Introduction
Gallbladder cancer is a rare, although aggressive, form of malignancy. They arise from the epithelial lining of the gallbladder, often linked to chronic inflammation from gallstones.
The most common histological subtype of gallbladder cancer is adenocarcinoma (Fig 1), comprising around 90% of cases, however rarer forms include adenosquamous, squamous, papillary, mucinous, neuroendocrine tumours, lymphoma, or sarcoma.
In the UK, approximately 700 new cases are diagnosed per year.
Gallbladder Cancer versus Cholangiocarcinoma
Gallbladder cancer and cholangiocarcinoma are both malignancies of the biliary system, however are distinct entities with different origins, presentations and management approaches.
Gallbladder cancer arises from the epithelial lining of the gallbladder, whereas cholangiocarcinoma originates within the bile ducts and is typically associated with primary sclerosing cholangitis, liver fluke infection, or chronic biliary tract inflammation.
Risk Factors
The main risk factors for gallbladder cancer include:
- Cholelithiasis – gallstones are present in 70-90% of patients with gallbladder cancer
- Porcelain gallbladder – a rare manifestation of chronic cholecystitis where there is presence of intramural calcification of the gallbladder*
- Gallbladder polyps (particularly if size > 10 mm) or biliary cysts
- Chronic infection, particularly Salmonella typhi and Helicobacter bilis
- Female sex
- Primary sclerosing cholangitis
*The risk of gallbladder cancer in patients with porcelain gallbladder is not thought to be as high as it once was; whilst it has previously thought to be pathognomonic for gallbladder cancer, more recent studies suggest a 2-3%-associated risk
Figure 1 – Histology of a moderately differentiated adenocarcinoma of gallbladder
Clinical Features
A large proportion of gallbladder cancers are identified histologically post-operatively in patients who have undergone a cholecystectomy for gallstone-related disease*.
Symptomatic patients may present with features that mimics biliary colic or cholecystitis, whereas larger lesions may cause a presentation with obstructive jaundice. Advanced disease often manifests with more vague symptoms, such as non-specific abdominal pain, nausea, malaise, or weight loss.
Examination findings may include a non-tender right-upper quadrant abdominal mass (Courvoisier’s law), jaundice, or in the presence of advanced disease hepatomegaly or ascites.
*Histology of approximately 1 in 500 gallbladders resected for benign biliary disease will demonstrate a gallbladder cancer, termed “incidental gallbladder cancer”
Investigations
Routine blood tests can be normal, especially in early stages, however Liver Function Tests (LFTs) can show elevated ALP levels or even raised bilirubin in advanced cases.
Tumour markers CA19-9 and CEA may be performed, but are not diagnostic, and are more useful in monitoring response to treatment.
Imaging
Imaging plays a crucial role in the diagnosis and management of gallbladder cancer. Abdominal ultrasound scan (USS) is typical first-line imaging for biliary pathology, which may detect gallbladder masses or wall thickening.
In suspected cases, further imaging is required to both confirm the diagnosis and help guide management:
- MRI imaging (MRCP) – provides detailed visualisation of the biliary tree and liver, and can assess for localised invasion and biliary obstruction
- CT imaging – a chest-abdomen-pelvis scan can be performed for staging, to assess for both distant metastases and local invasion (Fig. 2)
- Endoscopic ultrasound (EUS) – provides a higher resolution image of the gallbladder and facilitates biopsy if required
Figure 2 – CT imaging showing an adenocarcinoma of the gallbladder with associated lesions in the liver
Gallbladder cancers are commonly staged using the TNM staging system. The American Joint Committee on Cancer (AJCC) staging system combines TNM findings into overall stages:
| AJCC stage | TNM findings |
| Stage 0 | Tis, N0, M0 |
| Stage I | T1, N0, M0 |
| Stage II | T2 (T2a or T2b), N0, M0 |
| Stage IIIa | T3, N0, M0 |
| Stage IIIb | T1-3, N1, M0 |
| Stage IVa | T4, N0-1, M0 |
| Stage IVb | T1-4, N2 or M1 |
Table 1.- The AJCC staging system for gallbladder cancers
Management
All patients should be discussed in a multidisciplinary team (MDT) meeting which will recommend treatment plans according to disease stage and patient-specific factors.
Early-stage gallbladder cancer is primarily treated with surgical resection. This may involve a radical cholecystectomy with adequate margins, regional lymphadenectomy, and in some cases partial liver segmentectomy. If there is common bile duct involvement, further resection and biliary tree reconstruction may be required.
Incidental gallbladder cancer (identified histologically after laparoscopic cholecystectomy) is managed based upon pathological findings:
- T1a tumours: laparoscopic cholecystectomy is usually considered curative
- T1b, T2, T3 tumours: further surgical resection is generally recommended to achieve adequate resection margins
Non-Surgical & Palliative management
Advanced or unresectable gallbladder cancer may be treated with systemic therapy and supportive care.
Chemotherapy or radiotherapy may be offered to patients with advanced or unresectable disease. Endoscopic stenting may be performed for palliative patients to allow biliary drainage.
Ensuring adequate pain management and nutritional support is also essential in this management.
Key Points
- Gallbladder cancer is typically an adenocarcinoma
- Although rare, gallbladder cancer can be aggressive
- Risk factors include gallstone disease and other conditions causing local inflammation
- A high proportion of gallbladder cancers are picked up incidentally on laparoscopic cholecystectomy, in early stages of their disease their surgical treatment may be considered curative
