(Radiographics. 2001;21:295-314.)
© RSNA, 2001
Gallbladder Carcinoma: Radiologic-Pathologic Correlation1
Angela D. Levy, LTC, USA, MC,
Linda A. Murakata, CDR, USN, MC and
Charles A. Rohrmann, Jr, MD
1 From the Departments of Radiologic Pathology (A.D.L., C.A.R.), and Hepatic and Gastrointestinal Pathology (L.A.M.), Armed Forces Institute of Pathology, 6825 16th St NW, Bldg 54, Rm M-121, Washington, DC 20306-6000; the Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (A.D.L.); and the Department of Radiology, University of Washington, Seattle (C.A.R.). Received; revision requested; revision received; accepted. Address correspondence to A.D.L. (e-mail: levya@afip.osd.mil).
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Abstract
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Primary carcinoma of the gallbladder is an uncommon, aggressive malignancy that affects women more frequently than men. Older age groups are most often affected, and coexisting gallstones are present in the vast majority of cases. The symptoms at presentation are vague and are most often related to adjacent organ invasion. Therefore, despite advances in cross-sectional imaging, early-stage tumors are not often encountered. Imaging studies may reveal a mass replacing the normal gallbladder, diffuse or focal thickening of the gallbladder wall, or a polypoid mass within the gallbladder lumen. Adjacent organ invasion, most commonly involving the liver, is typically present at diagnosis, as is biliary obstruction. Periportal and peripancreatic lymphadenopathy, hematogenous metastases, and peritoneal metastases may also be seen. The vast majority of gallbladder carcinomas are adenocarcinomas. Because most patients present with advanced disease, the prognosis is poor, with a reported 5-year survival rate of less than 5% in most large series. The radiologic differential diagnosis includes the more frequently encountered inflammatory conditions of the gallbladder, xanthogranulomatous cholecystitis, adenomyomatosis, other hepatobiliary malignancies, and metastatic disease.
Index Terms: Gallbladder, neoplasms, 762.321
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LEARNING OBJECTIVES FOR TEST 1
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After reading this article and taking the test, the reader will be able to:
- Define the clinical features and risk factors associated with gallbladder carcinoma.
- Enumerate the varied radiologic features of carcinoma of the gallbladder.
- Describe the patterns of spread of carcinoma of the gallbladder.
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Introduction
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Primary carcinoma of the gallbladder is an uncommon malignancy with a distinctive demographic and geographic distribution. In the United States, it is the sixth most common gastrointestinal malignancy, following cancer of the colon, pancreas, stomach, liver, and esophagus. It is estimated that 7,000 new cases of extrahepatic biliary cancers—most of them carcinomas of the gallbladder—are diagnosed annually (1).
Gallbladder carcinoma is highly lethal, as anatomic factors promote early local spread. The ease by which this tumor invades the liver and surrounding structures including the biliary tree contributes to its high mortality. The median survival is 6 months, indicating that the majority of patients present with advanced disease.
Despite the widespread use of modern imaging techniques, early diagnosis is rare because there are no specific signs and symptoms, and many gallbladder carcinomas are not diagnosed preoperatively. This article reviews and illustrates the pathologic and radiologic spectrum of gallbladder carcinoma and its differential diagnosis.
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Clinical Features
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Epidemiology
Gallbladder carcinoma is three times more common in women than men. Higher prevalences have been reported from New Mexico, Bolivia, Chile, Israel, and northern Japan (2). It has also been reported that ethnic groups with an increased prevalence of cholelithiasis (eg, Native Americans and Hispanic Americans) have a greater risk of developing gallbladder carcinoma (3),(4). In addition, a recent review of the National Cancer Database revealed that white women were affected more frequently in the cases reported in the United States from 1989 to 1995 (5). The frequency of diagnosis increases with age; the average age at presentation is 72 years, and the median age is 73 years (6).
Risk Factors
Epidemiologic studies have shown that female sex, age, postmenopausal status, and cigarette smoking are risk factors (7). Ethnic origin, increased body mass, and physician-diagnosed typhoid are risk factors in the high-incidence populations of La Paz, Bolivia, and Mexico City, Mexico (8). It is postulated that chronic Salmonella typhi infection is associated with bile carcinogens and contributes to an increased risk of hepatobiliary carcinoma (9) and gallbladder carcinoma (10). Exposure to chemicals used in the rubber, automobile, wood finishing, and metal fabricating industries has been associated with an increased risk of gallbladder carcinoma (11),(12).
Cholelithiasis is a well-established risk factor for the development of gallbladder carcinoma (13), and gallstones are present in 74%–92% of affected patients (14). Gallstones cause chronic irritation and inflammation of the gallbladder, which leads to mucosal dysplasia and subsequent carcinoma (15). Porcelain gallbladder is an uncommon condition in which there is diffuse calcification of the gallbladder wall, and 10%–25% of patients with this condition have gallbladder carcinoma (16).
Several pathologic and congenital anatomic anomalies are associated with a higher prevalence of gallbladder carcinoma, compared with that in the general population. These conditions include congenital cystic dilatation of the biliary tree, choledochal cyst (17),(18), anomalous junction of the pancreaticobiliary ducts (with or without a coexistent choledochal cyst) (19)–(22), and low insertion of the cystic duct (23). Mucosal metaplasia and consequent carcinoma are postulated to occur in response to chronic biliary reflux of pancreatic secretions (14).
Gallbladder abnormalities are frequently seen in patients with primary sclerosing cholangitis, and in one study of these patients, 41% had intrinsic gallbladder abnormalities, with 4% of them having benign or malignant neoplasms (24). Bile duct dysplasia can be found histologically in patients with primary sclerosing cholangitis, and it is thought to be a precursor to cholangiocarcinoma (25) and gallbladder carcinoma (26). Approximately 5%–10% patients with primary sclerosing cholangitis develop cholangiocarcinoma (27). Although the risk of gallbladder carcinoma in these patients is unknown, the association is mentioned throughout the medical literature (24),(26),(28),(29).
Clinical Diagnosis
The diagnosis of gallbladder carcinoma is usually unsuspected. Early-stage carcinoma is typically diagnosed incidentally because of inflammatory symptoms related to coexistent cholelithiasis or cholecystitis. One percent of patients undergoing cholecystectomy for cholelithiasis has an incidental gallbladder carcinoma (30).
The majority of patients with gallbladder carcinoma present with advanced disease. Symptoms are typically indolent. Chronic abdominal pain, anorexia, or weight loss are common initial complaints (31),(32). Physical examination may demonstrate a palpable mass, hepatomegaly, and jaundice. Jaundice occurs more frequently as a result of malignant obstruction of the biliary tree rather than hepatic metastasis or coexistent choledocholithiasis (14). Elevated serum levels of 
-fetoprotein and carcinoembryonic antigen have been reported in association with gallbladder carcinoma (33)–(35).
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Pathologic Features
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Histologic Features
The normal gallbladder wall is composed of four layers: mucosa, lamina propria, an irregular muscle layer, and connective tissue (Fig 1). The surface epithelium is composed of a single layer of columnar epithelium with basal nuclei and eosin-ophilic cytoplasm. There is no muscularis mucosa or submucosa. Along the hepatic surface, the connective tissue is continuous with the interlobular connective tissue of the liver.
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Figure 1. Normal gallbladder. Photomicrograph (original magnification, x2; hematoxylin-eosin stain) shows the mucosa as a single layer of columnar epithelium with underlying lamina propria (solid arrows), irregular muscle layer (open arrows), and connective tissue (*).
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Gallbladder carcinomas are epithelial in origin and account for 98% of all gallbladder malignancies. The remainder are sarcomas, lymphomas, carcinoid, metastases, and other unusual malignancies. Adenocarcinomas account for 90% of gallbladder carcinomas and are characterized by glands lined by cuboidal or columnar cells, which may contain mucin. They may be well, moderately, or poorly differentiated, depending on the degree of gland formation (Fig 2). There are several histologic variants of adenocarcinoma recognized: papillary, intestinal, mucinous, signet-ring cell, and clear cell (36). Many tumors contain more than one histologic variant. The frequency of the most common histologic variants of gallbladder carcinoma reported to the Surveillance, Epidemiology, and End Results program from 1977 to 1986 is listed in Table 1 (6).
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Figure 2a. (a) Well-differentiated adenocarcinoma. Photomicrograph (original magnification, x100; hematoxylin-eosin stain) shows this well-differentiated adenocarcinoma is composed of variable-sized glands (arrows) that infiltrate the wall of the gallbladder. The glands are surrounded by a desmoplastic stroma. (b) Moderately well-differentiated adenocarcinoma. Photomicrograph (original magnification, x200; hematoxylin-eosin stain) shows mucosa lined by highly atypical epithelium consistent with high-grade dysplasia. Below the surface are malignant glands (arrows) and small clusters of tumor cells infiltrating the lamina propria. The stroma is scant, and there is a mild infiltrate of acute and chronic inflammatory cells.
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Figure 2b. (a) Well-differentiated adenocarcinoma. Photomicrograph (original magnification, x100; hematoxylin-eosin stain) shows this well-differentiated adenocarcinoma is composed of variable-sized glands (arrows) that infiltrate the wall of the gallbladder. The glands are surrounded by a desmoplastic stroma. (b) Moderately well-differentiated adenocarcinoma. Photomicrograph (original magnification, x200; hematoxylin-eosin stain) shows mucosa lined by highly atypical epithelium consistent with high-grade dysplasia. Below the surface are malignant glands (arrows) and small clusters of tumor cells infiltrating the lamina propria. The stroma is scant, and there is a mild infiltrate of acute and chronic inflammatory cells.
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The papillary adenocarcinoma consists of branching fibrovascular stalks lined by atypical cuboidal or columnar cells (Fig 3). Papillary carcinomas tend to fill the lumen of the gallbladder before invading the gallbladder wall; therefore, they are associated with a better prognosis than other variants (Table 1) (6). The invading portion of the tumor typically forms tubular structures rather than papillae. Both patterns may be seen in metastatic deposits.
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Figure 3. Invasive papillary adenocarcinoma. Photomicrograph (original magnification, x20; hematoxylin-eosin stain) shows tumor invasion through the muscle layer and into the subserosal adipose tissue (arrowhead). The tumor is adjacent to large vessels (arrow) and nerves in the perimuscular connective tissue. The gallbladder wall is thickened and fibrotic.
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The intestinal type adenocarcinoma resembles intestinal epithelium and is believed to be a variant of well-differentiated adenocarcinoma. This category has two subtypes, which are characterized by the appearance of the intestinal glands: (a) those lined chiefly by goblet cells (Fig 4) and (b) those resembling the glands of colonic adenocarcinoma (34). Often, these subtypes are mixed within the same tumor and may also contain foci of ordinary well-differentiated adenocarcinoma.
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Figure 4. Intestinal variant of well-differentiated adenocarcinoma of the gallbladder. Photomicrograph (original magnification, x10; hematoxylin-eosin stain) shows a predominance of goblet cells (arrows) lining the neoplastic glands that infiltrate the muscle layer. There is necrotic debris in the lumen of the glands.
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Mucinous adenocarcinomas are those tumors that consist of more than 50% extracellular mucin (36). There are two histologic variants: one contains large pools of extracellular mucin with small clusters of malignant epithelial cells (Fig 5), and the other is characterized by mucin-filled glands with cystic dilatation. Foci of both variants may be found admixed with conventional, well-differentiated adenocarcinoma.
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Figure 5. Mucinous adenocarcinoma. Photomicrograph (original magnification, x40; hematoxylin-eosin stain) shows small nests (arrow) of neoplastic epithelial cells in pools of slightly basophilic mucin.
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Signet-ring cell carcinoma contains cells with abundant intracytoplasmic mucin, which displaces the nuclei to the periphery. When the tumor is confined to the surface epithelium or invaginations (Rokitansky-Aschoff sinuses), it may be regarded as an in situ carcinoma. When stromal invasion occurs, the cells grow in cords, nests, and sheets and may form incomplete glandular structures within a mucoid stroma (34). Infiltrative submucosal growth can be a prominent feature of signet-ring cell tumors and may occasionally resemble linitis plastica of the stomach.
Clear cell adenocarcinoma of the gallbladder is composed of cords, sheets, nests, and trabeculae of clear cells with well-defined cytoplasmic borders (Fig 6) (37) and may be confused histologically with metastatic renal cell carcinoma. However, clear cell adenocarcinomas may also contain areas mixed with conventional adenocarcinoma and mucin production, findings that help distinguish these tumors from renal cell carcinoma.
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Figure 6. Clear cell adenocarcinoma. Photomicrograph (original magnification, x400; hematoxylineosin stain) shows a trabecular growth pattern of cells with ample clear cytoplasm (arrow) and hyperchromatic nuclei. The fibrous stroma is scant with scattered inflammatory cells.
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The remaining epithelial cell types occurring in the gallbladder include adenosquamous carcinoma, squamous cell carcinoma, small (oat) cell carcinoma, and undifferentiated carcinoma. The adenosquamous carcinoma contains a mixture of malignant glandular and squamous components. The pure squamous cell carcinoma constitutes only 1% of all malignant gallbladder tumors and consists of cords, islands, or sheets of malignant squamous cells separated by dense fibrous stroma (Fig 7) (34). These tumors most likely arise in areas of previous squamous metaplasia, and their histologic features may vary from anaplastic to well-differentiated, keratinizing squamous cell carcinoma. Small (oat) cell carcinomas of the gallbladder are rare and highly aggressive tumors. They are histologically identical to small cell carcinomas of the lung and gastrointestinal tract. Paraneoplastic syndromes may be associated with small cell carcinoma of the gallbladder, and Cushing syndrome has been reported in association with a corticotropin-secreting apudoma of the gallbladder (38).
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Figure 7. Squamous cell carcinoma. Photomicrograph (original magnification, x400; hematoxylineosin stain) shows nests of well-differentiated, neoplastic, keratinizing squamous cells that infiltrate the gallbladder wall. The fibrous stroma is scant.
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Gross Pathologic Features
The majority (68%) of gallbladder carcinomas are diffusely infiltrating lesions, and the remainder exhibit intraluminal polypoid growth (32%) (39). Approximately 60% of tumors originate in the gallbladder fundus, 30% in the body, and 10% in the neck (34). Submucosal spread of infiltrating carcinomas appears grossly as focal or diffuse areas of wall thickening, nodularity, or induration in the gallbladder wall (Fig 8). In some cases of direct invasion, a thick neoplastic wall encases the gallbladder when direct extension to the liver has occurred (34). In an autopsy series of 287 patients, direct extension to the liver was present in 65% of cases (39). The less common papillary adenocarcinomas exhibit intraluminal polypoid growth. This tumor is usually sessile and has a cauliflower-like appearance (Fig 9) (34).
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Figures 8. (8) Poorly differentiated adenocarcinoma. Photograph of a resected gallbladder (cut specimen) shows innumerable gallstones and diffuse neoplastic mural thickening (arrows). Scale is in centimeters.
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Figures 9. (9) Papillary adenocarcinoma. Photograph of a bisected gallbladder specimen shows the cauliflower-like intraluminal growth of a papillary adenocarcinoma. Scale is in centimeters.
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Radiologic Features
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Radiologic Evaluation of the Primary Tumor
Abdominal radiography may be the initial examination for a patient with gallbladder carcinoma who presents with abdominal distension or right upper quadrant pain. Calcified gallstones or a porcelain gallbladder may be present (Fig 10). In rare cases, calcification precipitating in mucus within the neoplastic glandular tissue may also be visible on radiographs (40), and it is analogous to calcium deposition in adenocarcinomas of the colon and stomach. Abnormal collections of gas in the right upper quadrant may be visible on radiographs when the tumor has invaded adjacent bowel and a fistula has formed (Fig 11). In some cases, gas may also be present in the biliary tree.
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Figure 10a. Porcelain gallbladder containing carcinoma and a fistula to the duodenum. (a) Abdominal radiograph shows curvilinear calcification and an abnormal gas collection within the right upper quadrant of the abdomen. (b) Image from an upper gastrointestinal series demonstrates a gallbladder-duodenal fistula, caused by invasive carcinoma of the gallbladder (arrows).
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Figure 10b. Porcelain gallbladder containing carcinoma and a fistula to the duodenum. (a) Abdominal radiograph shows curvilinear calcification and an abnormal gas collection within the right upper quadrant of the abdomen. (b) Image from an upper gastrointestinal series demonstrates a gallbladder-duodenal fistula, caused by invasive carcinoma of the gallbladder (arrows).
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Figure 11a. Gallbladder carcinoma with erosion into the duodenum. (a) Abdominal radiograph shows an abnormal collection of gas in the right upper quadrant containing a gas-fluid level. (b) Image from an upper gastrointestinal series shows a duodenum-gallbladder fossa fistula.
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Figure 11b. Gallbladder carcinoma with erosion into the duodenum. (a) Abdominal radiograph shows an abnormal collection of gas in the right upper quadrant containing a gas-fluid level. (b) Image from an upper gastrointestinal series shows a duodenum-gallbladder fossa fistula.
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The cross-sectional imaging patterns of gallbladder carcinoma have been described as a mass replacing the gallbladder in 40%–65% of cases, focal or diffuse gallbladder wall thickening in 20%–30%, and an intraluminal polypoid mass in 15%–25% (41)–(44).
Carcinomas that completely replace the gallbladder have irregular margins and heterogeneous echotexture at ultrasonography (US). Heterogeneous echotexture reflects varying degrees of tumor necrosis. Echogenic foci and acoustic shadowing associated with the tumor may be related to coexisting gallstones, gallbladder wall calcification (45), or tumoral calcification (Fig 12). Direct extension to the liver and biliary tree is a common associated finding with large, advanced carcinomas. In these cases, the tumor is inseparable from the adjacent liver (Fig 13).
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Figure 12a. Moderately well-differentiated adenocarcinoma in a 70-year-old woman with right upper quadrant pain and a history of gallstones. (a) Longitudinal sonogram shows a well-defined mass in the gallbladder fundus (*) that produces ill-defined posterior acoustic shadowing. Gallstones are also present. (b) Axial unenhanced computed tomographic (CT) scan shows linear tumoral calcifications in the soft-tissue mass within the gallbladder. (c) Photograph of the resected gallbladder (cut specimen) shows the tumor mass (*) and numerous gallstones.
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Figure 12b. Moderately well-differentiated adenocarcinoma in a 70-year-old woman with right upper quadrant pain and a history of gallstones. (a) Longitudinal sonogram shows a well-defined mass in the gallbladder fundus (*) that produces ill-defined posterior acoustic shadowing. Gallstones are also present. (b) Axial unenhanced computed tomographic (CT) scan shows linear tumoral calcifications in the soft-tissue mass within the gallbladder. (c) Photograph of the resected gallbladder (cut specimen) shows the tumor mass (*) and numerous gallstones.
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Figure 12c. Moderately well-differentiated adenocarcinoma in a 70-year-old woman with right upper quadrant pain and a history of gallstones. (a) Longitudinal sonogram shows a well-defined mass in the gallbladder fundus (*) that produces ill-defined posterior acoustic shadowing. Gallstones are also present. (b) Axial unenhanced computed tomographic (CT) scan shows linear tumoral calcifications in the soft-tissue mass within the gallbladder. (c) Photograph of the resected gallbladder (cut specimen) shows the tumor mass (*) and numerous gallstones.
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Figure 13a. Squamous cell carcinoma in a 64-year-old woman. (a) Transverse sonogram shows diffuse and irregular hyperechoic thickening of the gallbladder wall (arrows), which is contiguous with the adjacent liver parenchyma. There is a shadowing gallstone within the residual gallbladder lumen. (b) Autopsy photograph of the liver and gallbladder (posterior view) shows direct invasion of carcinoma into the adjacent liver parenchyma. The gallstones are enveloped by carcinoma. (c) Autopsy photograph of the heart (cut specimen) shows hematogenous myocardial metastases.
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Figure 13b. Squamous cell carcinoma in a 64-year-old woman. (a) Transverse sonogram shows diffuse and irregular hyperechoic thickening of the gallbladder wall (arrows), which is contiguous with the adjacent liver parenchyma. There is a shadowing gallstone within the residual gallbladder lumen. (b) Autopsy photograph of the liver and gallbladder (posterior view) shows direct invasion of carcinoma into the adjacent liver parenchyma. The gallstones are enveloped by carcinoma. (c) Autopsy photograph of the heart (cut specimen) shows hematogenous myocardial metastases.
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Figure 13c. Squamous cell carcinoma in a 64-year-old woman. (a) Transverse sonogram shows diffuse and irregular hyperechoic thickening of the gallbladder wall (arrows), which is contiguous with the adjacent liver parenchyma. There is a shadowing gallstone within the residual gallbladder lumen. (b) Autopsy photograph of the liver and gallbladder (posterior view) shows direct invasion of carcinoma into the adjacent liver parenchyma. The gallstones are enveloped by carcinoma. (c) Autopsy photograph of the heart (cut specimen) shows hematogenous myocardial metastases.
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Contrast material–enhanced CT in such cases may demonstrate a hypoattenuating or isoattenuating mass in the gallbladder fossa (Fig 14) and soft-tissue invasion of the liver, with protrusion of the anterior surface of the medial segment of the left lobe (46). The tumor mass may contain low-attenuation areas of necrosis. Areas of enhancement reflect viable tumor (42). The low-attenuation areas within the tumor mass or thickened gallbladder wall may appear nodular (47). Biliary obstruction at the level of the porta hepatis and lymph node metastasis are frequent associated findings. The location and characterization of calcification within the gallbladder or tumor can be well defined with CT (Fig 12b).
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Figure 14a. Poorly differentiated mucinous adenocarcinoma in a 45-year-old man. (a) Transverse sonogram shows an irregularly marginated hypoechoic mass in the gallbladder fossa. The mass is contiguous with the liver, and there is shadowing emanating from the mass and a large amount of ascites. (b) Axial contrast-enhanced CT scan shows a hypoattenuating mass in the gallbladder fossa with extension into the adjacent liver. Ascites and omental metastases (arrowhead) are present. (c) Autopsy photograph of the liver (cut specimen) shows the gallbladder carcinoma invading the liver. There is a gallstone in the residual gallbladder lumen.
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Figure 14b. Poorly differentiated mucinous adenocarcinoma in a 45-year-old man. (a) Transverse sonogram shows an irregularly marginated hypoechoic mass in the gallbladder fossa. The mass is contiguous with the liver, and there is shadowing emanating from the mass and a large amount of ascites. (b) Axial contrast-enhanced CT scan shows a hypoattenuating mass in the gallbladder fossa with extension into the adjacent liver. Ascites and omental metastases (arrowhead) are present. (c) Autopsy photograph of the liver (cut specimen) shows the gallbladder carcinoma invading the liver. There is a gallstone in the residual gallbladder lumen.
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Figure 14c. Poorly differentiated mucinous adenocarcinoma in a 45-year-old man. (a) Transverse sonogram shows an irregularly marginated hypoechoic mass in the gallbladder fossa. The mass is contiguous with the liver, and there is shadowing emanating from the mass and a large amount of ascites. (b) Axial contrast-enhanced CT scan shows a hypoattenuating mass in the gallbladder fossa with extension into the adjacent liver. Ascites and omental metastases (arrowhead) are present. (c) Autopsy photograph of the liver (cut specimen) shows the gallbladder carcinoma invading the liver. There is a gallstone in the residual gallbladder lumen.
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Wall thickening is the most diagnostically challenging of the three patterns because it mimics the appearance of more common acute and chronic inflammatory conditions of the gallbladder. Subtle areas of wall thickening may reflect early carcinomas. However, they are difficult to detect, since they may cause only mild elevation of the mucosa when viewed sonographically (48). Pronounced wall thickening (ie, >1.0 cm) demonstrated by US or CT (49), with associated mural irregularity or marked asymmetry should raise concerns for malignancy or complicated cholecystitis (45),(50). Use of contrast-enhanced CT is extremely helpful for distinguishing complicated cholecystitis from gallbladder carcinoma (Fig 15) (41),(45),(46). The CT demonstration of associated lymphadenopathy, soft-tissue extension into the liver, and evidence of hematogenous metastases favors the diagnosis of gallbladder carcinoma (Fig 15b). Although magnetic resonance (MR) imaging is typically not employed as a primary imaging modality for the gallbladder, it may be useful in cases of focal or diffuse mural thickening to distinguish gallbladder carcinoma from adenomyomatosis (51) and chronic cholecystitis (52).
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Figure 15a. Poorly differentiated adenocarcinoma in a 67-year-old man. (a) Longitudinal sonogram shows heterogeneous, hypoechoic, diffuse thickening of the gallbladder wall. There is peripancreatic lymphadenopathy (*) posterior to the gallbladder. (b) Axial contrast-enhanced CT scan shows diffuse gallbladder wall thickening with a hypoattenuating mass extending into the adjacent liver parenchyma. There is a large peripancreatic lymph node (arrow). (c) Autopsy photograph of the liver and gallbladder (cut specimen) shows tumor within the gallbladder extending into the adjacent liver, hematogenous liver metastases, and periportal and peripancreatic lymph nodes (arrow).
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Figure 15b. Poorly differentiated adenocarcinoma in a 67-year-old man. (a) Longitudinal sonogram shows heterogeneous, hypoechoic, diffuse thickening of the gallbladder wall. There is peripancreatic lymphadenopathy (*) posterior to the gallbladder. (b) Axial contrast-enhanced CT scan shows diffuse gallbladder wall thickening with a hypoattenuating mass extending into the adjacent liver parenchyma. There is a large peripancreatic lymph node (arrow). (c) Autopsy photograph of the liver and gallbladder (cut specimen) shows tumor within the gallbladder extending into the adjacent liver, hematogenous liver metastases, and periportal and peripancreatic lymph nodes (arrow).
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Figure 15c. Poorly differentiated adenocarcinoma in a 67-year-old man. (a) Longitudinal sonogram shows heterogeneous, hypoechoic, diffuse thickening of the gallbladder wall. There is peripancreatic lymphadenopathy (*) posterior to the gallbladder. (b) Axial contrast-enhanced CT scan shows diffuse gallbladder wall thickening with a hypoattenuating mass extending into the adjacent liver parenchyma. There is a large peripancreatic lymph node (arrow). (c) Autopsy photograph of the liver and gallbladder (cut specimen) shows tumor within the gallbladder extending into the adjacent liver, hematogenous liver metastases, and periportal and peripancreatic lymph nodes (arrow).
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The less common intraluminal polypoid carcinoma may exhibit a well-defined, round or oval shape (Figs 12, 16) on cross-sectional images. Sonographically demonstrating that the intraluminal mass is immobile with changes in patient position allows one to distinguish tumor mass from tumefactive sludge (Fig 17) (41). The tumor may be hypoattenuating or isoattenuating on CT scans. CT may more readily depict subtle extension of the tumor beyond the wall of the gallbladder (Fig 16b). MR imaging demonstrates prolongation of the T1 and T2 relaxation times in gallbladder carcinoma (53),(54). Ill-defined early enhancement is a typical appearance of these tumors at dynamic gadolinium-enhanced MR imaging (Fig 18) (52).
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Figure 16a. Moderately well-differentiated adenocarcinoma in a 55-year-old man. (a) Transverse sonogram shows a well-defined, sessile hyperechoic mass (*) along the medial gallbladder wall with adjacent focal wall thickening (arrow) and pericholecystic fluid. (b) Axial contrast-enhanced CT scan shows the soft-tissue mass with focal wall thickening, extension beyond the gallbladder wall (arrow), and pericholecystic fluid.
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Figure 16b. Moderately well-differentiated adenocarcinoma in a 55-year-old man. (a) Transverse sonogram shows a well-defined, sessile hyperechoic mass (*) along the medial gallbladder wall with adjacent focal wall thickening (arrow) and pericholecystic fluid. (b) Axial contrast-enhanced CT scan shows the soft-tissue mass with focal wall thickening, extension beyond the gallbladder wall (arrow), and pericholecystic fluid.
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Figure 17a. Papillary adenocarcinoma in an 80-year-old man. (a) Longitudinal sonogram demonstrates an illdefined echogenic mass (*) filling the gallbladder lumen. The mass was immobile with changes in patient position. (b) Photograph of the resected gallbladder specimen shows the large intraluminal mass and associated gallstone.
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Figure 17b. Papillary adenocarcinoma in an 80-year-old man. (a) Longitudinal sonogram demonstrates an illdefined echogenic mass (*) filling the gallbladder lumen. The mass was immobile with changes in patient position. (b) Photograph of the resected gallbladder specimen shows the large intraluminal mass and associated gallstone.
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Figure 18a. Squamous cell carcinoma in a 53-year-old woman. (a) Axial T1-weighted MR image shows an irregular hypointense mass within the gallbladder (arrow). (b) Gadolinium-enhanced axial T1-weighted image shows irregular enhancement of the gallbladder carcinoma (arrow). (c) Multiplanar gradient-echo coronal image shows the hypointense gallbladder carcinoma invading the extrahepatic bile duct (arrow).
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Figure 18b. Squamous cell carcinoma in a 53-year-old woman. (a) Axial T1-weighted MR image shows an irregular hypointense mass within the gallbladder (arrow). (b) Gadolinium-enhanced axial T1-weighted image shows irregular enhancement of the gallbladder carcinoma (arrow). (c) Multiplanar gradient-echo coronal image shows the hypointense gallbladder carcinoma invading the extrahepatic bile duct (arrow).
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Figure 18c. Squamous cell carcinoma in a 53-year-old woman. (a) Axial T1-weighted MR image shows an irregular hypointense mass within the gallbladder (arrow). (b) Gadolinium-enhanced axial T1-weighted image shows irregular enhancement of the gallbladder carcinoma (arrow). (c) Multiplanar gradient-echo coronal image shows the hypointense gallbladder carcinoma invading the extrahepatic bile duct (arrow).
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Radiologic Evaluation of Tumor Extension
The most common mode by which gallbladder carcinoma spreads to adjacent organs is direct extension, followed by lymphatic and vascular extension (55). Intraperitoneal (Fig 14b), intraductal, and neural spread of tumor also occur. The liver is the organ most frequently involved by direct contiguous spread (65% of cases), followed by the colon (15%) (Fig 19), duodenum (15%) (Figs 10, 11), and pancreas (6%) (39). Contiguous spread of tumor is facilitated by the thin gallbladder wall, which lacks a substantial lamina propria and has only a single muscular layer. In addition, the perimuscular connective tissue of the gallbladder is continuous with the interlobular connective tissue of the liver. This morphology permits uninterrupted spread of tumor (6). The tumor then spreads along portal tracts within liver (56).
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Figure 19. Gallbladder carcinoma with contiguous involvement of the transverse colon. Image from a single-contrast barium enema study shows irregularity and deformity to the superior aspect of the transverse colon (arrows).
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Radiographic studies such as a barium enema study (Fig 19) and an upper gastrointestinal series (Figs 10, 11) may demonstrate the findings of adjacent bowel invasion. Extension of the primary tumor into the liver or hepatoduodenal ligament is well depicted by CT and MR imaging. The CT findings of tumor invasion into the hepatoduodenal ligament include well-defined nodular masses caused by discrete lymph nodes; matted masses due to confluent adenopathy; mixed, well-defined, and confluent masses in various locations along the hepatoduodenal ligament; and infiltrating, enhancing areas of soft-tissue attenuation obscuring the portal vein margins (57). On MR images, tumor extension has the same signal intensity as the primary tumor (Fig 18c) (58).
Biliary dilatation is a common finding in gallbladder carcinoma, occurring in 38% of patients in one series (58). Infiltrative tumor growth with spread along the cystic duct to the extrahepatic bile duct (Fig 20), lymph node enlargement, and intraductal spread of tumor results in biliary dilatation and obstruction. Direct cholangiography (endoscopic retrograde cholangiopancreatography [ERCP], percutaneous transhepatic cholangiography, or intraoperative cholangiography) may be performed in cases with biliary involvement when the diagnosis of gallbladder carcinoma is unsuspected or when therapeutic management of biliary obstruction is necessary. Cholangiography may demonstrate malignant strictures or obstruction involving the extrahepatic bile ducts, confluence of the right and left hepatic ducts, and right lobe intrahepatic ducts (Fig 21) (59). Associated findings from cholangiography include intraluminal gallbladder filling defects that may represent tumor or stones, a mass displacing and invading the gallbladder, and intraductal filling defects that may represent tumor or coexistent choledocholithiasis (Fig 21c, 21d).
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Figure 20a. Intrahepatic and periportal extension of adenocarcinoma in a 53-year-old woman. (a) Axial contrast-enhanced CT scan shows intrahepatic extension of a gallbladder carcinoma, hepatoduodenal ligament spread, and periportal lymphadenopathy (arrows). On a more superior section (not shown), there was bile duct dilatation. (b) ERCP image shows a focal common bile duct stricture from periductal tumor extension.
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Figure 20b. Intrahepatic and periportal extension of adenocarcinoma in a 53-year-old woman. (a) Axial contrast-enhanced CT scan shows intrahepatic extension of a gallbladder carcinoma, hepatoduodenal ligament spread, and periportal lymphadenopathy (arrows). On a more superior section (not shown), there was bile duct dilatation. (b) ERCP image shows a focal common bile duct stricture from periductal tumor extension.
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Figure 21a. Spectrum of ERCP findings in gallbladder carcinoma. (a) ERCP image of a 65-year-old woman with well-differentiated adenocarcinoma shows cystic duct obstruction (arrow). (b) ERCP image of a 70-year-old woman shows a filling defect in the gallbladder fundus from carcinoma and a hilar stricture at the confluence of the right and left hepatic ducts from extension of carcinoma. (c) ERCP image of a 70-year-old man shows marked intrahepatic duct dilatation from a hilar stricture due to gallbladder carcinoma. Intraductal stones are present in the common bile duct. (d) ERCP image of an 80-year-old woman shows marked mass effect, intraductal extension of carcinoma, and biliary dilatation from gallbladder carcinoma. There are stones within the residual gallbladder lumen (arrow).
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Figure 21b. Spectrum of ERCP findings in gallbladder carcinoma. (a) ERCP image of a 65-year-old woman with well-differentiated adenocarcinoma shows cystic duct obstruction (arrow). (b) ERCP image of a 70-year-old woman shows a filling defect in the gallbladder fundus from carcinoma and a hilar stricture at the confluence of the right and left hepatic ducts from extension of carcinoma. (c) ERCP image of a 70-year-old man shows marked intrahepatic duct dilatation from a hilar stricture due to gallbladder carcinoma. Intraductal stones are present in the common bile duct. (d) ERCP image of an 80-year-old woman shows marked mass effect, intraductal extension of carcinoma, and biliary dilatation from gallbladder carcinoma. There are stones within the residual gallbladder lumen (arrow).
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Figure 21c. Spectrum of ERCP findings in gallbladder carcinoma. (a) ERCP image of a 65-year-old woman with well-differentiated adenocarcinoma shows cystic duct obstruction (arrow). (b) ERCP image of a 70-year-old woman shows a filling defect in the gallbladder fundus from carcinoma and a hilar stricture at the confluence of the right and left hepatic ducts from extension of carcinoma. (c) ERCP image of a 70-year-old man shows marked intrahepatic duct dilatation from a hilar stricture due to gallbladder carcinoma. Intraductal stones are present in the common bile duct. (d) ERCP image of an 80-year-old woman shows marked mass effect, intraductal extension of carcinoma, and biliary dilatation from gallbladder carcinoma. There are stones within the residual gallbladder lumen (arrow).
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Figure 21d. Spectrum of ERCP findings in gallbladder carcinoma. (a) ERCP image of a 65-year-old woman with well-differentiated adenocarcinoma shows cystic duct obstruction (arrow). (b) ERCP image of a 70-year-old woman shows a filling defect in the gallbladder fundus from carcinoma and a hilar stricture at the confluence of the right and left hepatic ducts from extension of carcinoma. (c) ERCP image of a 70-year-old man shows marked intrahepatic duct dilatation from a hilar stricture due to gallbladder carcinoma. Intraductal stones are present in the common bile duct. (d) ERCP image of an 80-year-old woman shows marked mass effect, intraductal extension of carcinoma, and biliary dilatation from gallbladder carcinoma. There are stones within the residual gallbladder lumen (arrow).
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The prevalence of lymphatic spread is high in gallbladder carcinoma. Lymphatic metastases progress from the gallbladder fossa through the hepatoduodenal ligament to nodal stations near the head of the pancreas (Fig 22). Three pathways of lymphatic drainage have been suggested: the cholecystoretropancreatic pathway, the cholecystoceliac pathway, and the cholecystomesenteric pathway (60). The cystic and pericholedochal lymph nodes are the most commonly involved at surgery (61) and are a critical pathway to involvement of the celiac, superior mesenteric, and para-aortic lymph nodes. The node of the foramen of Winslow, the superior pancreatoduodenal node, and the posterior pancreatoduodenal nodes are the most common nodes demonstrated by CT (62). Positive lymph nodes are more likely to be greater than 10 mm in anteroposterior dimension and have ringlike or heterogeneous contrast material enhancement (63). The masses produced by lymph node metastasis around the distal common bile duct and pancreatic head may mimic a pancreatic head carcinoma (45).
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Figure 22a. Adenocarcinoma in a 35-year-old woman. (a, b) Axial contrast-enhanced CT scans show peripancreatic lymphadenopathy (arrow in a) and a focal mass in the gallbladder fundus. (c) Photograph of the bisected specimen shows the focal mass in the gallbladder fundus. Cholesterolosis is also present (arrows).
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Figure 22b. Adenocarcinoma in a 35-year-old woman. (a, b) Axial contrast-enhanced CT scans show peripancreatic lymphadenopathy (arrow in a) and a focal mass in the gallbladder fundus. (c) Photograph of the bisected specimen shows the focal mass in the gallbladder fundus. Cholesterolosis is also present (arrows).
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Figure 22c. Adenocarcinoma in a 35-year-old woman. (a, b) Axial contrast-enhanced CT scans show peripancreatic lymphadenopathy (arrow in a) and a focal mass in the gallbladder fundus. (c) Photograph of the bisected specimen shows the focal mass in the gallbladder fundus. Cholesterolosis is also present (arrows).
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Hematogenous metastases are most commonly seen in the liver (39). Pulmonary, skeletal, cardiac (Fig 13c), pancreatic, renal, adrenal, and cerebral metastases occur less frequently. Hematogenous metastases to the liver are well depicted by CT and MR imaging.
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Staging, Therapy, and Prognosis
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The TNM (Tables 2 and 3) (64) and modified Nevin (Table 4) (65),(66) classifications are used for staging gallbladder carcinoma. There is very little information in the current medical literature on the accuracy of preoperative staging for gallbladder carcinoma. US is useful for detecting the primary tumor and adjacent liver invasion, but it cannot reliably depict the full extent of disease. Bach et al (67) showed that only 37% of patients with advanced disease were identified with US. In addition, the potentially curable stage 1 cancers are difficult to detect sonographically (48). Many of these lesions are flat or only minimally elevate the mucosa. Several authors have reported the successful use of endoscopic US for evaluating the depth of gallbladder carcinoma invasion (68)–(70).
CT is more useful than US for detecting lymph node involvement, adjacent organ invasion, and distant metastasis. CT does not reliably demonstrate all regional lymph nodes, but, when abnormally sized nodes (>10 mm) are present, it does indicate that lymphatic spread has occurred (63). In a retrospective study of 59 patients, the sensitivity of CT in the detection of abnormal lymph nodes was 36% for N1 nodes and 47% for N2 nodes; CT had a specificity of 99% for both N1 and N2 nodes (71). In the same study, CT had a sensitivity of 100% in the detection of tumor extension greater than 2 cm into the liver (T4 stage); however, its sensitivity in the detection of less severe tumor extension into the liver (<2 cm or T3 stage) was only 65% (71).
In general, the therapeutic options for gallbladder carcinoma are limited because of the late stage of disease at presentation in most cases. In addition, there is no standardized therapy for gallbladder carcinoma. Systemic or regional chemotherapy has had little success (2),(72). Some re-ports have demonstrated an increase in survival time for patients who underwent palliative or adjuvant radiation therapy (73),(74). Although surgical resection is the mainstay of therapy, the extent of resection for each stage of disease remains controversial. Most authors agree that T1N0M0 disease requires a simple cholecystectomy. Aggressive surgery (including cholecystectomy with en bloc segmental hepatic resection, lymph node dissection, and common bile duct resection and reconstruction if necessary) is performed to provide adequate control of local disease and potential cure for patients with stage T1b or TNM stage 2 and 3 carcinomas. It has been demonstrated that there are no long-term survivors among patients with node-positive disease treated with aggressive surgery (75). These same authors recommend that the presence of M1, N2, and N3 disease should preclude attempts at curative resection (75).
Laparoscopic cholecystectomy may inadvertently be performed in cases of gallbladder carcinoma when tumor is unsuspected. Iatrogenic dissemination of gallbladder carcinoma in the peritoneal cavity and port sites has been described in the surgical and radiologic literature, with 45 cases reported to date (76)–(78). Many authors advocate re-exploration for those patients in whom a T2 or T3 carcinoma was incidentally found at cholecystectomy and excision of port sites for those patients who underwent laparoscopic cholecystectomy (75),(79).
The overall 5-year survival rates for patients with gallbladder carcinoma are less than 5%, with a median survival of less than 6 months (6),(75). The most important prognostic factors are histologic type, histologic grade, and stage of the tumor. Patients with papillary carcinomas have the best survival time (median, 20 months) (Table 1) (6).
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Radiologic Differential Diagnosis
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Gallbladder carcinoma manifesting as diffuse gallbladder wall thickening has a differential diagnosis that includes the more common inflammatory and noninflammatory causes of wall thickening. These conditions include heart failure, cirrhosis, hepatitis, hypoalbuminemia, renal failure, and cholecystitis (Fig 23). Occasionally, a pericholecystic abscess, gallbladder necrosis, or fistula formation to adjacent bowel can complicate acute cholecystitis. The findings in these cases may simulate those of an aggressive neoplastic process. Gallbladder carcinoma should be suspected when there are features of a focal mass, lymphadenopathy, hepatic metastases, and biliary obstruction at the level of the porta hepatis (46).
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Figure 23a. Acute cholecystitis in a 19-year-old woman with a positive sonographic Murphy sign. (a) Transverse sonogram shows nonshadowing gallstones, thickening of the gallbladder wall, and pericholecystic fluid. (b) Photograph of the cut specimen shows diffuse purulent thickening of the gallbladder wall. The mucosa of the gallbladder is hemorrhagic, and there are stones present.
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Figure 23b. Acute cholecystitis in a 19-year-old woman with a positive sonographic Murphy sign. (a) Transverse sonogram shows nonshadowing gallstones, thickening of the gallbladder wall, and pericholecystic fluid. (b) Photograph of the cut specimen shows diffuse purulent thickening of the gallbladder wall. The mucosa of the gallbladder is hemorrhagic, and there are stones present.
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Xanthogranulomatous cholecystitis is a pseudotumoral inflammatory condition of the gallbladder that radiologically simulates gallbladder carcinoma (47),(80),(81). The CT features of xanthogranulomatous cholecystitis and gallbladder carcinoma overlap substantially; thus, these entities cannot be reliably differentiated (47),(80). Both diseases may demonstrate gallbladder wall thickening, infiltration of the surrounding fat, hepatic involvement, and lymphadenopathy (Fig 24).
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Figure 24a. Xanthogranulomatous cholecystitis in a 40-year-old woman with chronic right upper quadrant pain. (a) Transverse sonogram of the gallbladder fossa shows marked heterogeneous thickening of the gallbladder wall and narrowing of the gallbladder lumen (arrow). (b) Axial contrast-enhanced CT scan shows gallbladder wall thickening and soft-tissue stranding in the gallbladder fossa. The gallbladder lumen is very small (arrow). (c) Photograph of the bisected specimen shows fibrotic thickening of the gallbladder wall and narrowing of the gallbladder lumen.
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Figure 24b. Xanthogranulomatous cholecystitis in a 40-year-old woman with chronic right upper quadrant pain. (a) Transverse sonogram of the gallbladder fossa shows marked heterogeneous thickening of the gallbladder wall and narrowing of the gallbladder lumen (arrow). (b) Axial contrast-enhanced CT scan shows gallbladder wall thickening and soft-tissue stranding in the gallbladder fossa. The gallbladder lumen is very small (arrow). (c) Photograph of the bisected specimen shows fibrotic thickening of the gallbladder wall and narrowing of the gallbladder lumen.
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Figure 24c. Xanthogranulomatous cholecystitis in a 40-year-old woman with chronic right upper quadrant pain. (a) Transverse sonogram of the gallbladder fossa shows marked heterogeneous thickening of the gallbladder wall and narrowing of the gallbladder lumen (arrow). (b) Axial contrast-enhanced CT scan shows gallbladder wall thickening and soft-tissue stranding in the gallbladder fossa. The gallbladder lumen is very small (arrow). (c) Photograph of the bisected specimen shows fibrotic thickening of the gallbladder wall and narrowing of the gallbladder lumen.
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Adenomyomatosis is a common tumorlike lesion of the gallbladder with no malignant potential (34). It may involve the gallbladder in a focal, segmental, or diffuse form. Its histologic features include a proliferation of epithelial and mural elements, and Rokitansky-Aschoff sinuses are seen as prominent infoldings of the epithelium. At US, adenomyomatosis is characterized by focal or diffuse gallbladder wall thickening and anechoic or echogenic foci in the gallbladder wall (Fig 25) (82),(83). These echogenic foci may produce a ring-down reverberation artifact (Fig 25a). Rokitansky-Aschoff sinuses are best visualized with MR imaging performed with breath-hold technique and T2-weighted pulse sequences (51); therefore, MR imaging can be useful for distinguishing this benign entity from gallbladder carcinoma.
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Figure 25a. Adenomyomatosis in a 48-year-old man with chronic right upper quadrant pain. (a) Longitudinal sonogram shows diffuse gallbladder wall thickening and hyperechoic foci within the gallbladder wall that produce ring-down artifact (arrow). (b) Photograph of the bisected specimen shows marked thickening of the gallbladder wall and Rokitansky-Aschoff sinuses (arrows).
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Figure 25b. Adenomyomatosis in a 48-year-old man with chronic right upper quadrant pain. (a) Longitudinal sonogram shows diffuse gallbladder wall thickening and hyperechoic foci within the gallbladder wall that produce ring-down artifact (arrow). (b) Photograph of the bisected specimen shows marked thickening of the gallbladder wall and Rokitansky-Aschoff sinuses (arrows).
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The differential diagnosis for those tumors that manifest as an intraluminal polypoid mass includes adenomatous, hyperplastic, and cholesterol polyps; carcinoid tumor; metastatic melanoma (Fig 26); and a hematoma within the gallbladder. The differential diagnosis for a mass replacing the gallbladder fossa includes hepatocellular carcinoma, cholangiocarcinoma, and metastatic disease to the gallbladder fossa.
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Figure 26a. Metastatic melanoma in a 45-year-old woman with right upper quadrant tenderness. (a) Longitudinal sonogram shows a polypoid mass within the gallbladder. (b) Photograph of the bisected specimen shows melanotic pigmentation in the gallbladder mass.
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Figure 26b. Metastatic melanoma in a 45-year-old woman with right upper quadrant tenderness. (a) Longitudinal sonogram shows a polypoid mass within the gallbladder. (b) Photograph of the bisected specimen shows melanotic pigmentation in the gallbladder mass.
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Summary
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Primary carcinoma of the gallbladder is a highly aggressive malignancy that is found at a late stage in the majority of affected patients. Early-stage gallbladder carcinoma is most commonly an incidental finding in patients who have undergone cholecystectomy for inflammatory disease of the gallbladder. The radiologic findings in early-stage cancers are subtle and may mimic those of acute or chronic cholecystitis. The radiologic findings in advanced tumors reflect its behavior. Direct extension to the liver and biliary tree, biliary obstruction, lymph node metastases, and hematogenous metastases are characteristic findings of advanced cancers. Papillary adenocarcinoma has the best prognosis of the histologic types and typically manifests as an intraluminal polypoid mass. Knowledge of the varied appearances of gallbladder carcinoma at cross-sectional imaging, particularly US and CT, is important so that the diagnosis can be considered preoperatively.
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Footnotes
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See also the drawing by Cooper (p 322)
in this issue.
Abbreviation: ERCP = endoscopic retrograde cholangiopancreatography
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Departments of the Army, Navy, or Defense.
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LEARNING OBJECTIVES FOR TEST...
