Gallbladder Cancer

8 Interesting Facts of Gallbladder Cancer 

1. Gallbladder Cancer is a rare malignancy that is strongly associated with gallstones (present in up to 70%-88% of patients) and most common in women (female to male ratio is approximately 2 to 1)
2. Locally invasive into the liver and locoregional lymph nodes and often metastatic to noncontiguous areas of liver and the peritoneum
3. May be diagnosed preoperatively, intraoperatively, or postoperatively
   • May present preoperatively in a minority of patients, with symptoms suggestive of benign gallstone disease (eg, biliary colic), or as an imaging abnormality on abdominal ultrasonography
   • May present intraoperatively when surgeon discovers unexpected gallbladder mass during cholecystectomy performed for presumed benign gallbladder disease
   • May be discovered incidentally on pathologic examination of resected gallbladder; this finding occurs with early stage gallbladder cancer that may not be recognizable to surgeon
4. Diagnostic and staging work-up sequence varies depending on mode and timing of presentation and includes 3-dimensional imaging of the abdomen, pelvis, and chest in all patients, with magnetic resonance cholangiography and/or staging laparoscopy if indicated by presentation
5. Surgery is the only potentially curative therapy for gallbladder cancer; in the absence of absolute contraindications, it should be attempted for stages I to III disease, and considered for some stage IVa disease
6. Adjuvant chemotherapy, usually gemcitabine- or fluoropyrimidine-based (and sometimes followed by chemoradiation therapy), is usually recommended for disease that is stage T2 or greater and for node-positive disease; however, it may be considered in all patients following resection of gallbladder cancer
7. Unresectable or metastatic disease is managed with chemotherapy, radiation therapy, or chemoradiation, sometimes with biliary drainage for palliation of obstructive jaundice. Immunotherapy with pembrolizumab may be appropriate for select patients in these categories
8. Most patients are diagnosed at an advanced stage and the prognosis for these patients is very poor. If diagnosed when the cancer has not invaded beyond the muscular layer of the gallbladder wall, 5-year survival is 50%

Pitfalls

• Gallbladder Cancer is Usually diagnosed in late, incurable stage; a high index of suspicion is required for diagnosis
  • Most commonly encountered risk factors for gallbladder cancer are presence of gallstones, female sex, and obesity, all of which overlap with risk factors for benign gallbladder disease
  • It is often unclear if symptoms of gallbladder cancer are superimposed on those of benign gallstone-related disease or if the symptoms are mostly related to the presence of gallstones with silent malignancy
  • When evaluating a patient for cholecystectomy for presumed benign biliary disease, the presence of known risk factors increases the index of suspicion for the possibility of gallbladder cancer (eg, high-risk ethnicity or geographic area of residence, anomalous junction of the pancreaticobiliary ductal system, gallbladder polyp on imaging, chronic typhoid carrier status, comorbid primary sclerosing cholangitis)
• Usually invades adjacent structures with extensive regional lymph node involvement and often metastasizes to the liver and peritoneal surface
• Most cases are diagnosed at an advanced stage and are rarely curable 

Classification of Gallbladder Cancer

• By TNM staging
  • Primary tumor (T)
    • Tis
      • Carcinoma in situ
    • T1
      • T1a: tumor invades lamina propria
      • T1b: tumor invades muscular layer
    • T2
      • T2a: tumor invades perimuscular connective tissue on the peritoneal side without involvement of the serosa (visceral peritoneum)
      • T2b: tumor invades perimuscular connective tissue on the hepatic side, with no extension into liver
    • T3
      • Tumor perforates the serosa and/or directly extends into the liver and/or 1 other adjacent organ or structure (eg, extrahepatic bile ducts, stomach, duodenum, pancreas, omentum, colon)
        • Direct extension into the liver and direct invasion of an adjacent organ is not considered metastatic disease
    • T4
      • Tumor invades main portal vein or hepatic artery or invades 2 or more extrahepatic organs or structures
  • Regional lymph nodes (N)
    • N0: no regional lymph node metastasis
    • N1: metastasis to 1 to 3 regional lymph nodes
    • N2: metastasis to 4 or more regional lymph nodes
  • Distant metastasis (M)
    • M0: no distant metastasis
    • M1: distant metastasis
  • American Joint Committee on Cancer prognostic groups
    • Stage 0: TisN0M0
    • Stage I: T1N0M0
    • Stage IIa: T2aN0M0
    • Stage IIb: T2bN0M0
    • Stage IIIa: T3N0M0
    • Stage IIIb: T1 to 3, N1, M0
    • Stage IVa: T4, N0 to 1, M0
    • Stage IVb: any T, N2, M0 or any T, any N, M1
• By cell type
  • Adenocarcinoma (majority of cases)
  • Other types include: 
    • Squamous cell carcinoma or adenosquamous differentiation (about 5% of patients) 
    • Mesenchymal (eg, carcinosarcoma) or carcinoid differentiation 
• By histologic grade 
  • G1: well differentiated
  • G2: moderately differentiated
  • G3: poorly differentiated

What are the Clinical Features

History

• Early stage (American Joint Committee on Cancer stage I or II) Gallbladder Cancer is often detected incidentally at the time of planned cholecystectomy for presumed benign gallbladder disease
  • May be identified on pathologic review of the excised gallbladder in about 1% of patients 
• Rarely, gallbladder cancer is identified incidentally when an imaging study (eg, ultrasonogram) shows a gallbladder mass or other suspicious finding (eg, polyp larger than 1 cm) 
• Clinical presentation typically mimics biliary colic or cholecystitis
  • Early stage disease (stage I) usually does not cause tumor-related pain because the gallbladder is distensible 
  • Patients with stage II or stage III disease will most often present with acute episodic or chronic right upper quadrant abdominal pain of less than 1 month duration before diagnosis; pain may be due to gallstones rather than the tumor 
  • Other symptoms are similar to those of cholecystitis (eg, nausea and vomiting, anorexia) but are more often chronic or progressive as compared to the duration of symptoms in acute cholecystitis
• About 40% of patients report unintentional weight loss, which is more common with advanced (ie, stage III or IV) or metastatic disease 
• Tumor-associated obstruction of the extrahepatic biliary tree may be painless but result in jaundice 

Physical examination

• Findings may be normal in Gallbladder Cancer
• Gallbladder is rarely palpable on examination, most often in cases of advanced disease
• If acute cholecystitis is present, examination reflects this pathology
  • Focal right upper quadrant tenderness; less commonly, epigastric tenderness
  • Rebound tenderness, guarding, or rigidity may also be elicited
  • Positive Murphy sign, defined as inspiratory arrest owing to pain on deep palpation of the right upper quadrant
• In cases of involvement of the porta hepatis, jaundice is present and is a poor prognostic sign 

What Causes Gall Bladder Cancer?

• Specific cause uncertain, but chronic inflammation of gallbladder mucosa may result in dysplasia that progresses to carcinoma in susceptible patients 

What increases the risk of Gallbladder Cancer?

Age

• Mean age at diagnosis is 65 years; incidence of Gallbladder Cancer increases with age

Gender

• Female to male ratio of about 2 to 1 worldwide (varies by country) 
  • Higher risk in females is independent of gallstone disease 
• Risk is increased after menopause 
• Mortality rate is higher in females 

Genetics

• Genetic predisposition to lithogenic bile in certain ethnic populations suggests possible genetic link to gallbladder cancer 
• Familial risk has been observed in Swedish, Italian, and American reports, ranging from a relative risk of 2.1 to 13.9 for first-degree relatives; shared environment may be contributing factor 

Ethnicity/race

• In the United States, certain Native American populations and those of Mexican heritage have highest incidence 

Other risk factors/associations

• Conditions that result in gallbladder inflammation
  • Gallstones
    • Most patients with gallbladder cancer have (or have had) gallstones (70%-88%); however, the incidence of gallbladder cancer is small for a given person with gallstones (0.3%-3.0%) 
    • Increased risk with larger gallstones, which is a graded effect
      • Stones larger than 3 cm confer highest risk (10-fold) 
    • Increased risk with greater number, weight, and volume of gallstones 
  • Gallbladder polyps
    • Increased risk especially for those older than 50 to 60 years with polyps larger than 1 cm (considered an indication for cholecystectomy) 
    • Monitor benign-appearing polyps that are 6 to 10 mm using sonography to detect growth or other change 
  • Anomalous junction of the pancreaticobiliary ductal system 
    • Causes reflux of pancreatic fluid proximally into biliary tree
    • Associated with onset of gallbladder cancer at a young age
    • 10% to 15% of Asian patients will develop gallbladder cancer in the presence of this anomaly 
  • Gallbladder calcification
    • Older literature described up to 60% incidence of gallbladder cancer for patients with diffuse calcification pattern known as porcelain gallbladder 
    • More recent literature describes only weak association with an incidence of 2% to 3% 
  • Inflammation induced by chronic carriage of Salmonella typhi may increase risk 
• Environmental risk factors
  • Occupational exposure to chemicals in a variety of industries 
    • Petroleum refining
    • Textile industry
    • Paper milling
    • Rubber industry
    • Shoemaking
  • Cigarette smoking
  • Aflatoxin exposure may increase risk, but more study is needed to verify the association 
• Comorbidities associated with increased risk 
  • Primary sclerosing cholangitis
    • Lifetime risk of approximately 2% 
    • Screen annually for all biliary tract malignancies, including gallbladder cancer, using transabdominal ultrasonography; some centers use magnetic resonance cholangiopancreatography combined with contrast-enhanced MRI of the liver 
  • Obesity
    • Relative risk of 1.66 (stronger association in women) 
• Risk varies by region; in general, higher incidence in developing countries
  • Highest incidence is in South America, especially in the Andes region 
  • In Europe, highest rates are in Poland, the Czech Republic, and Slovakia 
  • Very high incidence in women from Delhi and South Karachi, Pakistan 
  • In some of these areas, incidence may be partly explained by prevalence of chronic typhoid carriage 

How is Gallbladder Cancer diagnosed?

• Gallbladder cancer: spectrum of appearances. – (A) and (B) Polypoid mass. (A) A large polypoid mass. (B) Examination with high-frequency linear probe shows no invasion beyond the gallbladder wall. (C) Contrast-enhanced examination confirms the solid vascular nature of the mass and rules out hepatic extension. (D) – (F) Wall thickening. (D) and (E) Extensive asymmetrical, heterogeneous wall thickening in a markedly enlarged gallbladder with abnormal flow on Doppler assessment. (F) Corresponding CT scan. (G) – (I) Invasive gallbladder cancer. (G) and (H) Huge mass replacing the gallbladder fossa and invading the liver. (H) Biliary obstruction caused by the invasive mass (arrow). (I) Corresponding CT scan.
• Patient with an asymptomatic, large calcified gallstone in the gallbladder (white arrow), with an associated soft tissue mass in the fundus (black arrow), which is concerning for malignancy.

Primary diagnostic tools

• Patients may present preoperatively (with suggestive imaging, symptoms, or signs), intraoperatively (as unexpected finding during cholecystectomy for presumed benign disease), or postoperatively (on pathology review after simple cholecystectomy) Diagnostic work-up depends on presentation 
  • Incidental finding of mass during laparoscopic cholecystectomy (most common presentation) 
    • Frozen sections of gallbladder and suspicious lymph nodes if diagnosis is not clear 
    • Intraoperative staging 
    • In cases of operative surgeon being uncertain or lacking experience with gallbladder malignancy, it is appropriate to close the patient and postpone definitive surgery 
      • In these cases, obtain multiphasic abdominal and pelvic imaging (CT or MRI scan with IV contrast material) and chest CT scan (with or without contrast enhancement) before second operation for definitive surgery
  • Incidental finding on pathologic review of resected gallbladder (early stage cancer may be difficult for surgeon to differentiate from chronic cholecystitis)
    • Careful re-review of pathology by a hepatobiliary pathology expert to check T stage and margins, with particular attention to the cystic duct margin
    • If tumor is T1a, no further evaluation is recommended 
    • If tumor is T1b or greater: 
      • Multiphasic abdominal and pelvic imaging (CT or MRI scan with IV contrast material) and chest CT scan (with or without contrast enhancement)
      • Consider staging laparoscopy
        • Relatively low-yield procedure unless tumor is poorly differentiated, tumor is stage T3, or there is any suspicion of metastatic disease on imaging that is not amenable to percutaneous biopsy 
      • If found to be unresectable, obtain microsatellite instability and/or mismatch repair testing to determine eligibility for programmed death receptor-1 blockade treatment (eg, pembrolizumab)
  • Mass suggestive of gallbladder cancer noted on imaging (eg, ultrasonogram) or patient presents with signs or symptoms suggestive of gallbladder cancer
    • Obtain 3-dimensional abdominal and pelvic imaging (multidetector multiphasic CT or MRI scan with IV contrast material) and chest CT scan (with or without contrast enhancement) to characterize the mass and evaluate for metastatic disease 
    • If jaundice is present, order cholangiography, preferably as magnetic resonance cholangiopancreatography 
    • Measurement of carcinoembryonic antigen and carbohydrate antigen 19-9 levels may be helpful; elevated levels are suggestive of gallbladder cancer but are not diagnostic 
    • Staging laparoscopy is recommended to identify radiologically occult distant metastasis 
    • If disease appears resectable based on these evaluations, biopsy is not recommended before definitive resection to minimize the risk of seeding the peritoneal cavity or the biopsy tract 
    • If disease appears unresectable and/or there is distant metastasis identified on imaging or laparoscopy, obtain tissue for: 
      • Diagnostic confirmation
      • Microsatellite instability and/or mismatch repair testing to determine eligibility for programmed death receptor-1 blockade treatment
• For all patients with suspected gallbladder cancer, order liver function tests and assessment by an experienced hepatobiliary surgeon 

Laboratory

• No laboratory test is diagnostic of gallbladder cancer
  • Obtain results of liver function tests, including measurements of synthetic capability (ie, prothrombin time, albumin and total protein levels), to help assess hepatic reserve
  • Bilirubin and alkaline phosphatase may be elevated if there is biliary obstruction by tumor
  • Carcinoembryonic antigen and carbohydrate antigen 19-9 levels may be helpful in patients in whom the diagnosis is considered preoperatively
    • Detected in serum by immunoassay 
    • Not considered sensitive or specific enough to be used individually as a screening or diagnostic test, but may be useful in monitoring if preoperative baseline is available 
    • Carcinoembryonic antigen
      • Less than 2.5 ng/mL is normal; 2.5 to 5.0 ng/mL is borderline; and greater than 5.0 ng/mL is elevated 
        • Upper reference limit in smokers is 5.0 ng/mL 
      • Sensitivity and specificity are 12% and 97% respectively 
      • Also may be elevated with inflammatory bowel disease, pancreatitis, cirrhosis, and chronic obstructive pulmonary disease 
    • Carbohydrate antigen 19-9
      • Upper limit of normal for a healthy adult is 37 units/mL 
      • Sensitivity and specificity of carbohydrate antigen 19-9 are 72% and 96% respectively 
      • May also be elevated in pancreatic carcinoma, other gastrointestinal cancers, chronic liver disease, and benign biliary tract disease 

Imaging

• Often found on transabdominal gallbladder ultrasonography done to evaluate biliary colic
  • Appearance varies with growth pattern of the tumor
    • Small masses intimate with the hepatic side of the gallbladder wall can appear as a lack of distinct separation, with the gallbladder blending into the liver
      • Abnormal appearance of the gallbladder in a patient with no history of cholecystectomy raises suspicion 
    • May show trapped gallstone (immobile stone engrossed by tumor) 
    • Malignant polypoid tumors are usually greater than 10 mm with prominent internal vascularity on contrast-enhanced ultrasonography examination 
    • Wall thickening that is extensive, asymmetrical, and heterogeneous is suggestive
  • Monitor benign-appearing polyps that are 6 to 10 mm by following sonographically to detect growth or other change 
• 3-dimensional imaging
  • Evaluates gallbladder, bile ducts, and regional lymph nodes when cancer is suspected preoperatively or when it is discovered intraoperatively with postponed definitive resection or on pathologic review 
    • Either multidetector, multiphasic CT or MRI scan of the abdomen and pelvis may be done, but MRI is preferable for visualization of masses within the gallbladder and for showing extent of biliary tract or hepatic involvement 
    • Characteristics of gallbladder cancer on 3-dimensional imaging
      • A mass replacing all or part of the gallbladder (seen in 40%-65%), often extending to the liver 
      • Wall thickening (seen in 20%-30%), which may be irregular or nodular 
      • Intraluminal polypoid lesion (seen in 15%-25%); cannot be reliably differentiated from benign polyp by imaging
    • Careful attention to regional lymph nodes is important, specifically the porta hepatis, left gastric, and aortocaval basins 
    • Overlap of findings with benign gallbladder disease can make radiologic diagnosis challenging 
  • Combined with magnetic resonance cholangiopancreatography (usually performed to evaluate patients with jaundice), offers best visualization of the bile ducts and may be useful for evaluating invasion into the hepatoduodenal ligament 
    • Mid–common bile duct obstruction in the absence of choledocholithiasis is concerning for gallbladder cancer and must be further investigated
  • Contrast-enhanced CT scan of chest is indicated for staging evaluation in all patients 
    • For cancers identified postoperatively on pathologic examination, imaging is indicated if stage Ib or greater 
• PET scan is not routinely used as it lacks sensitivity in distinguishing gallbladder cancer from cholecystitis; however, it can be useful for known malignancy to better assess for regional lymph node metastasis 

Other diagnostic tools

• Microsatellite instability testing 
  • Results determine eligibility for pembrolizumab immunotherapy for patients with disseminated disease
  • Tumor cells with defects in the ability to repair DNA mismatches are predisposed to mutation
  • Microsatellite instability is caused by defects in DNA mismatch repair proteins
  • Testing is done using polymerase chain reaction amplification of DNA regions that contain microsatellite repeats, followed by capillary gel electrophoresis
    • Can be done on either snap-frozen or formalin-fixed paraffin-embedded tissue
    • High-frequency microsatellite instability is defined as instability found in 2 or more of 5 markers
  • If high-frequency microsatellite instability is present in tumor tissue, consider pembrolizumab 

Differential Diagnosis

Here is the list of Differential Diagnosis of Gallbladder Cancer

• Gallbladder polyps. – Small size (10mm or less) and multiple tumors are features most suggestive of a benign lesion.
• Gallbladder adenoma. – Transverse image through the gallbladder shows a polypoid lesion found incidentally in a patient with mild acute cholecystitis. The lesion was a tubulovillous adenoma on resection.
• Adenomyomatosis. – The adenomyomatosis may be focal or diffuse small echogenic foci in the gallbladder wall that create a very specific comet-tail artifact.

Most common

• Gallstones are present in a majority of patients with gallbladder cancer, so the list of differential diagnoses typically consists of comorbid gallstone-related disease. The symptoms of gallbladder cancer may, in many cases, be due to biliary colic or acute cholecystitis rather than the cancer
  • Differential by clinical presentation
    • Right upper quadrant pain (without jaundice)
      • Cholelithiasis with biliary colic
        • Presents as right upper quadrant or epigastric pain that is steady and constant and radiates to the back or to the right subscapular region
          • May or may not occur after meals; nocturnal pain has also been reported
            • Episodes recur often (ranging from within hours to years)
        • Remainder of physical examination findings may be benign or there may be more diffuse upper abdominal tenderness. Other than voluntary guarding, signs of peritoneal irritation are absent
        • Results of laboratory testing are typically normal, although a mild elevation in serum alkaline phosphatase level may be present
        • Transabdominal ultrasonography is effective in the diagnosis of cholelithiasis; sensitivity and specificity is greater than 95% for the detection of gallstones greater than 1.5 mm. Order contrast-enhanced abdominal CT if there is any abnormality suspicious for malignancy 
        • Definitive differentiation of malignancy versus benign cholelithiasis can be via direct visualization during cholecystectomy but more commonly is confirmed by pathology examination of resected gallbladder
      • Acute cholecystitis
        • Manifestation of acutely inflamed and possibly infected gallbladder associated with obstruction of the gallbladder neck or cystic duct by gallstones
        • Presents as severe, unremitting pain in right upper quadrant or less commonly in epigastrium and may last several days if untreated; may have history of previous episodes of biliary colic. Fever, chills, nausea, vomiting, and anorexia are common
        • Physical examination shows focal right upper quadrant tenderness; less commonly, epigastric tenderness. Rebound tenderness, guarding, or rigidity may also be elicited with a positive Murphy sign (inspiratory arrest owing to pain on deep palpation of the right upper quadrant); a palpable mass is rarely present
        • Transabdominal ultrasonography is the primary mode of imaging but often cannot distinguish between malignancy and acute cholecystitis
          • Use axial contrast-enhanced CT and HIDA scintigraphy to aid in distinguishing acute from chronic cases and rule out differential diagnoses
          • CT imaging that does not show gallbladder mass, polypoid lesion, or wall thickening is reassuring for ruling out gallbladder cancer
        • Definitive differentiation of malignancy versus cholecystitis occurs with direct visualization during cholecystectomy and pathologic examination of resected gallbladder
    • Jaundice (with or without right upper quadrant pain)
      • Choledocholithiasis (presence of stones in the common bile duct)
        • Up to 50% of patients with common duct stones are asymptomatic 
        • Symptomatic patients may present with the following:
          • Colicky pain, usually in right upper quadrant or epigastrium, which may radiate to right shoulder; pain lasts longer than is typical for biliary colic and may be accompanied by nausea and vomiting
          • Intermittent jaundice, accompanied by acholic (pale) stools and dark urine. Pruritus usually accompanies jaundice
          • Jaundice is not usually accompanied by weight loss in benign choledocholithiasis
        • Physical examination shows right upper quadrant tenderness; laboratory abnormalities include elevated levels of serum γ-glutamyltransferase and alkaline phosphatase in majority of cases; bilirubin level may be significantly elevated
        • First line imaging is with transabdominal ultrasonography, but sensitivity is less than 50%. Dilated duct with abrupt narrowing may indicate malignancy; dilated duct with gradual tapering is consistent with benign biliary disease 
          • Magnetic resonance cholangiopancreatography is performed as next step if sonographic findings are negative for common bile duct stones and clinical index of suspicion is high
          • Review imaging carefully
            • Any mid–common bile duct obstruction is considered a gallbladder cancer until proven otherwise
            • Tumors of the gallbladder neck may infiltrate the common hepatic duct or porta hepatis
        • Definitive differentiation of malignancy versus choledocholithiasis will be with direct visualization during endoscopic retrograde cholangiography or on pathologic examination of resected gallbladder and biliary tree when resection is indicated
• Differential of abnormal gallbladder imaging findings
  • These findings may be differentiated from gallbladder cancer in some cases by additional imaging techniques but most often require cholecystectomy and histopathology to differentiate
  • Gallbladder wall thickening
    • Adenomyomatosis
      • Hyperplastic change in the gallbladder wall caused by exaggeration of invagination of the luminal epithelium (sinus pockets) and smooth muscle hypertrophy
      • Single or grouped papillomas (without malignant potential) may be scattered over a large part of the mucosal surface
      • Typically an incidental finding on imaging studies
        • Sonographically appears as focal or diffuse thickening of the gallbladder wall with internal cystic spaces
          • Comet-tail artifact due to echogenic foci is common
        • On 3-dimensional imaging, predominantly seen as fundal thickening and may show cystic spaces
      • Endoscopic ultrasonography may help to differentiate from malignancy
    • Xanthogranulomatous cholecystitis 
      • Characterized by xanthogranulomatous thickening of the gallbladder wall with increased intragallbladder pressure owing to presence of gallstones
      • Occurs predominantly in middle-aged women
      • Appears on CT scan as marked wall thickening with intramural abscess mimicking necrosis
      • May have adjacent hepatic abscess
    • Nonspecific wall thickening
      • May occur in the setting of heart failure, cirrhosis, hepatitis, and renal failure
      • Usually appears as mild diffuse thickening without nodularity or mass
  • Polypoid masses
    • Best predictors of malignancy in a sonographically identified gallbladder polyp:
      • Size larger than 10 mm 
        • Monitor stability of polyps that are 6 to 10 mm and appear benign by following sonographically at 6- to 12-month intervals 
        • Polyps larger than 10 mm require cholecystectomy owing to potential for malignant transformation 
      • Hypoechoic foci centrally within the polyp (representing vascular structures) has been shown to be significantly associated with neoplasia (sensitivity and specificity of 85% and 67%, respectively, on high-resolution transabdominal ultrasonography and 91% and 89%, respectively, on endoscopic ultrasonography) 
    • Cholesterol polyps (account for 50%-60% of polypoid masses of the gallbladder) 
      • Cholesterol-filled projections of gallbladder mucosa that protrude into the lumen without malignant potential
      • Most common pseudotumor of the gallbladder 
      • Usually asymptomatic unless they are associated with gallstones
      • Typically an incidental finding on imaging studies 
        • Sonographically, appear as multiple nonmobile ovoid filling defects that are usually smaller than 1 cm
    • Intracholecystic papillary-tubular neoplasms (formerly known as inflammatory polyps and adenomas)
      • Inflammatory polyps (account for 5%-10% of polypoid masses of the gallbladder) 
        • Small sessile lesions of granulation and fibrous tissue
        • Usually less than 10 mm; solitary in about 50% of patients. Occur as multiple lesions (2-5) in the remainder 
        • Sonographic appearance is not well defined 
      • Gallbladder adenomas (account for less than 5% of polypoid masses of the gallbladder) 
        • Benign epithelial tumors with malignant potential
        • Typically asymptomatic and noted on imaging
          • Sonographically appear as solitary, nonmobile filling defects
            • Thickening of the gallbladder wall adjacent to an adenoma suggests malignancy
            • Contrast-enhanced ultrasonography may provide additional information in differentiating benign and malignant polypoid gallbladder lesions 

How is Gall bladder cancer treated?

• If the cancer is localized and without an absolute surgical contraindication, curative resection is indicated
• Advanced cancers with locoregional spread can be considered for curative surgery by experienced surgeons in selected cases
• For patients with tumors that are not amenable to curative resection and for those with metastatic disease, treatment is palliative

Disposition

Admission criteria

• Admit to hospital for surgery and postoperative recovery
• Admission may be required for evaluation and management of associated biliary colic, choledocholithiasis, or acute cholecystitis (eg, pain, nausea and vomiting)

Recommendations for specialist referral

• Refer to an experienced hepatobiliary surgeon and center for surgical planning and surgery 
• Order postoperative evaluation of specimen by a pathologist with hepatobiliary expertise 
• A multidisciplinary team approach is recommended for advanced disease 
  • Refer to a medical oncologist for adjuvant chemotherapy and a radiation oncologist when chemoradiation therapy is considered
  • For patients with advanced disease, palliative care team involvement is appropriate
• Offer patients enrollment in clinical trials when appropriate 

Treatment Options

In the absence of absolute contraindications, consider curative surgical resection for stage I to III disease, and only selectively in stage IVa disease, as it is the only potentially curative therapy for gallbladder cancer 

• Operative management of resectable disease is by either simple or radical cholecystectomy
  • Simple cholecystectomy is excision of the gallbladder only 
  • Radical cholecystectomy is cholecystectomy with limited hepatic resection (typically involving en bloc resection of segments IVb and V) and portal lymphadenectomy 
    • Extended hepatic resections are warranted in order to obtain negative margins or when major intrahepatic biliary or vascular structures are involved
    • Resection of the common bile duct and common hepatic duct is required in cases where the cystic duct margin is positive or where gross infiltration into the biliary tree is identified
  • By stage:
    • T1a
      • Simple cholecystectomy is adequate 
    • T1b
      • Controversial; radical resection may lead to better outcome 
    • T2
      • Radical resection 
    • T3; selected patients with T4a
      • Radical resection 
• Adjuvant therapy recommendations differ between organizations and are based on limited high-quality evidence
  • Both the National Comprehensive Cancer Network and the American Society of Clinical Oncology recommend adjuvant therapy as an option for all patients following resection of gallbladder cancer; however, there is no consensus regarding optimal agents or regimen
    • National Comprehensive Cancer Network guidelines suggest either observation, systemic therapy, clinical trial, or fluoropyrimidine chemoradiation as options for patients with localized, resected (R0) gallbladder tumors: systemic therapy or clinical trial are preferred 
      • Systemic therapy; clinical trial; fluoropyrimidine chemoradiation; or fluoropyrimidine- or gemcitabine-based chemotherapy followed by chemoradiation or vice versa is recommended for patients with positive lymph nodes or margins; systemic therapy or clinical trial is preferred
    • American Society of Clinical Oncologists recommends patients with resected biliary tract cancer should be offered adjuvant chemotherapy with capecitabine for 6 months following resection of gallbladder cancer 
      • Capecitabine and chemoradiation therapy are recommended for those with microscopically positive surgical margins following resection
  • European Society for Medical Oncology states that either radiotherapy, chemoradiation, or chemotherapy alone may be offered as options for patients following resection of gallbladder cancer based on the available limited evidence and consideration of potential risks and benefits 

Treatment sequence presented by the National Comprehensive Cancer Network varies somewhat depending on whether presentation was preoperative, intraoperative during cholecystectomy for presumed benign disease, or postoperative during pathology review

• For patients with tumors discovered incidentally at cholecystectomy for presumed benign gallbladder disease
  • If discovered during laparoscopic cholecystectomy, may proceed to open resection or terminate the operation and refer to a high-volume center for definitive, radical resection 
    • Closing the patient and doing a second surgery later minimizes the risk of inadequate resection or peritoneal or port-site seeding
      • Consider neoadjuvant chemotherapy before definitive resection for locoregionally advanced disease (large mass extending into liver or nodal disease)
  • If resected tumor has negative margins (R0) and lymph nodes are negative, observation with ongoing surveillance is appropriate 
    • Alternatively, consider fluoropyrimidine- or gemcitabine-based chemotherapy, fluoropyrimidine chemoradiation, or clinical trial 
  • If resected tumor had microscopic positive margins (R1) or there was gross residual disease (R2) or positive regional lymph nodes 
    • Give fluoropyrimidine- or gemcitabine-based chemotherapy, fluoropyrimidine chemoradiation followed by fluoropyrimidine-based chemotherapy, or consider clinical trial
• For patients with tumor as incidental finding on pathology review (simple cholecystectomy has already been performed)
  • Patients with T1a tumor: observation without further treatment is sufficient 
    • Careful review of pathologic features is imperative to verify negative margins 
  • If cystic duct node is positive for tumor and imaging evaluation (and possibly staging laparoscopy) confirms resectability of residual tumor, consider neoadjuvant chemotherapy before re-resection (hepatic resection, lymphadenectomy, and possibly bile duct resection) 
    • Neoadjuvant chemotherapy regimens include 2-drug regimens (gemcitabine, capecitabine, platinum drugs, and 5-fluorouracil combinations)
  • Patients with T1b tumor or greater
    • If imaging evaluation/staging laparoscopy confirms resectability of residual tumor, proceed to re-resection to achieve negative margins (hepatic resection, lymphadenectomy, and possibly bile duct resection) 
      • Consider neoadjuvant chemotherapy (before definitive resection) for bulky or nodal disease with 2-drug regimen (gemcitabine, capecitabine, platinum drugs, and 5-fluorouracil combinations)
    • If imaging evaluation/staging laparoscopy shows tumor to be unresectable, either chemotherapy, radiation therapy, chemoradiation, or pembrolizumab (for high-frequency microsatellite instability/mismatch repair tumors) is indicated 
      • Choice of treatment depends on extent and location of disease for each patient and on institutional capabilities
• For patients presenting preoperatively with presumptive gallbladder cancer based on clinical presentation and/or suggestive finding on 3-dimensional imaging
  • If patient is jaundiced, consider preoperative biliary drainage with referral to an experienced specialist for consideration of surgery 
  • Radical cholecystectomy is recommended for resectable disease based on imaging and preoperative laparoscopy 
    • Neoadjuvant chemotherapy is not recommended in most cases but should be considered if jaundice is present
      • Fluoropyrimidine- or gemcitabine-based chemotherapy
    • If diagnosis is unclear, simple cholecystectomy with frozen section to confirm diagnosis and then definitive resection during same operation is appropriate
    • If R0 margins are obtained with negative regional lymph nodes, options include:
      • Observation with ongoing surveillance, or
      • Adjuvant fluoropyrimidine- or gemcitabine-based chemotherapy, fluoropyrimidine chemoradiation, or clinical trial (especially if presented with jaundice)
    • If margins are R1 or R2 or there are positive lymph nodes
      • Adjuvant fluoropyrimidine- or gemcitabine-based chemotherapy, fluoropyrimidine chemoradiation, or clinical trial

For nonresectable disease (ie, disease staged as N2 or M1, is accompanied by malignant ascites, or has significant involvement of the hepatoduodenal ligament or encasement of major vasculature) 

• Treatments options vary based on extent and location of disease and institutional capabilities 
  • Biliary drainage for palliation of obstructive jaundice
  • Gemcitabine-cisplatin combination therapy 
  • Other gemcitabine- or fluoropyrimidine-based chemotherapy regimen
  • Pembrolizumab (only for high-frequency microsatellite instability/mismatch repair tumors)
  • Clinical trial
  • Best supportive care
  • Entrectinib or larotrectinib for NTRK gene fusion–positive tumors

Rationale for treatment plans

• Surgery
  • Surgical resection with R0 margins is the only potentially curative therapy for gallbladder cancer
• Chemotherapy/chemoradiation
  • Neoadjuvant chemotherapy is given to inhibit rapid progression of disease that might result in futile surgery 
  • Adjuvant chemotherapy (or chemoradiation) has been associated with survival benefit in patients with biliary tract cancer (including gallbladder cancer) especially in patients with lymph node–positive disease 
  • Immunotherapy with pembrolizumab may be of benefit in the subset of patients with high-frequency microsatellite instability tumors, but there are limited clinical trial data to support this 

Outcomes

• Surgical outcomes
  • T1a tumor: near 100% long-term survival with simple cholecystectomy 
  • T1b tumor: controversial, but data suggest better outcomes with radical resection 
  • T2 tumors: better survival with radical cholecystectomy 
    • Extended hepatic resection and lymphadenectomy is beneficial in patients with T2 tumors (and in a subset of patients with T3 tumors) 
    • 5-year disease-specific survival rates more than doubled (from less than 40% to more than 80%) with radical cholecystectomy including portal lymphadenectomy as compared with simple cholecystectomy 
  • T3 and T4 tumors
    • Radical cholecystectomy with more extensive resections has not resulted in improved long-term survival except in node-negative tumors 
  • Advanced but still resectable tumor
    • Major hepatectomy and bile duct resection decrease local recurrence but also increase perioperative morbidity (53%) and are not independently associated with survival 
• Outcomes with adjuvant therapies
  • Most data are from studies with small, heterogeneous patient populations and mixed malignancy types (eg, include patients with extra- and intrahepatic cholangiocarcinoma)
  • The phase III BILCAP study shows improved overall survival for adjuvant capecitabine monotherapy in the per-protocol analysis, which lost statistical significance in the intent-to-treat analysis 
    • Based on this evidence, the American Society of Clinical Oncology recommends that patients with resected biliary tract cancer be offered adjuvant chemotherapy with capecitabine for 6 months following resection of gallbladder cancer 
  • For locally advanced unresectable and metastatic disease, the standard of care is combination chemotherapy with gemcitabine and cisplatin; however, no significant difference in overall survival has been demonstrated in trials of adjuvant gemcitabine and gemcitabine-based regimens 
    • The use of chemoradiotherapy and radioembolization or targeted therapies has not been supported by any phase III trials to date 
    • Some data support pembrolizumab for patients with high-frequency microsatellite instability tumors 
  • Studies have not found sufficient evidence to support routine use of neoadjuvant therapy in advanced disease 

Drug therapy

• Preferred regimen for unresectable or metastatic disease 
  • Gemcitabine-cisplatin
• Neoadjuvant and adjuvant therapy regimens (alternatives for unresectable or metastatic disease) 
  • Gemcitabine-oxaliplatin
  • Gemcitabine-capecitabine
  • Capecitabine-cisplatin
  • Capecitabine-oxaliplatin
  • 5-fluorouracil-cisplatin
  • 5-fluorouracil-oxaliplatin
  • Gemcitabine-cisplatin-albumin bound paclitaxel
  • Single agents
    • Gemcitabine
    • Capecitabine
    • 5-Fluorouracil
• Agent used with concurrent chemoradiation 
  • Capecitabine
  • 5-Fluorouracil
• Molecular targeted therapies
  • Pembrolizumab (for high-frequency microsatellite instability/mismatch repair tumors in patients with metastatic disease) 
  • Entrectinib or larotrectinib (for NTRK gene fusion–positive tumors in patient with metastatic disease) 
  • Other agents targeting mTOR, vascular endothelial growth factor, and epidermal growth factor receptor have been studied but have not been shown to be effective for advanced biliary tract cancers 

Nondrug and supportive care

Radiation therapy

• Benefit of radiation (usually given concurrently with chemotherapy) is uncertain and data are minimal because of the rarity of gallbladder cancer
  • A nomogram built from a model from the Surveillance, Epidemiology, and End Results Program–Medicare database can be used as a decision aid to predict which patients may benefit 
    • Subsets of patients with at least T2 or N1 disease will gain a survival benefit from adjuvant chemoradiation, and the magnitude of effect varies by patient 
• Phase II trial of adjuvant radiation therapy for resected disease (T2-T4 and/or node positive) showed benefit 
  • Gemcitabine and capecitabine followed by concurrent capecitabine and radiation therapy is effective and well tolerated with 2-year overall survival (67% and 60% in R0 and R1 margins, respectively), significantly higher than the rates expected based on historical controls 
• Unresectable disease:
  • All tumors irrespective of location may be amenable to radiation therapy (3-dimensional conformal radiation therapy, intensity-modulated radiation therapy, or stereotactic body radiation therapy) 
  • Conventionally fractionated radiation therapy with concurrent 5-fluorouracil-based chemotherapy is acceptable 
  • Dosing for stereotactic body radiation therapy is generally 30 to 50 Gy in 3 to 5 fractions. Other hypofractionated schedules of more than 5 fractions may also be used if clinically indicated 

Procedures

Cholecystectomy (simple and radical)

General explanation

• Simple cholecystectomy is excision of the gallbladder only 
• Radical cholecystectomy is, optimally, cholecystectomy with limited hepatic resection (typically involving en bloc resection of segments IVb and V) and portal lymphadenectomy, which results in negative tumor margins on all sides 
  • Lymphadenectomy includes removal of nodes in the porta hepatis, gastrohepatic ligament, and retroduodenal regions 
  • Extended hepatic resection (beyond segments IVb and V) may be required to obtain negative margins 
  • Resection of the bile duct may also be necessary in the case of direct invasion or adherent nodal disease 
• Incidentally encountered gallbladder cancers may be managed with immediate resection or by delayed resection after additional staging work-up and/or referral to a more experienced surgeon/hospital 
  • Unless extent and resectability of disease is established, delayed resection is recommended 

Indication

• Gallbladder cancer stages I to III (considered in select cases for stage IVA) without specific surgical or medical contraindication

Contraindications 

• M1 disease (eg, distant metastases to the liver, peritoneum)
• N2 disease (current American Joint Committee on Cancer staging criteria defines N status number of positive nodes, rather than which specific nodes are involved; however, involvement of these nodes is generally considered a contraindication to surgery: celiac, peripancreatic, periduodenal, or superior mesenteric lymph nodes)
• Significant involvement of the hepatoduodenal ligament
• Encasement of major vasculature

Complications

• Overall morbidity is 21% to 28% 
  • Most common complications 
    • Hemorrhage
    • Bile leak
    • Liver failure
    • Intra-abdominal abscess
    • Respiratory failure
• With extended hepatic resection and bile duct excision, perioperative morbidity is increased 
  • Not independently associated with long-term survival

Comorbidities

• Cholelithiasis in a variety of presentations (eg, biliary colic, acute cholecystitis, choledocholithiasis)

Monitoring

• For patients with resected tumor
  • Consider imaging every 3 to 6 months for 2 years if clinically indicated, then every 6 to 12 months for up to 5 years 
    • Multiphasic contrast-enhanced CT or MRI of the abdomen and pelvis
    • CT of the chest with or without contrast enhancement
  • Consider carcinoembryonic antigen and carbohydrate antigen 19-9 as clinically indicated 
    • Appropriate if carbohydrate antigen 19-9 or carcinoembryonic antigen was elevated on presentation and dropped with systemic therapy or operative resection
    • In patients without initial elevation in these tumor markers, monitoring is less useful

Complications

• Biliary obstruction
• Hepatic abscess
• Malignant ascites
• Rarely, duodenal obstruction or large-bowel obstruction due to direct invasion when peritoneal disease is present
• Death

Prognosis

• Often diagnosed at an advanced stage and has poor prognosis with overall 5-year survival of less than 5% 
• Tumor stage is strongest prognostic factor 
  • 5-year survival by stage, based on patients diagnosed with gallbladder cancer from 1989 to 1996 
    • Stage 0: 80%
    • Stage I: 50%
    • Stage II: 28%
    • Stage IIIa: 8%
    • Stage IIIb: 7%
    • Stage IVa: 4%
    • Stage IVb: 2%
• Other prognostic factors
  • Presence of jaundice
    • Associated with greater likelihood of advanced-stage disease and with decreased disease-free survival 
  • Histologic cell type
    • Adenocarcinomas are associated with better outcomes than squamous and adenosquamous cancers 
  • Histologic grade
    • Disease-specific survival better in well- or moderately differentiated versus poorly differentiated cancers 
  • Lymphovascular invasion
    • Lymphatic infiltration is associated with a 5-year survival of 4% 
    • Microscopic vascular invasion is associated with a 5-year survival of 0% 

Screening

At-risk populations

• Patients with gallbladder polyps identified on imaging
  • Gallbladder polyps are seen in about 5% to 7% of right upper quadrant sonography studies 
  • Risk is highest in polyps larger than 10 mm (45%-65% likelihood of malignancy) 
• Patients with primary sclerosing cholangitis 

Screening tests

• When a gallbladder polyp has been identified on imaging:
  • For asymptomatic polyps larger than 6 to 10 mm, perform regular transabdominal ultrasonography screening 
    • Sonography is highly accurate for gallbladder polyps; CT and MR imaging are not superior modalities 
    • American Society for Gastrointestinal Endoscopy guidelines suggest that asymptomatic patients with a 6- to 10-mm gallbladder polyp and without other risk factors for gallbladder cancer be followed by transabdominal ultrasonography every 12 months 
    • An alternative proposed algorithm suggests screening every 6 months for 1 year to ensure stability
      • Cholecystectomy if size of polyp increases 
      • Annual ultrasonography if size remains stable
    • Duration of follow-up with apparently stable gallbladder polyps has not been established, but up to 10 years has been suggested 
    • Follow-up of at least every 6 to 12 months for as long as 10 years has been suggested 
• When a patient has a diagnosis of primary sclerosing cholangitis 
  • Consider surveillance for gallbladder cancer in all adults regardless of disease stage especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age 
  • Should include imaging by ultrasonography, CT, or MRI every 6 to 12 months; also consider measurement of serum carbohydrate antigen 19-9 levels 

Prevention

• Prophylactic cholecystectomy
  • Recommended for patients with gallbladder polyp larger than 10 mm (and for any symptomatic patient with a polyp) 
  • Recommended for patients with primary sclerosing cholangitis for gallbladder polyps of any size 

References

1: Sachs TE et al: How should gallbladder cancer be managed? Adv Surg. 52(1):89-100, 2018  Cross Reference