Gallbladder Cancer

The gallbladder is a small organ beneath the liver that stores and concentrates bile. Gallbladder cancer is relatively uncommon, but because the gallbladder lies deep within the abdomen and early disease often causes few symptoms, some cancers are diagnosed only after they have progressed.

Adenocarcinoma is the most common histologic type. Less common forms include adenosquamous carcinoma, squamous cell carcinoma, neuroendocrine tumors, and sarcomas. Different subtypes may behave differently and require different treatment approaches.

Some very early cancers are discovered incidentally after gallbladder removal for gallstones or cholecystitis. These are often referred to as incidental gallbladder cancers.

The exact cause of gallbladder cancer is not fully understood. Chronic inflammation of the gallbladder appears to be an important pathway linking many known risk factors.

Factors associated with increased risk include:

• Gallstones, particularly long-standing gallstone disease

• Chronic inflammation of the gallbladder

• Porcelain gallbladder

• Certain larger or higher-risk gallbladder polyps

• Congenital biliary abnormalities such as choledochal cysts

• Abnormal pancreaticobiliary duct junctions

• Primary sclerosing cholangitis

• Obesity

• Older age

• Female sex

• Certain chronic infections and inherited risk factors

Gallstones are one of the most common risk factors, but most people with gallstones never develop gallbladder cancer.

Early gallbladder cancer may cause no symptoms and is sometimes discovered incidentally after gallbladder surgery.

Possible symptoms include:

• Pain in the upper right abdomen or upper abdomen

• Jaundice

• Nausea or vomiting

• Loss of appetite

• Unexplained weight loss

• Fever

• Abdominal swelling

• Itching

• Dark urine or pale stools

• An abdominal mass 

Jaundice may occur when the tumor blocks normal bile flow, although many noncancerous biliary conditions can cause similar symptoms.

For advanced disease with biliary obstruction, stents or drainage procedures may be used to restore bile flow, relieve symptoms, reduce infection risk, and help patients proceed with further cancer treatment.

Diagnosis usually combines imaging, laboratory testing, and pathology.

Ultrasound is often one of the first imaging tests and may identify gallbladder wall thickening, a mass, or a polyp.

When cancer is suspected, contrast-enhanced CT or MRI may be used to determine:

• Whether the tumor extends beyond the gallbladder wall

• Whether it involves the nearby liver

• Whether major blood vessels are involved

• Whether lymph nodes are affected

• Whether the cancer has spread to the peritoneum or distant organs

• Whether complete surgical removal appears possible

MRCP, PET/CT, or other imaging may also be used in selected patients.

Tumor markers such as CA19-9 and CEA may provide additional information but cannot establish the diagnosis on their own.

Pathologic examination confirms the diagnosis and tumor type. However, some gallbladder cancers are found only after the gallbladder has already been removed. For a patient with a highly suspicious and clearly resectable tumor, a preoperative needle biopsy is not always necessary, and the decision should be based on the overall treatment plan.

The first question in treatment planning is whether the cancer can be completely removed.

Surgery

For localized, resectable disease, surgery remains the main potentially curative treatment. More advanced but still resectable tumors may require removal of nearby liver tissue and regional lymph nodes.

For incidental gallbladder cancer discovered after a routine cholecystectomy, the pathology stage is particularly important. Current ESMO guidance recommends considering completion surgery for incidental gallbladder cancer at stage T1b or higher.

Surgical decisions therefore cannot be based simply on stage I, II, III, or IV labels. Tumor depth, lymph node involvement, invasion of nearby organs or blood vessels, and the ability to achieve complete tumor removal all need to be considered.

Adjuvant Treatment

Not every patient requires chemoradiation after surgery.

After complete resection, further treatment depends on the pathologic stage, lymph node involvement, surgical margins, and other factors associated with recurrence.

Capecitabine is an important standard adjuvant chemotherapy option after resection of biliary tract cancers, including gallbladder cancer.

Radiation or chemoradiation is generally reserved for selected patients with specific high-risk features rather than routinely given to everyone.

Unresectable, Recurrent, or Metastatic Disease

For unresectable, recurrent, or metastatic gallbladder cancer, older chemotherapy regimens based on drugs such as doxorubicin or mitomycin are no longer the main treatment framework.

Gemcitabine plus cisplatin remains an important chemotherapy backbone. Adding an immune checkpoint inhibitor such as durvalumab or pembrolizumab has become a standard first-line approach for advanced biliary tract cancers, including gallbladder cancer.

Treatment is individualized according to overall health, organ function, previous therapies, and tumor characteristics.

Molecular Testing and Targeted Therapy

Molecular and biomarker testing should be considered for unresectable, recurrent, or metastatic gallbladder cancer.

The molecular profile of gallbladder cancer differs somewhat from that of intrahepatic cholangiocarcinoma. HER2 amplification or overexpression and MSI-H/dMMR are particularly relevant, while alterations involving BRAF, NTRK, RET, and other genes may also provide treatment opportunities in selected patients. Current biliary tract cancer guidelines support performing broad molecular profiling before or during first-line treatment.

When an actionable biomarker is identified, targeted or biomarker-directed therapy may be considered according to previous treatment, the specific alteration, and local drug approvals.

Radiation Therapy

Radiation therapy may be used in selected patients after surgery, for unresectable local disease, or for metastatic lesions.

It can also help control symptoms caused by local tumor growth, pain, or certain metastatic sites.

Radiation is therefore used according to a specific clinical goal rather than simply because it has fewer systemic side effects than chemotherapy.

Biliary Drainage and Supportive Care

When a tumor causes significant bile duct obstruction and jaundice, endoscopic stent placement or percutaneous biliary drainage may be used to restore bile flow.

These procedures do not usually eliminate the cancer itself, but they can relieve jaundice and itching, reduce the risk of cholangitis, improve liver function, and make further cancer treatment possible.