Special Surgery 11. Malignant Diseases of the Gallbladder and the Biliary Tract: Symptomatics, Diagnostics and Treatments

I. Types, Epidemiology and Risk Factors

Main Tumors

1. Gallbladder carcinoma
2. Cholangiocarcinoma / bile duct cancer

• Both are usually adenocarcinomas
• Often diagnosed late
• Only curative treatment is complete surgical resection in resectable disease
• Many patients present with unresectable or metastatic disease

Gallbladder Carcinoma

• Malignant tumor from gallbladder mucosal lining
• Histology: mostly adenocarcinoma
• Rare but highly aggressive
• More common in women
• Often found incidentally after cholecystectomy for presumed benign gallstone disease

Risk Factors

• Cholelithiasis with chronic inflammation
• Large gallstones
• Chronic cholecystitis
• Porcelain gallbladder: calcified gallbladder wall
• Gallbladder polyp, especially > 1 cm, sessile, growing or symptomatic
• Anomalous pancreaticobiliary junction
• Primary sclerosing cholangitis can increase biliary malignancy risk
• Female sex, older age

Cholangiocarcinoma

• Malignant tumor derived from epithelial cells of biliary ducts
• Histology: adenocarcinoma
• Peak incidence: 60-70 years
• Male predominance in many series

Classification by Location

1. Intrahepatic cholangiocarcinoma
2. Perihilar cholangiocarcinoma: Klatskin tumor
3. Distal extrahepatic cholangiocarcinoma

• Intrahepatic: small-medium bile ducts within liver
• Perihilar: hepatic duct confluence / hilum
• Distal: distal common bile duct, near pancreas/ampulla

Bismuth-Corlette Classification for Perihilar Tumors

• Type I: below hepatic duct bifurcation; confluence free
• Type II: reaches hepatic duct bifurcation/confluence
• Type IIIa: extends into right hepatic duct
• Type IIIb: extends into left hepatic duct
• Type IV: involves both right and left hepatic ducts / multifocal hilar involvement

Risk Factors

• Primary sclerosing cholangitis (PSC)
• Choledochal cysts
• Hepatolithiasis / intrahepatic bile duct stones
• Choledocholithiasis and chronic biliary inflammation
• Liver flukes: Clonorchis sinensis, Opisthorchis viverrini
• Liver cirrhosis
• Chronic viral hepatitis B or C, especially for intrahepatic type
• Biliary strictures, recurrent cholangitis
• Toxins: Thorotrast exposure in classical teaching

II. Symptoms and Spread

Gallbladder Carcinoma: Clinical Features

• Early stage often asymptomatic
• May mimic gallstone disease or chronic cholecystitis
• Right upper quadrant pain / biliary colic-like pain
• Weight loss, anorexia, malaise
• Nausea and vomiting
• Jaundice usually late:

• Bile duct invasion/compression
• Liver hilum involvement
• Advanced nodal disease

• Palpable mass, hepatomegaly or ascites in advanced disease
• Acute cholecystitis-like presentation can occur

Cholangiocarcinoma: Clinical Features

• Progressive painless obstructive jaundice is typical for extrahepatic tumors
• Cholestasis:

• Jaundice
• Dark urine
• Acholic/pale stools
• Pruritus

• Weight loss, anorexia, fatigue
• RUQ discomfort; severe pain is less typical early
• Fever/chills if cholangitis develops
• Intrahepatic cholangiocarcinoma can present as liver mass with pain/weight loss and less jaundice

Courvoisier Sign

• Palpable, painless, enlarged gallbladder with obstructive jaundice
• Suggests malignant distal biliary obstruction rather than chronic gallstone obstruction
• Can be seen with pancreatic head cancer, distal cholangiocarcinoma or ampullary cancer

Spread and Metastasis

• Gallbladder carcinoma:

• Direct invasion into liver segments IVb/V
• Spread to hepatoduodenal ligament nodes
• Peritoneal dissemination
• Liver and distant metastases in advanced disease

• Cholangiocarcinoma:

• Longitudinal spread along bile duct wall
• Perineural and lymphatic invasion common
• Vascular invasion: portal vein/hepatic artery affects resectability
• Liver, peritoneal and nodal metastases

III. Diagnostics and Staging

Laboratory Tests

• Cholestatic pattern:

• Increased direct/conjugated bilirubin
• Increased ALP and GGT
• AST/GOT and ALT/GPT can be increased

• CBC and CRP if cholangitis/inflammation suspected
• Coagulation and albumin for liver function/preoperative risk
• Tumor markers:

• CA 19-9 and CEA can support diagnosis/follow-up
• Not diagnostic alone
• CA 19-9 can be falsely high in cholangitis or obstructive jaundice

Ultrasound

• First-line imaging for jaundice/RUQ symptoms
• Shows biliary dilatation and level of obstruction
• Gallbladder cancer signs:

• Mass replacing gallbladder
• Irregular wall thickening
• Polypoid lesion
• Loss of normal wall layers
• Liver invasion or stones may be seen

• Cholangiocarcinoma signs:

• Intrahepatic duct dilatation
• Hilar or distal obstruction pattern
• Mass may be difficult to visualize directly

CT and MRI/MRCP

• Contrast-enhanced CT chest/abdomen/pelvis:

• Local invasion
• Liver involvement
• Lymph nodes
• Vascular involvement
• Distant metastases
• Operability/resectability planning

• MRI/MRCP:

• Best non-invasive mapping of biliary tree
• Defines stricture length and ductal anatomy
• Useful for perihilar cholangiocarcinoma and bile duct involvement by gallbladder cancer
• Assesses liver invasion and vascular relation

ERCP / PTC

• ERCP:

• Brush cytology and biopsy from stricture
• Biliary stent placement for drainage
• More useful for distal obstruction

• PTC / PTBD:

• Percutaneous transhepatic cholangiography/drainage
• Useful for high hilar obstruction or failed ERCP
• Allows external/internal drainage and sampling

• Tissue diagnosis may be difficult in cholangiocarcinoma; negative brush cytology does not exclude cancer
• Biopsy is especially important before chemotherapy or when disease is unresectable/metastatic

Additional Staging Tools

• Endoscopic ultrasound:

• Distal bile duct tumors
• Regional lymph node sampling
• Differential with pancreatic/ampullary cancer

• PET-CT:

• Selected cases for occult distant metastasis
• Not a replacement for high-quality CT/MRI

• Diagnostic/staging laparoscopy:

• Can detect occult peritoneal or liver surface metastasis before laparotomy
• Useful in high-risk gallbladder cancer or cholangiocarcinoma considered for major resection

Resectability Assessment

• Assess:

• Distant metastasis
• Peritoneal disease
• Liver remnant volume/function
• Portal vein/hepatic artery involvement
• Bilateral hepatic duct involvement for hilar tumors
• Patient fitness for major hepatobiliary surgery

• Onco-team decision is essential
• Drain cholangitis urgently; preoperative biliary drainage is selective, not automatic for every jaundiced patient

IV. Treatment

General Principles

• Curative intent requires R0 resection
• Major operations should be done in hepatopancreatobiliary centers
• Unresectable/metastatic disease → biliary drainage if symptomatic + systemic therapy/palliation
• Relieve jaundice/pruritus/cholangitis when obstruction causes symptoms or prevents systemic therapy

Gallbladder Carcinoma Treatment

Incidental Cancer after Cholecystectomy

• T1a: tumor invades lamina propria
• Simple cholecystectomy is usually sufficient if margins are negative
• T1b or higher:

• Re-resection / extended radical cholecystectomy if no metastasis and patient fit
• Liver wedge resection or segment IVb/V resection
• Portal/hepatoduodenal ligament lymphadenectomy
• Resection of extrahepatic bile duct only if involved or needed for margin/lymphadenectomy, not routine for all

Known Resectable Gallbladder Cancer

• Radical cholecystectomy:

• Cholecystectomy
• En bloc liver resection of gallbladder bed, usually wedge or segments IVb/V
• Regional lymphadenectomy
• Adjacent organ resection if directly invaded and R0 possible

• Avoid laparoscopic simple cholecystectomy if cancer is suspected preoperatively, unless oncological plan supports it

Unresectable / Metastatic Gallbladder Cancer

• Palliative biliary stent or percutaneous drainage if obstructive jaundice/cholangitis/pruritus
• Systemic therapy:

• Gemcitabine + cisplatin backbone
• Checkpoint inhibitor added in many current first-line biliary tract protocols if patient eligible
• Molecular testing for MSI/MMR, HER2 and other actionable targets depending on local practice

• Palliative surgery/bypass only if endoscopic/percutaneous drainage is not feasible or for selected obstruction

Cholangiocarcinoma Treatment by Location

Intrahepatic Cholangiocarcinoma

• Curative option: liver resection with negative margins
• Regional lymphadenectomy often considered for staging/clearance depending on center and extent
• Portal vein embolization can be used before major hepatectomy if future liver remnant is small
• Unresectable/metastatic → systemic therapy, local liver-directed therapy only in selected centers

Perihilar Cholangiocarcinoma / Klatskin Tumor

• Requires detailed biliary and vascular mapping
• Curative surgery often includes:

• Extrahepatic bile duct resection
• Major hepatectomy depending on side/extent
• Caudate lobe resection often needed because caudate ducts drain near hilum
• Regional lymphadenectomy
• Roux-en-Y hepaticojejunostomy reconstruction

• Selected unresectable perihilar tumors may be candidates for liver transplantation under strict protocols after neoadjuvant therapy

Distal Extrahepatic Cholangiocarcinoma

• Curative operation: pancreaticoduodenectomy
• Whipple procedure includes:

• Pancreatic head resection
• Duodenum resection
• Cholecystectomy
• Distal common bile duct resection
• Regional lymphadenectomy
• Gastrointestinal and biliary/pancreatic reconstruction

Adjuvant and Palliative Therapy for Cholangiocarcinoma

• Adjuvant therapy after resection:

• Capecitabine is commonly used as reference adjuvant therapy after resected biliary tract cancer
• Chemoradiotherapy can be considered in selected margin-positive or node-positive extrahepatic disease depending on protocol

• Unresectable/metastatic disease:

• Biliary stent by ERCP or PTBD to treat obstruction
• Gemcitabine + cisplatin backbone
• Checkpoint inhibitor addition in many current first-line protocols if eligible
• Targeted therapy depending on molecular findings, especially IDH1 mutation or FGFR2 fusion in intrahepatic cholangiocarcinoma
• Photodynamic therapy, radiotherapy or local ablative therapy in selected centers/patients

Prognosis

• Generally poor because symptoms occur late
• Best prognosis: incidental early T1a gallbladder cancer fully removed by cholecystectomy
• Worse prognosis with:

• Positive margins
• Lymph node metastasis
• Vascular/perineural invasion
• Peritoneal or distant metastasis
• Poor performance status and cholangitis/malnutrition