Gall Bladder Cancer

Risk Factors

Exact causes of gall bladder cancer are not known. There are several risk factors for GBC that increases the risk of gall bladder cancers.

• Age- Gall bladder cancers are more frequent in older people [4]. In India GBC is more frequently observed above 45 years of age with maximum incidence at 65 years and above [6].

• Gender- Gall bladder cancer shows strong link to female gender [4]. More than half of the total gall bladder cases are in India are observed in women[6].

• Ethnicity- The risk of developing gall bladder cancer differs from one geographic region to another and for different racial groups [9]. Globally, gall bladder cancer is more in India, Pakistan, Eastern Europe, South American countries, East Asia and the lowest in Africa [3]. In India, the risk of developing gall bladder cancer is highest among north and North-east population while it is lowest among South Indians [6,7].

• Gallstones and Chronic Inflammation of Gall bladder- Gallstones are the most common risk factors for gall bladder cancer [10, 11]. Although direct evidence for causal relationship between gallstones and gall bladder cancer is lacking, studies show a significant association between the two [12]. Gallstones are mostly cholesterol, mixed with other substances found in bile and cause chronic inflammation of GB (cholelithiasis) [13]. Only about 1% patients with gall stones develop GBC [14]. Long standing inflammation of gall bladder (cholecystitis) by gallstones leads to the deposition of calcium on the gall bladder wall causing a condition called ‘porcelain gall bladder’ which increases the risk for GBC [11]. Around 25% (range 12% to 61%) of gall bladder cancers were associated with this condition [15]. A study from North India revealed that the prevalence of gallstones was more in females (5.59%) than males (1.99%) [16]. A family history of gallstones doubles risk of gall bladder cancer [1]. However, most people with an inflamed gall bladder or gallstones do not get gall bladder cancer.

• Genetic Factors

(a) Pancreas and bile duct abnormalities- Some congenital abnormalities (present since birth) of the pancreas and bile ducts increase the risk of getting gall bladder cancer [17,8].
(b) Choledochal cysts- Congenital choledochal cysts are bile-filled sacs (dilatations) along the bile duct that are connected to the common bile duct, the tube that carries bile from the liver and gall bladder and empties into the duodenum, a part of the small the intestine [18]. The cells lining these sacs often have areas of pre-cancerous changes, which increase a person’s risk for gall bladder cancer [4].

• Gall bladder polyps- Gall bladder polyp is a growth that develops on the inner surface of the gall bladder wall and may not be cancerous as such. These polyps may be formed either by cholesterol deposits in gall bladder, or may be caused by inflammation [9, 11]. Over a long period of time, a few of these polyps may develop into cancer [19].
  Polypoidal masses of the gall bladder are known to affect around 5% of adults [19]. Cancer risk depends on the size of the polyp; the larger the polyp the greater will be the risk that it will become cancerous. Polyps larger than one centimetre are more likely to be cancerous [9].

• Family History — If there is history of GBC in first degree relatives, a person’s chance of developing gall bladder cancer increases by almost five times [20]. Mutations in certain genes (BRCA2) which increase the risk of familial breast and ovarian cancers have been shown to slightly increase the risk for developing gall bladder and bile duct cancers [21]. 
  Variants of the APOB gene responsible for apolipoprotein B function, which influences cholesterol handling by the liver, have been associated with an increased risk for gallbladder can­cer; however this is independent presence of gall stones [22].

• Lifestyle Factors –

(a) Obesity- Being overweight can increase the risk of many types of cancers, including gall bladder cancer [12]. The association of GC with overweight was the second strongest among all cancer sites after that of cancer of the corpus uteri among women and liver cancer among men[12]. Obesity is in fact a risk factor for gallstones, which have a definite association with gall bladder cancer [23]. It has been estimated that one out of ten cases of gall bladder cancer in men and almost a fifth of cases in women are linked with obesity [20].

(b) Infection — Chronic infection with salmonella, the bacterium that cause typhoid, can cause gall bladder inflammation and this can increase the risk of gall bladder cancer in people who have gallstones [24,25]. Approximately 6% of carriers of Salmonella typhi developed gall bladder cancer and the association showed a 12-fold increase in risk for developing GBC [9]. A few studies show that Helicobacter pylori bacteria may also increase the risk of gall bladder cancer [26,27].

(c) Diabetes — Diet with increased quantities of proteins, fats and cholesterol and low in fibre, vegetables and fruits has been suggested as a risk factor for GBC [14]. Though a few studies from India which also suggest association but lack scientific evidence at a population level,  to prove the definite link between diet and GBC [29].

• Chemicals- Certain chemical compounds like nitrosoamines (found in cigarettes and in some industrial products) may increase the risk of GBC [30].
  Cluster analysis has showed a strong correlation with heavy metal pollutants in drinking water in an endemic population at high risk in specific villages of Vaishali district, Bihar, India [16]. Studies also show that people who smoke or work in the metal or rubber industry are more likely to develop gall bladder cancer than general public [16,30].

If you have one or more risk factors, it does not imply that you will get gall bladder cancer certainly. Many people with more or no exposure to risk factors also get cancer.
Gall bladder cancer is not common in all parts of India [6,8]. The symptoms and signs similar to the ones produced by GBC are more likely to be caused by some other more common conditions. For example, people with gallstones also have many of these symptoms. Yet, if you have any of these symptoms, it’s important to consult doctor without delay neglect so that the cause can be found and treated, if needed.

Prevention  

There is no sure way to prevent gall bladder cancers. We cannot modify risk factors such as age, gender, race, ethnicity and congenital abnormalities. But we can always take precautions to reduce the risk. Obesity is one of the important risk factor. It is always recommended to maintain healthy weight and lead an active life.

Healthy diet with cereals, whole grains instead of refined, at least two and half cups of fruits and vegetables daily, limiting intake of processed food and red meat have been shown to lower the risk of many cancers including GBC.

If the gall stones cause any problems that may warrant removal of gall bladder, it should be removed in consultation with the treating doctor.

Signs and Symptoms

Gall bladder cancer usually does not produce signs or symptoms in its early stages, but in late stages it presents with a number of symptoms. By the time your doctor diagnoses GBC, it may be at an advanced stage, where treatment options are limited. Many early stage gall bladder cancers are chance findings, when the patient comes for some other reason.
Other illnesses apart from gall bladder cancer can also cause symptoms similar to those produced by gall bladder cancer. However, it is important to consult a doctor and get yourself thoroughly examined and investigated to exclude GB pathology.

Common symptoms of gall bladder cancer:

Abdominal pain: Most people with gall bladder cancer have an aching feeling on the upper right part of the tummy. One may feel a sharper pain if the gall stones or cancer block the bile duct.

Nausea and/or vomiting:

Jaundice: Fifty per cent of the people diagnosed with gall bladder cancer have jaundice [15].  
Jaundice is a yellowing of the skin and the white part of the eyes. Jaundice is due to the accumulation of a bile salt called bilirubin (a chemical that gives bile its yellow colour) in the blood [17]. If the cancer grows large enough to block the bile ducts, bile from the liver can’t drain into the intestines. This can cause build-up of bilirubin in the blood and body tissues causing jaundice [17]. It may produce symptoms like severe itching, darkened urine, or pale coloured stools.
Having jaundice does not always imply that you have gall bladder cancer. A much more common cause of jaundice is a viral infection of the liver (hepatitis). However, if it is due to GBC, it indicates an advanced stage of cancer.

Lump in the abdomen: If the cancer growth blocks the bile ducts, the gall bladder may swell much larger than its normal size and may present as a lump in the right side of the tummy.

Other symptoms: Less common symptoms of gall bladder cancer includes loss of appetite, fever, weight loss.
Gall bladder cancer is not common in all parts of India [6,8]. The symptoms and signs similar to the ones produced by GBC are more likely to be caused by some other more common conditions.  For example, people with gallstones also have many of these symptoms. Yet, if you have any of these symptoms, it’s important to consult doctor without delay neglect so that the cause can be found and treated, if needed.

Diagnosis

• History: Gallbladder cancer (GBC) does not usually cause signs or symptoms in early stages, but in late stages patients may present with vague symptoms like abdominal pain, nausea and/or vomiting, jaundice, lump in the belly, loss of appetite, weight loss, swelling in the abdomen (belly), fever, etc.
• Physical Examination: The physical examination focuses mostly on the abdomen to check for any lumps, tenderness, or collection of fluid. Eyes are checked for jaundice (a yellowish color). Sometimes, cancer of the gallbladder spreads to lymph nodes, causing enlarged nodes that can be felt beneath the skin.
• Blood tests: 
  There are no biochemical tests of importance for early diagnosis.
  Hemogram:
  Liver Function Tests: Elevated alkaline phosphatase and bilirubin levels are often found with more advanced disease.
  Imaging tests: detect structural changes in the gallbladder induced by GBC which include replacement of gallbladder lumen by mass (40-65%), focal or diffuse parietal thickening (20-30%) and intraluminal polyp (15-25%).
• Ultrasound of the abdomen: Ultrasonography is a standard initial study in patients with right upper quadrant pain. It also can delineate metastatic lesions in the liver.The diagnostic accuracy of USG is over 80% in detecting carcinoma gallbladder [31].It is seen as a fixed polypoidal mass projecting in to the lumen of the gallbladder with absence of acoustic shadowing or as an asymmetric thickening of the gallbladder wall. Advanced tumours also show loss of interface between gallbladder and liver indicating tumour invasion, lymph node and hepatic metastases, dilated bile ducts and ascites.
• Contrast Enhanced Computed Tomography scan (CECT)/Magnetic Resonance Imaging of the abdomen (MRI): The main advantage of CT lies in showing tumour infiltration into adjacent viscera or vessels,lymph node and distant metastases.The morphologic appearances of carcinoma gallbladder are similar on MRI and CT.
• MRI is poor in detecting peritoneal deposits. MRCP (Magnetic resonance cholangiopancreatography) and MRA (Magnetic Resonance Angiography) are of superior diagnostic validity in detection of biliary invasion, vascular invasion, hepatic invasion and lymph node involvement MRCP is especially indicated in patients with jaundice [32].
• Endoscopic retrograde cholangiopancreatography (ERCP): This is a procedure used to X-ray the tubes that carry bile from the liver to the gallbladder and from the gallbladder to the small intestine. A thin, lighted tube is passed through the mouth, esophagus, and stomach into the first part of the small intestine. A smaller tube is then inserted through the endoscope into the bile ducts. A dye is passed through the catheter into the ducts and an X-ray is taken. Sometimes gallbladder cancer causes these ducts to narrow and block or slow the flow of bile, causing jaundice. This tube may be left in place to keep the duct open. Tissue samples may also be taken.
• Biopsy: This procedure is usually performed under the ultrasound guidance.

Fine needle aspiration biopsy/cytology (FNAB/FNAC): a very thin needle attached to a syringe is used to aspirate a sample of cells without using anesthesia.
FNAC is not indicated in resectable GBC because the tumor has propensity for seeding the biopsy tracts and resection should be performed even if FNAC is negative. However, if there is clinical evidence of distant metastatic disease (e.g. left supraclavicular lymph node, umbilical nodule, liver nodule, pelvic deposits or ascites) a tissue diagnosis should be obtained (FNAC, fluid cytology) from the metastasis. A few centers use Endoscopic ultrasound-guided FNAC in suspicious gallbladder lesions and has been reported to have sensitivity rate of 80% and specificity of up to 100% [33].

Core needle biopsy: A larger, hollow needle is inserted into the mass and cylindrical piece of tissue (core) is taken out for histopathological examination to confirm cancer. A core biopsy provides more tissue for examination than FNA.
If the surgeon is planning for removal of gallbladder tumour, then it is not always necessary to have a biopsy report.

In a Jaundiced patient:

a. Coagulation profile (prothrombin time, etc.)
b. Magnetic Resonance CholangioPancreaticography (MRCP)
c. Endoscopic Retrograde CholangioPancreaticography (ERCP)/Percutaneous Transhepatic Cholangiography (PTC) if a therapeutic intervention (biliary stenting) is planned
d. Informed Consent for Extended Cholecystectomy (EC)

Optional Investigations
– Positron Emission Tomography (PET) scan
– Tumor markers: Serum Ca 19-9, CEA are not very specific in the diagnosis of gall bladder cancer. But their rise may add to the diagnosis [34]

Staging

Primary tumor (T)

TX Primary tumor cannot be assessed
T0  No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor invades lamina propria or muscular layer
T1a  Tumor invades lamina propria
T1b  Tumor invades muscular layer
T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver
T3  Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum or extrahepatic bile ducts
T4 Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures

Regional lymph nodes (N)

NX  Regional lymph nodes cannot be assessed
N0  No regional lymph node metastasis
N1  Metastases to nodes along the cystic duct, common bile duct, hepatic artery and/or portal vein
N2  Metastases to periaortic, pericaval,superior mesenteric artery and/or celiac artery lymph nodes

Distant metastasis (M)
M0  No distant metastasis
M1  Distant metastasis

Stage grouping
Stage 0  Tis N0 M0
Stage I   T1 N0 M0
Stage II  T2 N0 M0
Stage IIIA  T3 N0 M0
Stage IIIB  T1–3 N1 M0
Stage IVA  T4 N0–1 M0
Stage IVB  Any T N2 M0
            Any T Any N M1

Histological Grade (G)
GX  Grade cannot be assessed
G1  Well differentiated
G2  Moderately differentiated
G3  Poorly differentiated
G4  Undifferentiate

For more information please visit http://www.icmr.nic.in/guide/cancer/Gall%20Bladder/GALLBLADDER%20CANCER.pdf

Treatment

A. Resectable GBC [pT1-3 (Selected T4), N0-1, M0]

(Medically fit patients)

1. Surgery

pT1a* – Simple Cholecystectomy (with negative cystic duct margin)

pT1b, pT2† – Extended Cholecystectomy (enbloc wedge resection/segment

IVb+V resection of the liver + LND#) + CBD resection

pT3, pT4**#† – Enbloc hepatic resection + cholecystectomy 

*It is very difficult to diagnose pT1, pT2 GBC preoperatively. It is usually diagnosed upon HPE of the cholecystectomy specimen. Relaparotomy and hepatic resection+ LND ±CBD resection is indicated in pT1b and above incidental GBC.

It is advisable to open every cholecystectomy gallbladder specimen to look for any suspicious mass lesion/thickening and intraoperative frozen section if facilities and the necessary expertise are available.

2. Adjuvant Therapy

pT2 and above (following complete tumor resection):

Adjuvant chemotherapy/chemoradiotherapy 

B. Metastatic /Unresectable GBC

1. Palliative Chemotherapy (Medically fit patients) 

2. Palliative Radiotherapy

May be used for relief of pain in selected patients

3. Other Palliative procedures

•• for relief of jaundice and pruritis – ERCP and stenting (metallic/plastic stent)

•• for pain relief – Medicines as per the WHO step-ladder or celiac plexus block in refractory cases

•• for relief of gastric outlet obstruction – Gastrojejunostomy in patients with good performance status

4. Neoadjuvant Chemotherapy/Chemoradiotherapy

Only in context of a clinical trial

Follow-up

Every 6 months for 2 years

There is no robust data to support aggressive surveillance post resection. Patients may be followed up by imaging. Re-staging according to initial workup should be considered in the event of disease relapse or progression. 

For detailed treatment protocols, please refer to the pdf.

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