Gallbladder cancer

Epidemiology

• Generally occurs 50-70yo
• High incidence in:
  • Bolivia
  • Chile
  • India
  • Pakistan
  • Poland
• Rare in Western countries (1.13 per 100,000)
  • F:M 2:1
  • Found in approximately 1% of cholecystectomy specimens
  • Porcelain gallbladder - 2-3% have cancer
    • This is probably reflective of long-term inflammation

Risk factors

• Gallstones present in 70-90%
  • Large stones (>3cm) seem to give a ten-fold increase in risk compared to small stones
  • Type of stone not important
• Females
• Older age
• Obesity
• Chronic cholecystitis
• Occupational carcinogen exposure
• Poor diet
• Chronic salmonella infection
• Biliary cysts
• Aberrant PBDJ (long common channel)
• Choledochal cysts
• PSC
• Medications
  • Methyldopa
  • Isoniazid

Pathophysiology

• Generally adenocarcinoma (90%), with some squamous or adenosquamous type
  • Subtypes:
    • Infiltrative - most common - spread in sub-serosal plane (same plane dissected during cholecystectomy)
    • Nodular - tend to grow as a more circumscribed mass and can invade the liver
    • Papillary - better prognosis - tend to be limited to GB wall at time of diagnosis
    • Combined
• Two proposed pathways:

• • Chronic inflammation leading to mucosal transformation (most likely)
  • Aberrant PBDJ with pancreatic juice reflux

• There is some suggestion of an adenoma-carcinoma sequence, as carcinomas are often adjacent to carcinomas-in-situ or severe dysplasia, but no known increased risk from small polyps <10mm
• Location

• • 60% fundus
  • 30% body
  • 10% neck

• The GB wall is thin, with only a narrow lamina propria, and is only a single muscular layer with no serosal covering between it and the liver, so early liver invasion is common
• Spreads via lymphatics, blood and via local invasion into peritoneal cavity or along surgical tract wounds

• • First draining nodal basin includes the cystic and peri-choledochal nodes, then to the retro-portal and pancreaticoduodenal nodes, and then the coeliac, superior mesenteric, and finally aortocaval nodes (so full staging may require a Kocher manoeuvre
  • High propensity to spread to peritoneum, causing carcinomatosis
  • Can also directly extend into porta hepatis structures
  • Common metastatic locations:
    • Noncontiguous liver mets (91%)
    • Lung (32%)
    • Brain (5%)

Presentation

• Frequently asymptomatic, since most cancers form in body/neck
• Symptoms are a good prognostic indicator, since it means they present earlier
  • Can present with symptoms of acute or chronic cholecystitis
  • Constitutional symptoms
• Specific situations:

• • Pre-operative workup for biliary symptoms

• • Cancer can cause similar symptoms to biliary colic

• • Incidental imaging finding

• • Any GB mass, or polyp > 1cm, or presence of porcelain GB, should raise suspicion
  • DDx of GB mass
    • Benign:
      • Cholesterolosis
      • Cholesterol polyps
      • Adenomyomatosis
      • Intracholecystic papillary-tubular neoplasms (ICPN/inflammatory polyps and adenomas)
    • Malignant
      • GB cancer
      • Mets

• • Intra-operatively

• • Do not need to immediately convert to open - best to abort operation and refer to HPB surgeon

• • Post-operatively on histopathology
    • Early GB cancer may be difficult to differentiate from chronic cholecystitis

Workup

• USS as initial evaluation
• MRCP is better at differentiating benign from malignant lesions, and looking for invasion
• CT C/A/P indications:
  • Suspected GB cancer pre-op
  • Post-op if intra-op impression of >T1a stage
• CEA - >4ng/mL is 93% sp for GB cancer but only 50% sensitive
• CA19-9 >20units/mL is 79.4% sp / 79.2% se
• Imaging review for liver involvement, biliary extension, vascular involvement, ascites, and/or mets
• PTC/ERCP has low yield
• FDG-PET: 86% of GB cancer is avid, however there is a low overall sensitivity for detecting mets, and rarely changes management
  • Utility increased among patients without a prior cholecystectomy, or patients with suspicious nodal disease on CT, or consider when looking for distant mets while deciding whether to operate
• Avoid percutaneous biopsy - tends to seed biopsy tracts

Staging

• If T2/3/4 disease is present, >50% chance of regional lymphatic mets
• Mostly diagnosed at a late stage
  • 35% nodal disease and 40% metastases

• Gallbladder cancer TNM staging AJCC UICC 8th edition - to follow

Management

• Principles
  • Resection is the only chance for cure
• Based on TNM stage
• T1a disease:
  • Cholecystectomy is sufficient
  • Out of 706 patients, only 1.8% had LN mets, and only 1.1% died from disease
  • Carefully verify negative margins, especially cystic duct
  • If GB wall margin is involved, liver resection will be necessary
  • If cystic duct margin is involved, CHD and extra-hepatic CBD excision with Roux-en-Y reconstruction, but no staging workup or nodal dissection necessary
• T1b disease:
  • Need complete staging workup
  • Traditionally, simple cholecystectomy, but now aggressive resection is favoured, especially in setting of high-risk histopathological factors (perineural, lymphatic or vascular invasion)
  • Higher rate of LN mets than T1a (10.9%) and up to 13% have residual disease at re-excision
  • Offer re-excision with radical/extended cholecystectomy
• T2a disease:
  • May not need to re-resect because rate of liver involvement is obviously lower, although this is partly controversial, and UTD still recommends re-resection as for T2b
• T2b disease:
  • 10.4% have hepatic disease
  • 31% have N1 LN involvement
  • Strong indication for definitive extended re-excision - extend 5-year survival from 20% to >80%
  • Radical cholecystectomy
• Advanced tumours (T3):
  • Radical resection may be potentially curative in some patients, although outcomes are poor
  • Start with staging laparoscopy - peritoneal or hepatic metastases preclude an operation
  • Everything aimed at getting complete resection - no role for debulking if R0 cannot be obtained
  • Likely to be considered for adjuvant chemotherapy
• T4
  • UTD states that attempts at resection are likely futile. Could still be considered.
• Choice of re-resection procedure
  • 2cm rim of liver tissue vs anatomic IVb/V resection - similar recurrence rate, as long as negative margins are obtained, but the anatomic resection has a lower complication rate
  • Either way, remove lymph nodes from cystic triangle, hepatoduodenal ligament and porta hepatis
  • May require resection of CBD margin, in which case reconstruction will be needed
  • Consider port site resection although probably not
• Unresectable or metastatic disease
  • Chemotherapy and radiotherapy have not shown survival benefits
  • Jaundiced patient with advanced unresectable disease should have PTC or ERCP drainage
    • Biliary bypass is generally difficult because of advanced disease in porta hepatis
  • Neurolysis of coeliac plexus can help with pain
  • Can get GOO from local extension of tumour, which can be managed by an endoscopic duodenal stent
• Portal lymphadenectomy
  • Indicated in T2-T4 tumours
  • Most surgeons resect cystic, periportal, and hepatic artery nodes
  • Guidelines suggest that you need six nodes to be considered node negative
• Port site resection
  • Not associated with improved overall or disease-free survival
• Absolute contraindications to surgery:
  • Medical comorbidities preventing surgery
  • Distant mets including liver, peritoneum
  • Involvement of N2 lymph nodes (coeliac, peripancreatic, peri-duodenal, or SMA
  • Malignant ascites
  • Significant involvement of hepatoduodenal ligament
  • Encasement of major vasculature

Five year survival rate

• Stage I: 40%
• II: 12%
• III: 5%
• IV: 1%, median survival 13 months