Laboratory Studies

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.

Imaging Studies

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]

Procedures

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.

Histologic Findings

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

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)

Stage	T	N	M
0	Tis	N0	M0
I	T1	N0	M0
IIA	T2a	N0	M0
IIB	T2b	N0	M0
IIIA	T3	N0	M0
IIIB	T1-3	N1	M0
IVA	T4	N0-1	M0
IVB	Any T	N2	M0
IVB	Any T	Any N	M1

Treatment & Management

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