with RNA synthesis.

Pembrolizumab (Keytruda)

Anti PD-1 humanized monoclonal antibody which inhibits programmed cell death 1 activity by binding the PD-1 receptor on T cells to block PD-1 ligands (PDL-1 and PDL-2) from binding

Entrectinib (Rozlytrek)

Inhibitor of tropomyosin tyrosine receptor kinases. Entrectinib also inhibits proto-oncogenic tyrosine-protein kinase (ROS1) and anaplastic lymphoma kinase (ALK). Entrectinib targets these oncogenic drivers to disrupt this unchecked cell proliferation

See the list below:

• Because survival is usually very short in patients with advanced disease, close follow-up is essential to preserve the best quality of life. For patients with earlier stage disease who are treated with surgery and postoperative radiation therapy and chemotherapy, intermittent posttreatment imaging studies can be considered (particularly in the first few years).

• Hospice referral is important early in the disease course for patients with metastatic disease because their survival is typically 6 months or less.

See the list below:

• Because a calcified (porcelain) gallbladder has up to a 25% incidence of associated gallbladder cancer, this is an indication to consider a cholecystectomy even in an asymptomatic patient.

• A small percentage (< 10%) of patients with gallbladder polyps are found to have underlying gallbladder cancer. The risk increases with age and the size of the polyp. A cholecystectomy should be considered if a gallbladder polyp greater than 1 cm in size is found in a patient older than 50 years.

Survival at 5 years is correlated with stage of disease at presentation. Only 10-20% of patients present with localized disease. The remainder present with regional or distant spread. From 1989 to 1996, 5-year survival in patients with primary gallbladder cancer was 50% for stage I disease and 2% for stage IV disease.[19]