Gallbladder Cancer (and polyps)
DEFINITION

Gallbladder malignancy.
Gallbladder polyps also discussed here.
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EPIDEMIOLOGY

An uncommon tumour but perhaps 1% of cholecystectomies

Risk Factors
75-98% have cholecystitis / gallstones
Chronic inflammation with high cellular turnover, including in:
- cholecystoenteric fistula, typhoid bacillus,
- anomalous pancreatico-biliary jx.

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AETIOLOGY

AdenoCa
See below re polyps
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BIOLOGICAL BEHAVIOUR

Natural History
5-y survival historically <5%
- median 5-8m
- essentially all survivors are Stage I or II
But being improved by modern radical surgical approaches
--> treatment of choice for pts with disease confined to local region or liver and porta hepatis

Pathophysiology
60% originate in fundus, 30% in body, 10% in neck.
Most grow diffusely infiltrative, tend to involve whole gallbladder by spreading in the subserosal plane.
... i.e. the same plane dissected in a lap chole.
--> hence a) tumour generally not recognised at surgery; and b) tends not to be completely excised.
Nodular type
A distinct variety that grows as a lump,
- easier to treat surgery as margins are better defined.
--> but bad prognosis as aggressive with earlier invasion to liver and adjacent structures.
Papillary growth pattern
Better prognosis, even large tumours may have minimal wall invasion.

Spread patterns
Gallbladder sits on segments IVb and V, hence these tend to be involved early in tumours of the fundus and body.
Direct extension in portal triad structures - portal vein, hepatic artery and bile duct - is common
- a major cause of symptoms
Lymph invasion is also common, most often involving cystic and pericholedochal nodes,
--> then to nodes behind pancreas, portal vein and common heaptic artery.
--> when advanced, gets to celiac axis, SMA, aortocaval nodes.
In general, gallbag Ca has an 'incredible' propensity to seed and grow.
- readily grows along needle biopsy tracts and laparotomy port sites.
- any bile spillage during a lap chole may portend widespread seeding.
Haematogenous spread less common, but may present as noncontiguous liver mets, more rarely lung and brain.

Gallbladder Polyps
Adenoma to carcinoma sequence has been demonstrated with adenomatous polyps
Gallbladder polyps noted in 3-6% of population undergoing USS.
- most are cholesterol polyps or adenomyomatosis; no malignant potential.
- but 1% of GB specimens from lap chole contain adenomatous polyps with malignant potential.
Risk factors of polyps:
- >1 cm
- patients >50 yrs
- multiple lesions.
Conservative recommendation is to remove all polyps >0.5mm in size
- though extremely low risk if polyps are <1cm
Best to remove polyps >1cm
- if  <0.5cm, can certainly just follow safely with serialultrasounds.

Porcelain Gallbladder
Deposition in gallbladder wall, due to state of chronic inflammation.
Risk of malignancy is probably <10%, greater if stippled vs diffuse.
--> perform lap chole.

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MANIFESTATIONS

Often identical to biliary colic and chronic cholecystitis
- often found incidentally on pathology

When symptomatic with obstructive biliary or vascular problems, will be advanced disease.

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INVESTIGATIONS

Labs
Blood tests not typically distinguishable from benign gallbladder diseases
Elevated ALP and Bili in advanced tumours
CEA is specific in this context but 50% sensitive
CA19-9 > 20 units/mL has 80% sensitivity and specificity

Imaging
Vigilant imaging is key; may be only distinguishing point.
Any mass or polyp, or presence of porcelain gallbladder should be treated seriously.
Even at late stages may be mistaken for benign disease or Mirizzi syndrome.
- any obstruction of mid-CBD should be considered gallbladder cancer until proven otherwise.
Typically, CT and USS requested first
ERCP for duct obstruction.
MRCP very suitable for low grade duct concern.
Doppler USS and MR angiography may provide vital information on resectability if concern for hepatic artery involvement.
PET = useful in diagnosin nodal, peritoneal and distant mets, may alter therapy in ~25%, by showing pts unsuitable for operative intervention.

Staging
AJCC System.
I = mucosal (T1N0M0)
II = muscular invasion (T2N0M0)
IIIA = transmural, directly invasive (T3N0M0)
IIIB = T1-3 but with nodal involvement (T1-3N1M0)
IV = vascular invasion, metastatic disease.
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MANAGEMENT

Principles
Surgical excision is the treatment of choice.
--> i.e. when confined to the local region of the liver and porta hepatis.
Radical surgery may be appropriate
- currently no RCT evidence
- but, routine resection of gallbladder bed / segments IVb and V +/- CBD gaining popularity, even when cystic duct margin clear.

Surgical Management

1. Controversy exists without much good evidence.
Practically, base management on the T stage, as it is closely related to prognosis.

2. Tis or T1 cancer
May be discovered incidentally and luckily on lap chole
If limited to muscularis propria and staging -ve --> no need for further surgery.
- excellent 5-year survival of 90-100%
Lap chole is sufficient for T1 cancer.
- no nodal excision
--> an abundance of data to support this view; lymph mets very uncommon.
But great care must be taken with histology:
- rule out areas of deeper invasion, because if wall margin involved, liver resection required.
- and if cystic duct stump involved, then CBD excision required. 

3. T2 disease
Tumour invades subserosal layer.; invade muscular coat but don't penetrate serosal plane.
When performing a lap chole, the cystic plate is left behind,because subserosal plane is least-bloody for dissection.
- so all the gallbladder is not removed.
And rate of LN involvement now exceeds 50%
Radical resection including liver and regional nodes
- these patients stand to benefit most from further surgery
--> may improve survival from 20-60% up to 70-100%
Regional LN dissection includes periportal, peripancreatic and celiac nodes.
- and resection of the CBD, which greatly facilitates nodal clearance.
- full Kocher and taking lymphatic tissue behind duodenum and pancreas.
- Roux-en-Y hepaticojejunostomy.
Controversy as to extent of liver resection:
- leading centers perform anatomic segments IVb and B if possible; greatest chance of tumor clearance while being safe.
- some prefer a limited wedge excision of 2cm around GB bed, particularly if patients high risk.
Excise all laparoscopic port sites in full-thickness manner if post-cholecystectomy diagnosis.
- else port site seeding rate up to 14%

4. T3 and T4 tumours
Advanced disease with hepatic mass.
Debate over benefits of radical surgery, but long-term survivors are being reported with radical therapy.
- median survival is 10m
Leading centres will operate aggressively with a view that it remains a potentially curative situation.
- careful staging workup for signs of mets or unresectability; including PET
Major liver resection and regional lymphadenectomy as for T2.
Complications are common; bile leak, liver failure, abscesses, respiratory failure.
For T4 diseaese, with or without liver invasion greater than 2cm, extended hepatectomy is required.

5. Adjuvant Therapy?
Single prospective RCT exists.
Survival improved with post-op adjuvant chemo but data not definitive.
Yuman Fong et al in Cameron recommend radiotherapy for node-positive disease, and chemo as a radiation-sensitizing agent following resection.

6. Palliation of unresectable disease
Median survival is just 2-4m
Only radiologic or endoscopic biliary drainage is justifiable, not surgical.
Systemic chemo and radio generally ineffective.

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REFERENCES

Cameron 10th