Gall Bladder Cancer as a “Silent Killer”

About Author: Rinki Verma (Research fellow)
Institute of Medical science (CEMS)
Banaras Hindu University
Varanasi - 221005

Abstract:
Gallbladder cancer is a comparatively rare cancer and has poor outcome due to their anatomy and location. It has peculiar geographical distribution being common in central and South America, central and eastern Europe, Japan and northern India; it is also common in certain ethnic groups e.g. Native American Indians and Hispanics (Kapoor VK, McMichael AJ ,2003. It is fifteen uncommon cancers in the world with high mortality rate. The diagnosis is made very late due to its silent course. The majority of patients have advanced disease at the time of presentation which carries a poor prognosis. The modes of spread of gall bladder carcinoma are direct, lymphatic, vascular, neural, intraperitoneal and intraductal. Ultra Sound, CT and MRI are helpful in diagnosis and staging of the disease. Surgery remains the mainstay of treatment and chemotherapy has a very limited role.

Reference Id: PHARMATUTOR-ART-1194

Introduction:
Gall bladder cancer (GBC) is an uncommon but highly fatal malignancy; fewer than 5000 new cases are diagnosed each year in the United States. The majority are found incidentally in patients undergoing exploration for cholelithiasis; a tumor will be found in 1 to 2 percent of such cases [Carriaga M.,et alr 1995; Hamrick RE Jr,et al 1982; Yamaguchi K, et al 1996;A prospective analysis of 1518 laparoscopic cholecystectomies. The Southern Surgeons Club. N Engl J Med 1991]. The gallbladder is a pear-shaped (fig.1) organ that lies just under the liver in the upper abdomen. The gallbladder stores bile, a fluid made by the liver to digest fat. When food is being broken down in the stomach and intestines, bile is released from the gallbladder through a tube called the common bile duct, which connects the gallbladder and liver to the first part of the small intestine.The wall of the gallbladder has 3 main layers of tissue. Mucosal (innermost) layer, Muscularis (middle, muscle) layer and Serosal (outer) layer. Between these layers is supporting connective tissue. Primary gallbladder cancer starts in the innermost layer and spreads through the outer layers as it grows.The poor prognosis associated with GBC is thought to be related to advanced stage at diagnosis, which is due both to the anatomic position of the gallbladder, and the vagueness and nonspecificity of symptoms

Figure-. Showing the development of tumor blocks in the Gall bladder.

Epidemiology:
Globally, there is a prominent geographic variability in GBC incidence that correlates with the prevalence of cholelithiasis. High rates of GBC are seen in South American countries, particularly Chile, Bolivia, and Ecuador, as well as some areas of India, Pakistan, Japan and Korea [Strom BL et al 1995 & Randi G et al 2006]. In Chile, mortality rates from GBC are the highest in the world. These populations all share a high prevalence of gallstones and/or salmonella infection, both recognized risk factors for GBC [Lazcano-Ponce EC et al 2001; Wistuba II et a 2004 & Miquel JF et al 1998]. Both genetic factors and socioeconomic issues that delay or prevent access to cholecystectomy for gallstones are thought to be contributory [Serra I , 1996 & Randi G et al 2009]. (See 'Risk factors' below and 'Molecular pathogenesis' below.) North America is considered a low incidence area. In the United States, GBC is the most common cancer arising in the biliary tract [Carriaga M.,et alr 1995]. Estimates from the SEER (Surveillance, Epidemiology and End Results) database reveal an incidence of 1 to 2 cases per 100,000 population in the US [Carriaga M.,et alr 1995]. In contrast to the general population, GBC is the most common malignancy in both Southwestern Native Americans and in Mexican Americans [Diehl AK 1980].The incidence of gall bladder disease is high among people living near the Ganga and its tributaries, says the largest-ever study of the local population over six years. In this region the prevalence. Recent study shows the high rate of gall bladder in the Bihar , located near the river Gandak (journal of the International Hepato-Pancreato-Biliary Association).About 20,000 and 30,000 people develop gall bladder disease each year because of the environmental factors in Uttar Pradesh and Bihar.In addition to geography, there are also age, race, and gender-related differences in the incidence of GBC. Incidence steadily increases with age, women are affected two to six times more often than men [Duffy A et al 2008 &Konstantinidis IT et al 2009], and GBC is more common in Caucasians than in blacks [Scott TE 1999]. At least some data suggest that the incidence is increasing in younger individuals [Kiran RP 2007].

Risk factor and Causing symptom:
Inspite of high frequency and grave mortality risk factors for this disease have not been clearly understood (Adson MA 1973). Because of their elevated humanity rate researches found some risk factor such as gallstones, duration of disease, dietary factors including vitamin intake and smoking. Numerous individuals suggested that the reality may be a corollary of the older age of the population (Khan ZR 1999). Even though, it occurs most often in people with porcelain gall bladders. Due to recurring inflammation and from passing gallstones leads to calcification of the gall bladder.
                Gallstones are the most common risk factor for gallbladder cancer because of these are so hard, rock-like formations of cholesterol and other substances that form in the gallbladder and can cause chronic inflammation ultimately developed the growth of undefined cells . Approximately, 3 out of 4 people with gallbladder cancer have gallstones but this is quite rare. Another second condition is, Porcelain gallbladder in which the wall of the gallbladder becomes covered with calcium deposits. It sometimes occurs after long-term inflammation of the gallbladder and this have high possibility to . developing gallbladder cancer .
        According to the report, gallbladder cancer occurs more than twice as often in women. Gallstones and gallbladder inflammation are the 2 important risk factors for gallbladder cancer and are also much more common in women than men. Gallbladder cancer can occur in younger people, but it’s seen mainly in older people. The average age of people when they are diagnosed is 73. Almost 3 out of 4 people with gallbladder cancer are older than age 65 when it is found. Studies also suggested the Obesity or overweight or obese than people without this disease a risk factor for gallstones, and link to cancer. Most important risk factor are , Choledochal cysts are bile-filled sacs that are connected to the tube that carries bile from the liver and gallbladder to the small intestine. The cysts can grow over time and may contain as much as 1 to 2 quarts of bile. The cells lining the sac often have areas of pre-cancerous changes, which increase a person's risk for developing gallbladder cancer.
             The pancreas is another organ that releases fluids through a duct into the small intestine to help digestion. This duct normally meets up with the common bile duct just as it enters the small intestine. Due to abnormalities in the bile duct that allow juice from the pancreas to reflux (flow backward) into the bile ducts. This backward flow also prevents the bile from being emptied through the bile ducts as quickly as normal. Abnormalities passing of bile involved in the DNA damage and initiate the uncontrolled growth of cell.
            A gallbladder polyp is a growth that bulges out from the surface of the inner gallbladder wall. Some polyps are formed by cholesterol deposits in the gallbladder wall. Others may be small tumors (either cancerous or benign) or may be caused by inflammation. Polyps larger than 1 centimeter (almost a half inch) are more likely to be cancerous, so doctors often advise removing the gallbladder in patients with gallbladder polyps that size or larger. Typhoid, chronically infected with salmonella and those who are carriers of the disease having more chance to develop gallbladder cancer than those not infected. But typhoid is rare in the United States. Some chemical have been identified as risk factor for gallbladder cancer nitrosamines, rubber and textile industries but still is not common and clear.
         We know that most of cancers are hereditary but gallbladder cancers are not found in people with a family history of the disease. A history of gallbladder cancer in the family seems to increase a person's chances of developing this cancer, but the risk is still low because this is a rare disease.

Gall bladder act as a silent killer but some condition which are identified as causing symptom of this carcinoma such as:

Jaundice (yellowing of the skin and whites of the eyes).
Pain above the stomach.
Fever.
Nausea and vomiting.
Bloating.
Lumps in the abdomen. One of the most common and late development is Jaundice and the other symptoms have been present for a long time. Itching may result from the buildup in the skin of a derivative of bile, bilirubin, which turns the skin yellow. This symptom usually reflects advanced disease.

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Stages of Gall Bladder Cancer:
American cancer society suggested ,there are five stages: stage 0 (zero) and stages I through IV (one through four) ,depending on how far they have grown. These are define common pathway of cancer and also described, how many possibility to cure the cancer.
TNM is an abbreviation for tumor (T), node (N), and metastasis (M) and three factors to determine the stage of cancer:

Location , their place and largamente of the primary tumor? (Tumor, T)
Tumor spread to the lymph nodes? (Node, N)
The cancer metastasized to other parts of the body? (Metastasis, M)

Some stages are also divided into smaller groups that describe the tumor in detail and treatment. Specific tumor stage information is listed below.

TX:The primary tumor cannot be evaluated.

T0:No evidence of cancer was found in the gallbladder.

Tis:This refers to carcinoma (cancer) in situ, which means that the tumor remains in a pre-invasive state and its spread, if any, is very confined.

T1:The tumor is only in the gallbladder and has only invaded the lamina propria (a type of connective tissue found under the thin layer of tissue covering a mucous membrane) or muscle layer.

T1a:The tumor has invaded the lamina propria.

T1b:The tumor has invaded the muscle layer.

T2:The tumor has invaded the perimuscular connective tissue (the layer between the muscle layer and the serosa) but has not extended beyond the serosa (the outer layer) or into the liver.

T3:The tumor extends beyond the gallbladder and/or has invaded the liver and/or one other adjacent organ or structure, such as the stomach, duodenum (part of the small bowel), colon, or pancreas.

T4:The tumor has invaded the main portal vein or hepatic artery or has invaded more than one organ or structure beyond the liver.

Node. The “N” in the TNM staging system stands for lymph nodes, the tiny, bean-shaped organs that help fight infection. Lymph nodes near the gallbladder are called regional lymph nodes.

NX:The regional lymph nodes cannot be evaluated.

N0 (N plus zero): There is no regional lymph node metastasis.

N1: There is regional lymph node metastasis.

N2:There is more distant lymph node metastasis.

Distant metastasis. The “M” in the TNM system indicates whether the cancer has spread to other parts of the body.

M0 (M plus zero):There is no distant metastasis.

M1: There is metastasis to one or more other parts of the body.

Cancer stage grouping
The stage of the cancer by combining the T, N, and M classifications.
Stage 0:Describes cancer in situ (Tis, N0, M0).
Stage I:A tumor is only in the gallbladder and has not spread (T1, N0, M0).
Stage II: A tumor has extended to the perimuscular connective tissue but has not spread elsewhere (T2, N0, M0).
Stage IIIA:A tumor has spread beyond the gallbladder but not to nearby arteries or veins. It has not spread to any lymph nodes or other parts of the body (T3, N0, M0).
Stage IIIB:A tumor of any size has spread to nearby lymph nodes but not to nearby arteries and/or veins or to other parts of the body (T1, T2, T3; N1; M0).
Stage IVA:A tumor has spread to nearby arteries, veins, and/or nearby lymph nodes, but it has not spread to other parts of the body (T4, N0 or N1, M0).
Stage IVB:Describes any tumor that has spread to other parts of the body (any T, any N, M1) or any tumor that has distant lymph node spread, even if it has not spread to distant organs (any T, N2, M0).

Diagnosis:
In order to plan treatment, it is important to know if the gallbladder cancer can be removed by surgery. Tests and procedures to detect, diagnose, and stage gallbladder cancer are usually done at the same time but there are so many facing difficult to detect and diagnose for the following reasons:

There aren't any noticeable signs or symptoms in the early stages of gallbladder cancer.
The symptoms of gallbladder cancer, when present, are like the symptoms of many other illnesses.
The gallbladder is hidden behind the liver.

Sometimes found cancer after the removal of gall bladder due to other reasons so there are following examination which may be used to detect:

•Physical exam and history:
An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

•Ultrasound exam:
A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. An abdominal ultrasound is done to diagnose gallbladder cancer.

•Liver function tests:
A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by the liver. A higher than normal amount of a substance can be a sign of liver disease that may be caused by gallbladder cancer.

•Carcinoembryonic antigen (CEA) assay:
A test that measures the level of CEA in the blood. CEA is released into the bloodstream from both cancer cells and normal cells. When found in higher than normal amounts, it can be a sign of gallbladder cancer or other conditions.

•CA 19-9 assay:
A test that measures the level of CA 19-9 in the blood. CA 19-9 is released into the bloodstream from both cancer cells and normal cells. When found in higher than normal amounts, it can be a sign of gallbladder cancer or other conditions.

•CT scan (CAT scan):
A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

•Blood chemistry studies:
A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that produces it.

•Chest x-ray:
An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.

•MRI (magnetic resonance imaging):
A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI). A dye may be injected into the gallbladder area so the ducts (tubes) that carry bile from the liver to the gallbladder and from the gallbladder to the small intestine will show up better in the image. This procedure is called MRCP (magnetic resonance cholangiopancreatography). To create detailed pictures of blood vessels near the gallbladder, the dye is injected into a vein. This procedure is called MRA (magnetic resonance angiography).

•ERCP (endoscopic retrograde cholangiopancreatography)
A procedure used to x-ray the ducts (tubes) that carry bile from the liver to the gallbladder and from the gallbladder to the small intestine. Sometimes gallbladder cancer causes these ducts to narrow and block or slow the flow of bile, causing jaundice. An endoscope (a thin, lighted tube) is passed through the mouth, esophagus, and stomach into the first part of the small intestine. A catheter (a smaller tube) is then inserted through the endoscope into the bile ducts. A dye is injected through the catheter into the ducts and an x-ray is taken. If the ducts are blocked by a tumor, a fine tube may be inserted into the duct to unblock it. This tube (or stent) may be left in place to keep the duct open. Tissue samples may also be taken.

•Biopsy:
The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. The biopsy may be done after surgery to remove the tumor. If the tumor clearly cannot be removed by surgery, the biopsy may be done gusing a fine needle to remove cells from the tumor.

•Laparoscopy:
A surgical procedure to look at the organs inside the abdomen to check for signs of disease. Small incisions (cuts) are made in the wall of the abdomen and a laparoscope (a thin, lighted tube) is inserted into one of the incisions. Other instruments may be inserted through the same or other incisions to perform procedures such as removing organs or taking tissue samples for biopsy. The laparoscopy helps to determine if the cancer is within the gallbladder only or has spread to nearby tissues and if it can be removed by surgery.

•PTC (percutaneous transhepatic cholangiography):
A procedure used to x-ray the liver and bile ducts. A thin needle is inserted through the skin below the ribs and into the liver. Dye is injected into the liver or bile ducts and an x-ray is taken. If a blockage is found, a thin, flexible tube called a stent is sometimes left in the liver to drain bile into the small intestine or a collection bag outside the body.

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Treatment and Managmnet:
All treatment are depend on the age and wide-ranging of the patient health and whether the cancer is causing symptoms.
Surgery: Surgical removal of the gallbladder usually offers the best option to save the people from gallbladder cancer but condition is there the tumor is very small and hasn't spread to the deeper layers of gallbladder tissue, than perform a simple cholecystectomy, which removes only the gallbladder. Sometimes this may be done laparoscopically, using a camera and miniature instruments inserted through small incisions in abdomen. Sometime cancer is more advanced, than an extended cholecystectomy - an operation in which some liver tissue and nearby lymph nodes are removed along with gallbladder. Once the cancer has spread beyond the walls of gallbladder, it can no longer be completely removed with an operation.. These may include radiation - either external beam radiation (high-energy X-rays) or implanted radiation "seeds" - or chemotherapy, which is anti-cancer medication. These additional treatments may be used alone or in combination.
Radiation together with chemotherapy after surgery is more effective than either alone.
Radiation and chemotherapy may also be used for palliative care to help make more comfortable if cancer is so advanced that treating the cancer is no longer an option. For example, either treatment may be used to help shrink a tumor that's blocking a bile duct, these three advance standard treatment allow to as soon as possibly cure gall bladder cancer.

Conclusion:
Carcinoma gall bladder has high mortality of up to 80% mainly because the diagnosis is very late. There was a prevalence of GBD of 6.2% among men and women over 30 years of age (4.45% in men and 7.37% in women).Unknown factors are responsible to affect three times more in female of than males, with average age of 65 years. Gall stones are present in 75 to 90% of cases but it is not necessary to developed cancer .They remain asymptomatic and are is covered incidentally during or after cholecystectomy or present with non specific symptoms like upper abdominal pain, nausea vomiting weight loss, jaundice or gall bladder mass. Now a day, various clinical techniques are developed but the rate of mortality day by day increasing and more in gangatic region in India and due to feature cancer act as silent killer.

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