Gallbladder Carcinoma

• Malignancy of biliary epithelium. Chronic inflammation → dysplasia → carcinoma (adenocarcinoma most common).

Description

Gallbladder carcinoma is a rare but highly aggressive malignancy of the biliary tract. It arises from the epithelium lining of the gallbladder and displays poor prognosis due to its often late-stage diagnosis and rapid progression. This cancer is notoriously difficult to diagnose in its early stages as it frequently mimics benign gallbladder diseases.

Pathogenesis

Gallbladder carcinoma is a malignant condition originating from the biliary epithelial lining of the gallbladder. It characteristically progresses through a sequence of chronic irritation and inflammation induced by gallstones, leading to cellular dysplasia and eventually carcinoma over a period of 5–15 years. Gallbladder carcinoma is typically aggressive, often presenting with invasion of nearby structures and metastases at diagnosis, likely due to the absence of a submucosal layer in the gallbladder wall, which facilitates early local invasion. Other pathogenic factors include anomalous pancreaticobiliary duct junction, gallbladder polyps, and exposure to carcinogens.

In terms of tumour distribution within the gallbladder, 60% originate in the fundus, 30% in the body and infundibulum, and 10% in the cystic duct.

Three distinct patterns of spread include:

1. Direct spread
2. Subperitoneal spread
3. Intraperitoneal spread

Direct spread into the liver is the most frequent pattern of dissemination.

Subperitoneal spread mainly traverses mesenteric planes and lymphatic pathways, often involving the hepatoduodenal and gastrohepatic ligaments. The hepatoduodenal ligament, encompassing the portal triad of the proper hepatic artery, common bile duct, and portal vein, is a common route for tumour extension to the pancreas, duodenum, and mesentery. Spread via the gastrohepatic ligament frequently leads to tumour involvement of the stomach and omentum.

Lymph node metastases are common, with nodal disease progressing to the coeliac station along the anterior drainage pathway and to the pancreaticoduodenal and para-aortic nodes along the posterior route.

Approximately 20% of patients exhibit intraperitoneal spread at the time of surgery, a process wherein the tumour penetrates the serosal surface of the gallbladder into the peritoneal cavity, typically manifesting early in the disease course.¹

Epidemiology, Risk Factors & Associations

Gallbladder carcinoma is more prevalent in females and older individuals (mean age at diagnosis is around 70 years). Globally, the incidence varies significantly, with the highest rates reported in Chile, North India, and Japan.

Risk factors include:

• Large gallbladder and chronic cholecystitis: Most common risk factors, associated in about 70-90% of cases.
• Risk increases with age.
• Females are 2-3 times more likely to develop the disease.
• Obesity, diabetes mellitus and dietary factors
• Porcelain gallbladder
• Primary sclerosing cholangitis
• Anomalous pancreaticobiliary duct junction: Pancreatic and bile ducts join outside the duodenal wall, forming an abnormally long common channel. This congenital anomaly results in pancreatic juice reflux into the gallbladder, leading to an increased risk.

Clinical Features

Symptoms of gallbladder cancer can be non-specific and often mimic benign gallbladder disease.

Typically it is an incidental finding. If large, the most common symptoms include:

• Abdominal pain: Typically located in the right upper quadrant.
• Jaundice: Occurs when the bile duct becomes blocked by the tumour.
• Nausea and vomiting: Common nonspecific symptoms.
• Anorexia and weight loss: More indicative of advanced disease.
• Palpable gallbladder (Courvoisier sign): May be found on physical examination.

Complications

Due to its aggressive nature and late-stage diagnosis, complications are common and include liver invasion, bile duct obstruction leading to jaundice and cholangitis, peritoneal dissemination, and distant metastases (especially to the liver, lymph nodes, and peritoneum).

Subtypes

• Adenocarcinoma: The most common subtype, accounting for about 80-90% of all gallbladder cancers. This cancer originates in the gland-like cells of the gallbladder and can further be divided into well-differentiated, moderately differentiated, and poorly differentiated categories. The prognosis worsens with decreasing differentiation.
• Papillary adenocarcinoma: Represents about 6% of gallbladder cancers. Tends to grow in a single, large mass and is less likely to invade the liver and lymph nodes, giving it a relatively better prognosis compared to other types.
• Mucinous adenocarcinoma: Represents round 2% of gallbladder cancers. Characterised by the production of mucin and tends to have a worse prognosis due to its higher likelihood of peritoneal spread and formation of malignant ascites.
• Squamous/Adenosquamous carcinoma: Rare variants that contain both glandular (adenocarcinoma) and squamous components. They tend to have a more aggressive course with a poorer prognosis.
• Small cell (oat cell) carcinoma: A very rare type of gallbladder cancer. It grows and spreads more quickly than adenocarcinoma and is often diagnosed at a late stage.

Pathological Features

Morphology

Tumours may be polypoid, infiltrative, or present as diffuse wall thickening. The surface can appear nodular, ulcerated, or scirrhous. Tumour spread is usually local, with direct extension into the liver in more than half of the cases.

Histopathology

The most common histological subtype, adenocarcinoma, shows glandular or papillary structures. Other types present different histological features: squamous cell carcinoma shows squamous differentiation, and undifferentiated carcinoma lacks specific differentiation.

Biochemistry

No specific biochemical markers for gallbladder cancer exist, but elevated levels of serum alkaline phosphatase, gamma-glutamyl transferase, and bilirubin can suggest biliary tract obstruction.

Genetics

Mutations in several genes, including TP53, KRAS, and ERBB2, have been associated with gallbladder carcinoma.

Radiological Features

General Features

• May appear as an intraluminal mass, diffuse mural thickening or mass-replacing gallbladder.
• Regional lymphadenopathy, loss of tissue planes with adjacent structures and direct invasion into the liver or other adjacent structures in advanced disease.
• Lymph nodes are considered suspicious when pathologically enlarged according to size criteria (>10 mm in the short axis) or showing abnormal intrinsic signal intensity or morphology
• Assessment of the peritoneum is important to evaluate for tumour implants. Typical locations include:
  • Subdiaphragmatic regions
  • Gastrosplenic ligament
  • Gastroduodenal ligament
  • Transverse mesocolon
  • Morison pouch
  • Paracolic gutters
  • Undersurface of the anterior abdominal wall
  • Pelvic side walls and within dependent pelvis
• Gallstones are commonly present (60 – 90%)
• Features that favour malignancy include:
  • Size >10 mm (majority are malignant, < 5 mm more likely to be cholesterol polyp)
  • Sessile morphology (vs pedunculated)
  • Solitary lesion (>50% of cholesterol polyps are multiple)
  • Interval growth
  • Enhancement greater than adjacent gallbladder wall
  • Absence of comet tail artefact (cholesterol polyp)

CT

• Non-contrast: Typically large heterogenous hypodense mass, with areas of necrosis
• Arterial: Peripheral enhancement may be seen
• Portal Venous: Moderate patchy enhancement.
• May also appears as irregular or focal gallbladder wall thickening
• Features of advanced disease includes:
  • Direct invasion of liver or adjacent organs
  • Lymphadenopathy porta hepatis, coeliac axis, or peripancreatic region.
  • Peritoneal carcinomatosis
  • Hepatic or distant metastasis

MRI

• T1: Typically hypo- to isointense to liver
• T2: Typically heterogenous iso- to hyperintense to liver.
• T1 Gd+: Hetoergenous enhancement
• DWI: Often non-specific. May help with detection and staging.

US

• Hypoechoic, heterogenous echotexture mass with irregular margins. Hyperechoic foci with posterior acoustic shadowing may represent concomitant gallstones or mural calcification as seen in porcelain gallbladder.
• Wall thickening and intraluminal polypoid mass.
• Direct invasion into the liver can be observed.

Grading and Staging

The AJCC (American Joint Committee on Cancer) TNM system is widely used for staging gallbladder carcinoma.

T (Tumour):

• Tis: Carcinoma in situ, confined to the gallbladder wall’s epithelial layer
• T1: Tumour invades the lamina propria (T1a) or muscle layer (T1b)
• T2: Tumour invades the perimuscular connective tissue; no extension beyond the serosa or into the liver
• T3: Tumour 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: Tumour invades the main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

N (Nodes):

• N0: No regional lymph node metastasis
• N1: Metastases to regional lymph nodes (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

M (Metastasis):

• M0: No distant metastasis
• M1: Distant metastasis present

Stage 0 (Tis, N0, M0)

• The disease is confined to the innermost layer of the gallbladder, with no spread to lymph nodes or distant sites.

Stage I (T1, N0, M0)

• The tumour has grown into the lamina propria or the muscle layer, but has not spread to nearby lymph nodes or distant sites.

Stage II (T2, N0, M0)

• The tumour has grown into the perimuscular connective tissue and has not spread to nearby lymph nodes or distant sites.

Stage IIIA (T3, N0, M0)

• The cancer has grown through the thin layers of tissue that cover the gallbladder and/or into the liver or into another adjacent organ (like the stomach, duodenum, colon, pancreas, or bile ducts outside of the liver) and has not spread to nearby lymph nodes or distant sites.

Stage IIIB (T1-3, N1, M0)

• The cancer has spread to regional lymph nodes and can be any T stage (T1, T2, or T3), but has not spread to distant sites.

Stage IVA (T4, Any N, M0)

• The cancer has grown into the main blood vessels of the liver (portal vein or hepatic artery), or it has invaded 2 or more extrahepatic organs or structures. It may or may not have spread to regional lymph nodes, but it has not spread to distant sites.

Stage IVB (Any T, N2, M0 or Any T, Any N, M1)

• This stage can be one of two situations:
  • The cancer may be any T stage and might or might not have spread to regional lymph nodes. It has spread to distant lymph nodes or distant sites (M1).
  • The cancer can be any T stage and has spread to nearby blood vessels. It has also spread to distant lymph nodes (N2), but not to distant sites.

Differential Diagnosis

Imaging-based

Mural thickening

• Chronic cholecystitis: This condition is characterised by long-term inflammation of the gallbladder. It can cause thickening and hardening of the gallbladder walls, which could be mistaken for gallbladder cancer on imaging studies.
• Xanthogranulomatous cholecystitis: This rare form of chronic cholecystitis is characterised by severe inflammation, leading to the destruction of the gallbladder wall. The inflammatory mass may mimic carcinoma.
• Adenomyomatosis: This is a benign condition of the gallbladder characterised by hyperplastic changes in the gallbladder wall. While generally considered benign, it may be mistaken for gallbladder cancer due to the presence of gallbladder wall thickening and intramural diverticula (Rokitansky-Aschoff sinuses).
• Porcelain gallbladder
• Gallbladder tuberculosis

Intraluminal Mass

• Gallbladder polyps: Seen with Peutz-Jegher and familial adenomatous polyposis syndromes. These are growths that protrude from the surface of the inner gallbladder wall. They can be benign or malignant, and the differentiation between a benign polyp and a malignant lesion can sometimes be challenging. See Features that favour malignancy.
• Gallbladder metastasis: Rarely, cancers from other primary sites (in order: melanoma, renal cell carcinoma, breast, lung, or gastric cancer) can metastasise to the gallbladder and may be mistaken for primary gallbladder cancer. Widespread metastatic disease elsewhere is highly suggestive.
• Tumefactive sludge: Non-mobile polypoid mass appears sonographically as a hypoechogenic well-defined intraluminal mass with no posterior acoustic shadowing or internal vascularity. On MRI, it appears T1 hyperintense with variable T2 signal, with no enhancement or diffusion restriction.² Regional lymph nodes non-enlarged.
• Pericholecystic abscess: Usually develop in the setting of perforated acute cholecystits distinguishable by fulminant acute clinical presentation.

Management

• Treatment typically involves surgical resection, often in the form of cholecystectomy for early-stage disease.
• If the disease is advanced or the patient is not fit for surgery, palliative therapies such as stent placement for biliary drainage, chemotherapy, or radiation therapy might be considered.
• Referral to a gastroenterologist or a surgical oncologist should be the next step after imaging findings suggest gallbladder carcinoma.
• Confirmatory diagnosis is usually made with tissue biopsy.

References

1. Lopes Vendrami, C., Magnetta, M.J., Mittal, P.K., Moreno, C.C. and Miller, F.H., 2021. Gallbladder carcinoma and its differential diagnosis at MRI: what radiologists should know. Radiographics, 41(1), pp.78-95. Vancouver ↩︎
2. Seong, M., Kang, T.W., Kim, M., Kim, S.S., Jang, K.M., Kim, Y.K. and Kim, S.H., 2016. Tumefactive gallbladder sludge: the MRI findings. Clinical Radiology, 71(4), pp.402-e9. ↩︎