Editing 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

[[Category:Biliary]]