Gallbladder carcinoma

In the United States, Gallbladder Carcinoma (GBC) is the fifth most common gastrointestinal (GI) cancer, and the most common involving the biliary tract; fewer than 5000 new cases are diagnosed each year in the United States.

• The majority are found incidentally in patients undergoing exploration for cholelithiasis; a tumor will be found in 1 to 2 percent of such cases.
  
• The poor prognosis associated with GBC is thought related to advanced stage at diagnosis, which is due both to the anatomic position of the gallbladder, and the vagueness and nonspecificity of symptoms.

EPIDEMIOLOGY

• High rates of GBC are seen in South American countries, particularly Chile, Bolivia, and Ecuador, as well as some areas of India, Pakistan, Japan and Korea.
  • In Chile, mortality rates from GBC are the highest in the world.
    
  • These populations all share a high prevalence of gallstones and/or salmonella infection, both recognized risk factors for GBC.

• Worldwide, there is a prominent geographic variability in GBC incidence that correlates with the prevalence of cholelithiasis.

Gallbladder carcinoma affects women three times more often than men and its incidence increases steadily with age, with a steep rise beyond the age of sixty.

• The incidence of gallbladder cancer is higher in certain ethnic groups, mirroring the incidence of cholelithiasis in these groups.
  
• Alaskan and American Indian natives have a frequency of gallbladder cancer that is six times that of the rest of the country.
• GBC is more common in Caucasians than in blacks

In the United States, however, the incidence and mortality rates of gallbladder cancer have been decreasing since 1970, related at least in part to increasing numbers of cholecystectomies performed annually for gallbladder disease in the United States.

RISK FACTORS
Gallstone disease

• Gallstones are present in 70 to 90 percent of patients with GBC, and a history of gallstones appears to be one of the strongest risk factors for the development of GBC.
• Despite the increased risk of GBC in patients with gallstones, the overall incidence of GBC in patients with cholelithiasis is only 0.5 to 3 percent.
  
• The risk is higher with larger gallstones (in one study, patients with stones larger than 3 cm had a 10-fold higher risk of GBC compared to those with stones <1>

Cholecystoenteric fistula

• There is a 15% incidence of gallbladder cancer in patients with a history of a cholecystoenteric fistula and the presence of Mirizzi’s syndrome.

Porcelain gallbladder

• Porcelain gallbladder is an uncommon manifestation of chronic cholecystitis that is characterized by intramural calcification of the gallbladder wall.
  
• It is associated with cholelithiasis in more than 95 percent of cases.
  
• As with other gallstone-related conditions, these patients are at increased risk of GBC.
  
• The reported incidence of GBC in patients with a porcelain gallbladder ranges from 12.5 to 60 percent.

Gallbladder polyps

• Gallbladder polyps are outgrowths of the gallbladder mucosal wall that can be benign or malignant, and benign lesions are further classified as nonneoplastic (eg, cholesterol and inflammatory polyps, adenomyomas) or neoplastic (eg, adenomas, leiomyomas).

• The most common benign neoplastic lesion is an adenoma, a glandular tumor composed of cells resembling biliary tract epithelium.
  
• It is unclear whether adenomatous polyps represent a premalignant lesion, and if so, the frequency with which they progress to carcinoma.
  
• Unlike GBC, gallbladder polyps tend not to occur in patients with cholelithiasis, chronic inflammation is generally absent, and cancer-related molecular changes that are seen in GBCs have not been identified in adenomas.
  
• Nevertheless, larger polyps are more likely to contain foci of invasive cancer, and some studies suggest a correlation between the presence of gallbladder polyps and the risk of GBC.

Chronic infection

• Salmonella
  • In endemic settings, approximately 1 to 4 percent of acutely infected individuals become chronic asymptomatic carriers of salmonella typhi (S. typhi).
    
  • Several reports suggest an association between chronic S. typhi carriage and elevated risk of GBC.
    
  • A prospective case control study of patients with carcinoma of the gallbladder and gallstones (cases) or gallstones alone (controls) identified the S. typhi carrier state as an independent risk factor for carcinoma of the gallbladder (OR=14).
    
  • Because chronic carriage occurs more often in individuals with cholelithiasis, gallstones are thought to represent a potential nidus for ongoing infection.

• Helicobacter
  • Helicobacter colonization of the biliary epithelium (particularly H. bilis) has been implicated in the pathogenesis of gallbladder disease including gallbladder cancer based upon detection of Helicobacter-derived cytotoxins and surface proteins using sensitive molecular and immunohistochemical techniques.
    
  • The strength of this association requires further clarification.

Congenital biliary cysts

• Biliary cysts are associated with an increased risk of cancer, particularly cholangiocarcinoma.
  
• The incidence of malignancy varies with age.
  
• In a 1983 review of all published series of biliary cysts, the incidence of cancer was 0.7 percent in patients under 10 years of age, 6.8 percent in patients 11 to 20 years of age, and 14.3 percent in patients over 20 years of age.
  
• An incidence as high as 50 percent has been reported in older patients.
  
• At least one study suggests that the increased incidence of carcinoma in biliary cysts is confined to patients with an anomalous pancreaticobiliary duct junction.

Abnormal pancreaticobiliary duct junction

• Anomalous pancreaticobiliary duct junction is a rare anatomic variation in which the pancreatic duct drains into the common bile duct, resulting in a long common channel (usually over 2 cm in length).
  
• This condition may represent failure of the embryological ducts to migrate fully into the duodenum.
  
• This condition is most prevalent in Asians populations, mostly Japanese.

The long common channel may predispose to reflux of pancreatic juice into the biliary tree, since the ductal junction lies outside of the sphincter of Oddi.

• Elevated sphincter of Oddi pressures have been documented in anomalous pancreaticobiliary duct junction, and could also promote pancreaticobiliary reflux.
  
• The result is increased amylase levels in bile, intraductal activation of proteolytic enzymes, alterations in bile composition, and presumed biliary epithelial damage, inflammation, ductal distension, and cyst formation.

• Anomalous pancreaticobiliary duct junction appears to increase the risk of biliary and pancreatic malignancy even in patients without a biliary cyst or ductal dilation.
  
• Gallbladder cancer is the most common malignancy seen in patients with anomalous pancreaticobiliary duct junction and no bile duct cyst.
  
• As a result, prophylactic cholecystectomy is recommended in affected patients.

The molecular pathogenesis of GBC arising in patients with an anomalous pancreaticobiliary duct junction appears to be different from that underlying the development of GBC in the setting of gallstone disease.

Medications

Some drugs have also been implicated in biliary carcinogenesis, including

• methyledopa,
  
• oral contraceptives, and
  
• isoniazid.

Others have found no convincing evidence for an association between oral contraceptive use and GBC.

Carcinogen exposure

• Evidence is accumulating that carcinogen exposure may also be involved in the etiology of GBC. An increased risk of GBC has been described in workers in the oil, paper, chemical, shoe, textile, and cellulose acetate fiber manufacturing industries, and in miners exposed to radon.

MOLECULAR PATHOGENESIS

Differences in the demographics, clinical presentation, and gender distribution suggest that there are two key pathways to developing GBC in patients with cholelithiasis and anomalous pancreaticobiliary duct junction.

The main mechanism involves cholelithiasis and resultant cholecystitis, and seems to be the driving force in most regions of the world where GBC is strongly associated with gallstone disease, female gender bias, and age over 65.

• It is hypothesized that chronic irritation of the gallbladder mucosa over a period of years may predispose to malignant transformation, or act as a promoter for carcinogenic exposure or genetic predisposition.
  
• In keeping with this hypothesis, bile samples from patients in endemic areas are more mutagenic than those from patients from low incidence areas.
  
• Despite these data, there is no conclusive evidence linking bile composition to GBC.

A second mechanism involves anomalous pancreaticobiliary duct junction, which is associated with a relatively high proportion of cases of GBC in Japan.

• Cancers associated with this condition occur at a younger age, show less female gender bias, and have a lower incidence of associated cholelithiasis.

• There are also histologic and molecular differences in GBCs associated with an anomalous pancreaticobiliary duct junction and those associated with gallstones, providing further evidence that two distinct pathogenetic pathways are involved.
  • GBCs arising in Japan in the setting of an anomalous pancreaticobiliary duct junction are characterized by K-ras mutations and relatively late onset of p53 mutations.
    
  • By contrast, in Chilean patients with cholelithiasis and chronic cholecystitis, K-ras mutations are rare, while p53 mutations arise early during multistage pathogenesis.

Multistage pathogenesis

Most epithelial cancers are preceded by a series of histologic and molecular changers that evolve over a period of several years or decades.

• Similar to other GI tract adenocarcinomas, adenocarcinomas involving the gallbladder progress from dysplasia, to carcinoma in situ (CIS), and then to invasive cancer.
  
• The molecular changes that characterize these sequential changes are less well characterized than those in colorectal cancer.

• Preneoplastic changes can be found in the mucosa adjacent to over 90 percent of GBCs, and they are relatively frequent in routine cholecystectomy specimens.
  
• The entire sequence appears to take approximately 15 years.
  
• metaplasia is a rare premalignant lesion found in association with invasive squamous cell GBC.

By contrast, in both adults and children with an anomalous pancreaticobiliary duct junction, epithelial hyperplasia with a papillary or villous appearance is present in 39 to 61 percent of cases, and is thought to represent a premalignant histologic change in the gallbladder mucosa. Hyperplasia then progresses to dysplasia, similar to the usual form of GBC.

CLINICAL FEATURES

The symptoms of gallbladder cancer are typically those of benign gallbladder disease. Common symptoms include right upper quadrant abdominal pain, nausea, and fatty food intolerance.
More advanced symptoms include jaundice, anorexia, and weight loss.

Rarely, patients present with extraabdominal metastases, hepatomegaly, a palpable mass, ascites, or paraneoplastic syndromes (eg, ectopic hormone secretion or acanthosis nigricans).

DIAGNOSTIC MODALITIES

• Given the nonspecific presentation of patients with gallbladder carcinoma, the disease is difficult to diagnose preoperatively.
  
• Accordingly, the disease is usually diagnosed either incidentally after cholecystectomy or at a very advanced stage.
  
• If a gallbladder cancer is suspected preoperatively, usually as a result of an abnormally thickened gallbladder wall or the presence of a gallbladder mass on ultrasound, then further investigation with contrast-enhanced computed tomography scan or magnetic resonance imaging is warranted.
  
• These imaging modalities are critical in the determination of resectability, providing information about the local extent of disease, including portal vascular invasion, as well as the presence of lymphadenopathy and liver metastases.
  
• At The University of Texas M. D. Anderson Cancer Center, we perform percutaneous fine needle aspiration preoperatively to confirmthe diagnosis of gallbladder carcinoma in order to determine the extent of the planned surgical resection and any associated treatment, including portal vein embolization and neoadjuvant chemoradiation.

Ultrasound

• Findings that are suggestive but not diagnostic of GBC include mural thickening or calcification, a mass protruding into the lumen, a fixed mass in the gallbladder, loss of the interface between the gallbladder and liver, or direct liver infiltration.

• Small polypoid lesions within the gallbladder may represent adenomas, papillomas, cholesterolosis, or carcinomas.
  • Polyps over 1 cm in diameter are more likely to contain an invasive cancer than smaller ones.

Endoscopic ultrasound

Endoscopic ultrasonography (EUS) is more accurate for imaging the gallbladder than is extracorporeal US. It is useful both in the differential diagnosis of gallbladder polyps, and in staging tumor extent.

CT and MRI

• On CT, GBC can appear as a polypoid mass protruding into the lumen or completely filling it, a focal or diffuse thickening of the gallbladder wall, or a mass in the gallbladder fossa with the gallbladder itself being indiscernible; liver invasion, suspected nodal involvement, or distant metastases may be shown.

• CT is less helpful in distinguishing benign from malignant polyps.
  
• In contrast, dynamic MRI and MR cholangiopancreatography (MRCP) can help to differentiate benign from malignant gallbladder lesions in equivocal cases, and provide information as to disease extent.
  
• MRI is particularly useful for visualizing invasion into the hepatoduodenal ligament, portal vein encasement, and lymph node involvement.

Cholangiography

These procedures may be helpful in planning the surgical procedure as they may indicate tumor growth in intrahepatic biliary ducts or in the common bile duct.

Laboratory studies

• Laboratory studies are typically unremarkable unless the patient has developed obstructive jaundice an elevated alkaline phosphatase or serum bilirubin may be related to bile duct obstruction.
• Unfortunately, there are no reliable tumor markers, including CEA and CA 19-9 levels which are often elevated, but not diagnostically useful because they lack specificity and sensitivity.

HISTOLOGY

• The majority are adenocarcinomas, although other histologic types are occasionally found, including small cell cancer, squamous cell carcinoma, lymphoma, and sarcoma.
  
• Grossly, GBC can appear infiltrative, nodular, papillary, or a combination of these morphologies.
  
• Papillary carcinomas, which can sometimes fill the entire gallbladder, have the most favorable prognosis.

• Adenocarcinomas originate as mucosal lesions, invading the gallbladder wall as they grow.
  
• The lack of a well-defined muscularis layer permits early vascular, lymphatic, and neural invasion.
  
• Tumors frequently extend outside of the gallbladder, invading adjacent organs, particularly the liver, as they grow.

STAGING

Nevin staging system — Originally described in 1976, the Nevin staging system for GBC includes five stages that are defined as follows :

Stage I — Intramucosal only

Stage II — Involvement of mucosa and muscularis

Stage III — Involvement of all three layers

Stage IV — Involvement of all three layers and the cystic lymph node

Stage V — Involvement of liver by direct extension or metastases to any other organ.

TNM Staging

Primary tumor (T)

TX -Primary tumor cannot be assessed

T0 -No evidence of primary tumor

Tis -Carcinoma in situ

T1 -Tumor invades lamina propria or muscle layer

T1a -Tumor invades lamina propria

T1b -Tumor invades muscle layer

T2 -Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver

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, or pancreas, omentum or extrahepatic bile ducts

T4 -Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

Regional lymph nodes (N)

NX -Regional lymph nodes cannot be assessed

N0 -No regional lymph node metastasis

N1 -Regional lymph node metastasis

Distant metastasis (M)

MX -Distant metastasis cannot be assessed

M0 -No distant metastasis

M1 -Distant metastasis

Stage grouping

Stage 0 -Tis N0 M0

Stage IA -T1 N0 M0

Stage IB -T2 N0 M0

Stage IIA -T3 N0 M0

Stage IIB -T1 N1 M0, T2 N1 M0, T3 N1 M0

Stage III -T4 Any N M0

Stage IV -Any T Any N M1