Gallbladder Carcinoma

Published on 29/07/2015 by admin

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 Several different possible imaging appearances

– Mass completely replacing gallbladder (GB) (2/3 of cases)
– Irregular focal or diffuse GB wall thickening (20-30%)
– Intraluminal polyploid GB mass (∼ 20% of cases)
image Typically hypodense on venous phase, but may have peripheral vascularity on arterial phase
image Frequently invades liver and porta hepatis
image Bulky porta hepatis/paraaortic adenopathy common
image Most common sites of metastasis: Liver and peritoneum
image Calcified gallstones or porcelain GB may be present
• US findings

image Asymmetric GB wall thickening or a discrete polyploid, heterogeneous, moderately echogenic GB mass
image Hepatic invasion with loss of normal echogenic GB wall dividing mass from liver
image Internal color flow vascularity on color Doppler

TOP DIFFERENTIAL DIAGNOSES

• Complicated or chronic cholecystitis
• Xanthogranulomatous cholecystitis
• Metastatic disease to gallbladder
• Gallbladder polyp or adenomyomatosis

PATHOLOGY

• Major risk factors: Cholelithiasis, chronic cholecystitis, porcelain GB, and GB polyps

CLINICAL ISSUES

• Most common in elderly female patients
• Many patients are asymptomatic, with incidental diagnosis after cholecystectomy for gallstones or cholecystitis
• Very poor prognosis: 5-year survival rate of 4%

image 75% of patients have metastases at time of diagnosis
• T stage determines surgical approach (simple or extended cholecystectomy ± radical resection (liver, colon, etc.)
image
(Left) Schematic drawing of gallbladder (GB) carcinoma shows gallstones and a focal mural mass arising from the GB wall, invading the adjacent liver and obstructing the common hepatic duct.

image
(Right) Coronal CECT demonstrates a soft tissue mass image arising from the GB and extending superiorly to invade the liver and porta hepatis. Note the presence of multiple gallstones image, a known major risk factor for GB carcinoma.
image
(Left) Axial CECT demonstrates a large, enhancing polyploid mass image in the GB, in keeping with GB carcinoma. Such polyploid masses only account for roughly 20% of all GB cancers detected on CT.

image
(Right) Ultrasound demonstrates a soft tissue mass image filling the GB fundus, in keeping with a GB carcinoma. Note that the echogenic GB wall image is intact between the mass and liver, suggesting that there is no liver invasion.

TERMINOLOGY

Definitions

• Malignant epithelial neoplasm arising from gallbladder (GB) mucosa

IMAGING

General Features

• Best diagnostic clue

image Large GB mass completely replacing the gallbladder and extending into liver
image Polypoid mass within GB lumen
image Diffuse or focal irregular gallbladder wall thickening
• Location

image GB fundus and body, uncommon in cystic duct
• Size

image Variable: Smaller polypoid mass in early stage, large infiltrating lesions are more typical in later stages
• Morphology

image Large soft-tissue mass infiltrating GB fossa; polypoid mucosal mass in GB

Radiographic Findings

• Radiography

image Plain abdominal radiographs

– Calcified gallstones or porcelain GB
image Oral cholecystogram (OCG)

– Nonvisualization of GB
– Rarely pneumobilia secondary to GB enteric fistula
• ERCP

image Limited utility since GB is usually nonvisualized
image May demonstrate common hepatic duct obstruction with dilated intrahepatic ducts

CT Findings

• Accuracy of CT for GB cancer between 84-92%
• Intraluminal polyploid GB mass (∼ 20% of cases), irregular focal or diffuse GB wall thickening (20-30% of cases), or mass completely replacing GB (2/3 of cases)

image May be difficult to differentiate from primary liver mass when large mass replaces GB and invades liver
image May be difficult to differentiate from Klatskin tumor (cholangiocarcinoma) when tumor invades porta hepatis
image GB cancer presenting as wall thickening (especially when diffuse) difficult to differentiate from chronic cholecystitis; look for irregular wall thickening, metastases, and locoregional enlarged lymph nodes
image Typically a hypodense mass on portal venous phase, but may have peripheral vascularity on arterial phase

– 2-layer pattern of enhancement in thickened GB wall (hypoenhancing outer layer and hyperemic inner layer)
– May have calcifications (possibly engulfed gallstones) and cystic components (usually mucinous tumors)
• Frequent invasion of liver and porta hepatis
• Bulky porta hepatis and paraaortic lymphadenopathy common
• Most common sites of metastasis: Liver (either via direct invasion or hematogenous metastases) and peritoneum (usually in RUQ omentum)
• Calcified gallstones or porcelain GB may be present
• Adenosquamous and squamous cell carcinomas of GB tend to be larger at presentation with greater tendency for invasion of adjacent structures (especially liver)

image Possible lesser risk of distant or lymph node metastases
image Usually unresectable due to local aggressiveness

MR Findings

• MR findings parallel CT in terms of tumor morphology
• GB carcinoma usually T1 hypointense, T2 intermediate to hyperintense, and hypoenhancing on T1WI C+ images
• MR may provide some value for T-staging and may be slightly more sensitive than CT for early liver invasion
• Malignant GB lesions often show restricted diffusion

Ultrasonographic Findings

• Asymmetric GB wall thickening or a discrete polyploid, heterogeneous, moderately echogenic GB mass

image Mass may completely replace the GB making it difficult to establish site of origin
image Frequent hepatic invasion with loss of normal echogenic GB wall dividing mass from liver
• Should be immobile when patient positioning is altered
• Associated with gallstones and porcelain GB
• Usually associated with internal color flow vascularity on color Doppler ultrasound

image Lack of vascularity cannot exclude malignancy when confronted with suspicious wall thickening or mass

Nuclear Medicine Findings

• Hepatobiliary scan: Nonfilling of GB can mimic cholecystitis
• PET/CT: Most GB cancers are FDG avid, although role for PET/CT in preoperative evaluation is unclear

image May identify occult metastases and change management in ∼ 20%

Imaging Recommendations

• Best imaging tool

image US, CECT, MR
• Protocol advice

image Longitudinal and transverse images of GB fossa with both grayscale and color Doppler

DIFFERENTIAL DIAGNOSIS

Complicated or Chronic Cholecystitis

• Contracted, thick-walled, hyperemic gallbladder (frequently associated with gallstones) ± pericholecystic abscess
• May be indistinguishable from carcinoma based on imaging

Xanthogranulomatous Cholecystitis

• Rare form of GB inflammation characterized by accumulation of lipid-laden macrophages and fibrous tissue
• Usually requires histologic examination to differentiate from GB carcinoma

Metastatic Disease to GB or GB Fossa

• Melanoma may directly metastasize to GB mucosa and present as an intraluminal mass or focal thickening
• Hepatocellular carcinoma and other hepatic tumors may secondarily invade GB
• Several tumors may spread to porta hepatis lymph nodes (especially GI tract malignancies and lymphoma) and mimic pattern of spread for GB carcinoma

GB Polyp

• Nonshadowing, moderately echogenic, nonmobile mucosal mass ± internal color flow vascularity on Doppler
• Risk of malignancy directly related to polyp size: Most polyps under 1 cm have low risk of malignancy

Adenomyomatosis

• Localized or diffuse gallbladder wall thickening with “comet tail” artifact
• May rarely present as discrete mass at fundus

PATHOLOGY

General Features

• Etiology

image Risk factors (mostly related to chronic GB inflammation): Cholelithiasis, chronic cholecystitis, chronic infection (Salmonella), porcelain GB, GB polyps, abnormal pancreaticobiliary duct junction (seen with choledochal cysts), obesity

– 70-90% have cholelithiasis, which is strongly associated with GB carcinoma

image ↑ risk with larger stones (> 3 cm increases risk by 10x) and long duration of gallstone disease
– Strength of association between porcelain GB and GB carcinoma is controversial, although likely greater risk with irregular, discontinuous GB wall calcification
– Highest risk of GB carcinoma with GB polyps > 2 cm
– Abnormal pancreaticobiliary junction (with pancreatic duct directly draining into common bile duct) increases risk of GB carcinoma even in absence of choledochal cyst

image Major risk for GB carcinoma in Asian populations
• Genetics

image Adenoma-carcinoma sequence in GB carcinoma is less certain compared to colon cancer

– KRAS and CTNNB1 gene mutations may play a role, with possible familial predilection for GB cancer
• Associated abnormalities

image Gallstones (> 70%)
image Chronic cholecystitis
image Porcelain GB (4-60%)
image Ulcerative colitis, rarely Crohn disease
image Primary sclerosing cholangitis
image Familial polyposis coli

Staging, Grading, & Classification

• Nevin staging system

image Stage I: Carcinoma confined to mucosa
image Stage II: Mucosal and muscularis involvement
image Stage III: Serosal extension
image Stage IV: Transmural involvement with positive cystic duct nodes
image Stage V: Invasion into liver, distant organ metastasis, or nodal metastases
• AJCC TNM staging system

image Preferred staging system: Better correlation with prognosis (particularly T stage, which has high correlation with prognosis and treatment)
image Strong correlation between lymph node/distant metastases and patient’s T stage
image T1 tumors: Confined to lamina propria or muscular layer of GB wall
image T2 tumors: Extending into perimuscular connective tissue (but not serosa)
image T3 tumors: Extends beyond GB wall into serosa, liver, or other adjacent organs
image T4 tumors: Tumor invades main portal vein, hepatic artery, or 2 extrahepatic structures/organs

Gross Pathologic & Surgical Features

• Early stage: Polypoid mucosal mass
• Late stage: Scirrhous infiltrating mass extending from GB wall to obliterate GB fossa and invade liver; porta hepatis adenopathy
• Direct invasion of liver, duodenum, stomach, bile duct, pancreas, right kidney
• Lymphatic spread to porta hepatis, peripancreatic and retroperitoneal nodes
• Intraperitoneal spread common with ascites, omental nodules, peritoneal implants
• Hematogenous spread (late in clinical course) to lungs, liver, bones
• Perineural invasion common

Microscopic Features

• 90% are adenocarcinoma
• Less common subtypes include squamous, adenosquamous, small cell, lymphoma, and sarcoma

CLINICAL ISSUES

Presentation

• Most common signs/symptoms

image Many patients are asymptomatic, with incidental diagnosis of tumor on pathologic examination after cholecystectomy for gallstones or cholecystitis

– May account for ∼ 50% of all diagnosed GB cancers
image Patient symptoms include RUQ pain, anorexia, nausea, vomiting, weight loss, and jaundice
• Other signs/symptoms

image  
• Clinical profile

image ↑ CEA and CA19-9 (lack sensitivity and specificity)
image ↑ bilirubin/alkaline phosphatase with biliary obstruction

Demographics

• Age

image Usually elderly patients (mean 65 years)
• Gender

image M:F = 1:3
• Epidemiology

image Wide geographic variability paralleling prevalence of cholelithiasis and biliary tract infections

– Higher incidences in South America and Asia
image 6th most common GI cancer and most common biliary tract malignancy

– Incidence of 1-2 cases per 100,000 people
– 6,500 deaths per year in USA
– 9x more common than extrahepatic cholangiocarcinoma

Natural History & Prognosis

• Spreads by local invasion to liver, nodal spread to porta hepatis and paraaortic nodes, and hematogenous spread to liver and peritoneum
• Very poor prognosis: 5-year survival rate of 4%

image 75% of patients have metastases at time of diagnosis
image Median survival for stage I-III: 12 months
image Median survival for stage IV: 6 months

Treatment

• Stage I or II (T1-T2, N0, M0) tumors resectable with curative intent; stage III tumors (T3 or T1-2, N1) usually (but not always) unresectable; stage IV almost always unresectable (T4 or N2 or M1)
• T stage critical for determining surgical approach

image T1 lesions treated with simple cholecystectomy
image T2 lesions: Extended cholecystectomy (GB removed with portions of liver around GB fossa)

– If detected incidentally, repeat surgery needed to assess for residual disease (T2/T3 tumors)
image T3 or T4 tumors: Extended cholecystectomy ± further resection (liver, colon, etc.) for local invasion
• Unresectable cancers (due to local invasion or metastatic disease) treated with stent for palliation of biliary obstruction and systemic chemotherapy

DIAGNOSTIC CHECKLIST

Consider

• GB cancer when confronted by large mass replacing GB and invading liver
• GB cancer when confronted by bulky porta hepatis and paraaortic lymphadenopathy or carcinomatosis (especially in RUQ)

Image Interpretation Pearls

•  
image
(Left) Axial CECT demonstrates a GB cancer invading both the liver image and the adjacent descending duodenum image. If considered resectable, such a cancer would undoubtedly require an extended cholecystectomy with radical resection.

image
(Right) Axial CECT demonstrates a mass in the GB fossa image directly invading the liver image. In many cases, such as this, the site of origin for the mass can be difficult to determine.
image
(Left) Axial CECT shows extensive circumferential wall thickening of the GB. This was prospectively felt to represent xanthogranulomatous cholecystitis, but was found to be GB carcinoma at surgery.

image
(Right) Ultrasound image shows a GB fossa mass image and a shadowing stone image. The mass is inseparable from the adjacent liver. CT (not shown) demonstrated local invasion of the central liver by GB carcinoma.
image
(Left) Axial CECT shows marked irregular GB wall thickening image, direct liver invasion image, and peripancreatic/portocaval image and retroperitoneal image adenopathy. Bulky lymphadenopathy in these locations is typical for GB carcinoma.

image
(Right) Axial CECT demonstrates a large hepatic hypodense mass. While a primary hepatic tumor is possible, note the gallstone image at its center and the failure to visualize a GB. This was a GB cancer with extensive invasion of the liver.
image
Axial CECT demonstrates a large hypodense mass infiltrating the GB fossa and invading the liver image. The GB is also seen image.

image
Transverse ultrasound of a patient with GB carcinoma shows a large hypoechoic mass obliterating the GB. Note the gallstone image.
image
Transverse ultrasound of GB carcinoma invading the liver demonstrates a hypoechoic mass infiltrating the GB fossa and invading the right and left lobes of the liver image.
image
Axial CECT shows invasive GB carcinoma. Note the hypodense mass invading the liver image and infiltrating along the portal vein image.
image
Axial CECT in a 74-year-old woman presenting with RUQ pain and elevated alkaline phosphatase and bilirubin levels demonstrates a hypodense mass image extending from the GB wall and invading the right lobe of the liver.
image
Axial CECT in an 81-year-old man who presented with weight loss and a palpable mass in the RUQ demonstrates a hypodense mass emanating from the GB wall image.
image
Axial CECT in the same patient illustrates direct invasion of the liver by the GB carcinoma image. Direct extension of GB carcinoma into the liver precludes surgical resection.
image
Gross pathologic section of a central liver specimen from a 55-year-old woman with confirmed invasive GB adenocarcinoma shows focal GB wall thickening image and direct invasion of the adjacent liver by tumor image, a typical pattern of local spread of GB carcinoma. The GB lumen is filled with stones.
image
Preoperative CECT of the same patient shows subtle thickening of the wall of the GB fundus image, several adjacent partially calcified stones image, and focal invasion of the medial segment image.
image
T1WI C+ FS MR of the same patient shows local invasion of the medial segment image. Recent work has suggested that delayed enhanced MR may play a role in staging early-stage (T1, T2) disease, although most patients with GB carcinoma present with at least transerosal (T3) tumor, as in this case.

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