Everything You Need To Know About Gallbladder Cancer
Gallbladder cancer as the name suggests, begins in the gallbladder, an organ that stores a substance called bile. Depending on the tissue or organ where the cancer begins, there are around 200 types of cancers and these are called primary cancers. Some cancers have a high likelihood of spreading from one tissue to another and this is called metastasis.
The gallbladder is a pear-shaped hollow organ on the right side of the abdomen, under the liver. It is a part of the human biliary system. It is a muscular sac with an approximate capacity of 50 ml in adult humans. Gallstones, gallbladder attack, gallbladder diseases are some of the conditions linked with the gallbladder.
The gallbladder stores and concentrates the bile coming from the liver in between the meals. The liver produces a yellow brown digestive enzyme called bile. It flows directly into the small intestine during the meals and is stored in the gallbladder in between meals. It thereby serves as a reservoir for bile. It has an absorbent lining that concentrates the bile. Bile is responsible for the digestion and absorption of fats and fat soluble vitamins.
Signs and Symptoms of Gallbladder Cancer
Early detection of gallbladder cancer:
Gallbladder cancer is hard to find in its early stages, the organ is located deep in the body and tumours cannot be seen or felt during routine examinations. Gallbladder cancer has no reliable screening tests to detect the cancer early and so these are usually detected after the tumour has grown enough to show symptoms. The few cases that are detected early are due to other conditions related to the gallbladder such as gallstones or inflammation. There are no early signs of gallbladder cancer noticeable other than the above mentioned conditions.
What are the symptoms of gallbladder cancer?
Most of the gallbladder cancers are detected during diagnosis or treatment of other problems of the gallbladder or the liver. These cancers do not show any signs in the beginning and the symptoms do not appear until the advanced stages. Following are the most common symptoms of gallbladder cancer the a patient might experience:
- Abdominal pain
- Nausea or Vomiting
- Lumps in the abdomen
Other common symptoms:
- Loss of appetite
- Weight loss
- Itchy skin
- Dark urine
- Greasy or light-colored stools
Risk Factors And Causes of Gallbladder Cancer
Cancer begins when there is abnormal growth and division of the cells in any part of the body and the cancer that develops in the gallbladder is known as gallbladder cancer. The gallbladder which is located on the right side of the abdomen, behind the liver and is responsible for the storage of bile. This is a very rare cancer and is one of the most treatable forms when diagnosed in the early stages. But most gallbladder cancers are diagnosed in the advanced stages which affects its survival rate.
What are the causes of gallbladder cancer?
Gallbladder cancer is caused due to the mutations in the DNA of the cells in the gallbladder. These mutations lead to division and abnormal growth of the cells. These extra cells form tumours that spreads to other organs. The exact cause of the cancer varies from each person. Gallbladder cancer can be caused due to a lot of risk factors, however the exact causes of the cancer are still being researched.
Risk factors of gallbladder cancer:
When the exact causes of a disease are not known, certain factors that are involved with it are noted and these are called the risk factors. The risk factors are the conditions that suggest higher probabilities for developing a certain disease, in this case gallbladder cancers. Presence of risk factors does not imply that a person will get cancer but only indicates likelihood. Same is true with the converse, a person can get gallbladder cancer even in the absence of all the risk factors. Some risk factors for gallbladder cancer are as follows:
The age of the patient is one most common risk factors for gallbladder cancer. It is often observed in people over 70 years and rarely in people younger than 50 years.
Gallbladder is more common in women than men. For every 10 cases of gallbladder cancer, 7 are women.
Cholecystitis and gallbladder cancer:
The existence of gallstones or inflammation of the gallbladder known as cholecystitis is a major risk factor of gallbladder cancer. Almost 80% of the patients with gallbladder cancer have gallstones. The gallstones are formed due to depositions of cholesterol and bile minerals.
People whose predecessors have gallstones are more prone to develop gallbladder cancer. BRCA2, a genetic mutation also increases the risk of gallbladder cancer.
Smoking and exposure to chemicals:
People who smoke are more likely to develop gallbladder cancer. Also, exposure to chemicals like nitrosamines causes the mutations in the DNA. Workers in rubber and metal industries are usually exposed to these chemicals.
This occurs when calcium deposits on the inner wall of the gallbladder as a cause of repeated cholecystitis and this condition can lead to gallbladder cancer in a few patients.
Primary sclerosing cholangitis:
The inflammation of the bile duct also increases the risk of gallbladder cancer.
Defects of the pancreas and bile ducts:
Abnormal attachment between the bile duct and the pancreas and the outgrowths in the bile duct raise the risk of patients developing gallbladder cancer. These defects of the pancreas and bile ducts are formed during the birth itself, but they show up in the later ages.
These are non-malignant growths in the gallbladder and in time, these can develop into cancers.
Obesity and diet:
Overweight or obesity leads to hormonal changes in the body that caused repeated cholecystitis, which increases the risk of developing gallbladder cancer. Foods low in fibre and high in carbohydrates contribute in raising the risk of gallbladder cancer.
People with high diabetes are more prone to develop gallbladder cancers.
Hormone replacement therapy
Hormone transfusion or replacements raise the risk of the person developing gallbladder cancer. Women who are exposed to high levels of oestrogen during these therapies are more inclined to develop the cancer.
Patients who have gallstones are at a higher risk of developing gallbladder cancer due to typhoid causing salmonella infection.
How Gallbladder Cancer is Diagnosed?
Gallbladder cancer as the name suggests, begins in the gallbladder, an organ that stores a substance called bile.
How is gallbladder cancer diagnosed?
Sometimes gallbladder cancer is detected due to gallstones or inflammation of the gallbladder or during surgical procedures for the same though most cases are found out until the patient goes to the doctor with the presented symptoms, and the following tests may be used to diagnose gallbladder cancer.
Medical history and physical exam:
If the doctor suspects the patient to have gallbladder cancer, a complete medical history is taken to check for risk factors and symptoms that can point out to the cancer. A physical examination may include checking the abdominal area for lumps, tenderness or fluid buildup. Eyes and skin may be checked to see if there are any signs of jaundice.
Liver function tests:
Lab tests may be done to find out the levels of bilirubin, albumin, liver enzymes such as alkaline phosphatase, AST, ALT and GGT and certain other substances in the blood and these are collectively called liver function tests and they can help diagnose gallbladder cancer and related conditions, liver or bile duct disease.
Tumour marker tests:
A blood sample is taken and is tested for biomarkers that can be elevated in the presence of a particular type of cancer and this procedure is called tumour marker test. People with gallbladder cancer may have high levels of markers called CEA and CA 19-9, though these are not unique to gallbladder cancer and are high only in the advanced stages. Prior to any treatment, the levels of the serum tumour marker can be taken and compared to the tumour marker levels after to see the patient’s response to treatment.
This procedure uses ultrasounds which bounce back on internal tissues or organs in the neck, and make echos. These echoes give a picture of the organs,also known as sonograms. Ultrasounds are used during biopsies too, to guide the fine-needle aspiration.
Magnetic resonance imaging uses radio waves and strong magnets for imaging and it provides great detail and is useful to image gallbladder, nearby bile ducts and other organs.
CAT or CT scan:
Also known as tomography, computerized tomography, or computerized axial tomography, this scan gives the detailed pictures of the organs from different angles, generated by a computer which is linked to an x-ray machine. For the scan, a dye is given to the patients intravenously or orally for the tissues to be imaged clearly.
This is an imaging test to check if the bile ducts are blocked, narrowed or dilated and it is used to plan for surgeries to treat gallbladder cancer. Magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are the types of cholangiograms available to diagnose gallbladder cancer.
Angiogram is an X ray used to look at the blood vessels of the patient. A thin plastic tube is inserted into the artery and a small amount of contrast dye is injected to outline the blood vessels. This can show the tumours or blockages in the blood vessels that can be noted if the cancer has spread beyond the gallbladder into the surrounding blood vessels.
Laparoscope is a thin tube with a light and a video camera than is inserted into the patient’s abdomen through a small incision, to look at the gallbladder, the liver and nearby organs and if needed a biopsy can be done too to confirm cancer. Laparoscopy can help determine the stage and extent of gallbladder cancer too.
Biopsy for involves the removal of cells from the suspicious areas and examining them under a microscope and is not the prefered method of diagnosis for gallbladder cancer. This is because in case of gallbladder cancer, it can cause the cancer to spread and even if required, surgical biopsy is the prefered option, it means examination of cells removed through or post surgery.
Stages Of Gallbladder Cancer
How is Gallbladder Cancer Staged?
Staging of gallbladder cancer helps the doctors figure out how much the cancer has spread in the pancreas and determine its best treatment. Staging also helps calculate survival statistics. The lower the number of the stage, the less is the cancer has spread, with early stages being 0 called carcinoma in situ, followed by stage 1 and the most advanced stage being stage 4. The following are the factors taken into consideration for staging of gallbladder cancer:
TNM Stagining Of Gallbladder Cancer
Cancer types that form tumours are staged using TNM system and the same method is used for gallbladder cancer too. The extent of the primary tumour (T), the presence of cancerous lymph nodes (N) and how far the gallbladder cancer has spread to a different part of the body (M) can be described using the TNM system.
The grade describes how closely the cancer cells resemble the normal cells of the gallbladder when seen under a microscope. The scaling is from 1 to 3 in grading gallbladder cancer:
Grade 1 (G1): The cancer cells look like the normal gallbladder cells
Grade 2 (G2): The cells look somewhat in between grade 1 and grade 3
Grade 3 (G3): The cancer cells look abnormal and unlike the normal cells
Extent of resection:
Resection means removal of the cancer tumour through surgery, and based on the extent of resection the gallbladder cancers can be classified as:
Resectable: Those that the doctors believe can be completely removed by surgery
Unresectable: Those that have spread too far or in a location that cannot be operated on through surgery.
Only a small number of gallbladder cancer cases are resectable even when first diagnosed. The exact staging of gallbladder cancer and characteristics of each stage are discussed in the further articles.
Gallbladder Cancer Treatment and Therapies
Surgery for gallbladder cancer:
Surgical procedures for treating gallbladder cancer can be broadly categorized into two types: potentially curative surgery and palliative surgery. Potentially curative surgeries are for resectable cancers, that is for the cancers which can be completely removed by the surgical procedures while, palliative surgeries are used for metastasized cancers for which surgical methods alone cannot eliminate the cancer from the body.
Before performing the surgery, staging laparoscopy is done to get a closer look at cancer and it’s affected areas. This procedure is carried out by making small incisions near the abdomen and inserting a thin, long tube which is attached to a camera. The doctors will see have an inner view of the gallbladder and the surrounding organs through the camera that is inserted.
Types of surgery for resectable gallbladder cancer:
Depending on the diagnostic results of the patient, the doctor will decide the best surgical procedure for patients. Following are the surgical procedure used for treating gallbladder cancer:
The procedure of removing the gallbladder is known as cholecystectomy. This surgery is used for removing both the gallstones or the gallbladder. Gallbladder cancer surgeries might be a part during the treatment of other diseases also. If the cancer is detected in the early stages, cholecystectomy alone eliminates the cancer from the body. Incase, the cancer is diagnosed in the advanced stages, more complicated surgeries are required. Cholecystectomy can be performed in the following two ways:
This treatment is the most recommended one for removing non-cancerous tumours or the gallbladder. The procedure is carried out with the surgeon making small incisions in the abdomen and putting a laparoscope to get an inner view of the gallbladder. Long surgical tools are then used to remove the gallbladder through the incisions. The surgeons observe their accuracy with the help of the video camera attached to the laparoscope. This procedure seems easier to the patients due to the smaller incision size, but it is not recommended if cancer is suspected/detected because this treatment has a very small range of view of the gallbladder which can lead to a lot of cancerous regions being left in the body.
This treatment is often used for non-cancerous gallbladder problems which leads in detecting the cancer. The procedure is carried out by the surgeon making a large incision along the abdominal wall, through which the gallbladder is removed. If the cancer is suspected to have spread beyond the gallbladder, extended cholecystectomy is done.
Extended (radical) cholecystectomy:
This procedure is used to treat gallbladder cancer. It includes the removal of the gallbladder through the incisions that the surgeons make along the abdominal wall. Since the risk of recurrent gallbladder cancer is high, an extensive and a complicated surgery is done to avoid the recurrence.
The patients who are recommended extended cholecystectomy as a part of the treatment to cure gallbladder cancer will experience a removal of the lymph nodes in the region and one or more inches of the nearby tissues of the liver along with the resection of the gallbladder. Depending on the tolerance levels of the patient and the spreading of the cancer, the doctors shall decide which extra parts to be removed. The following are the parts that are generally removed in extended cholecystectomy:
- Part of the liver, a wedge-shaped section close to the gallbladder (wedge resection) or a whole lobe of the liver (hepatic lobectomy)
- Part or all of the ligament that runs between the liver and the intestines A portion or all of the ligament between the liver and the pancreas
- Lymph nodes around the pancreas and the major nearby blood vessels
Surgery for unresectable gallbladder cancer:
Unresectable gallbladder cancers are those which cannot be completely removed by surgeries. It is mostly used for metastasized gallbladder cancer. Palliative surgery is used for treating unresectable gallbladder cancers. It does not aim in eliminating the cancer, but at relieving the patients from the pain and symptoms that the cancer causes.
Biliary stent or a catheter:
Due to blockage caused by cancer, if bile cannot move from the gallbladder or the liver into the small intestine, the buildup of bile can cause jaundice. A stent or a catheter may be placed through the blockage to allow the movement of bile.
Depending on where the tumour is, a bypass can be creating through surgery to remove the blockage to allow bile to drain from the liver and the gallbladder. A bypass lasts longer than a stent or a catheter but the patient has to be healthy enough to withstand the procedure.
The doctors may deaden the nerves that carry pain signals from the gallbladder and the intestinal area to the brain by giving alcohol injections, this can be done during a surgery or as a separate procedure through CT scan.
Side effects of surgery for gallbladder cancer:
Though surgery is the preferred course of treatment for gallbladder cancer, it has its side effects too. Read about the side effects of radiotherapy for gallbladder cancer here
Surgeries show successful results in treating early stages of gallbladder cancer. These procedures are required for almost all types and stages of gallbladder cancer. They aim at removing the gallbladder, gallstones and tumours along with the affected lymph nodes.
For advanced stages of the cancer or recurrent gallbladder cancer, surgeries are a part of the treatment which can includes other treatments too. Read about the follow up of gallbladder cancer treatment here
Chemotherapy Treatment For Gallbladder Cancer
How does chemotherapy work for gallbladder cancer?
The chemotherapeutic drugs travel through the bloodstream aiming at killing the malignant cells in the body. Chemotherapy for gallbladder cancer cannot show successful results along, it is often combined with other treatments to see significant results. Chemotherapy alone is used to minimize the risk of recurrent cancer.
When can chemotherapy be given?
Chemotherapy is often given in cycles and in combinations with other treatments also. Based on a few factors like stage and type of cancer, spreading of cancer, tolerance of the patient towards the drugs and overall health of the patient, chemotherapy is given:
- After surgery: Chemotherapy is often given as an adjuvant treatment for treating gallbladder cancer. This treatment is given after post surgical procedures to minimize the risk of recurrent cancer.
- Before Surgery : Sometimes before surgery to reduce the size of tumor for better surgical outcomes in locally advanced cases.
As a combination with other treatments: Chemotherapeutic drugs are given along with other treatments to eliminate cancer from the body.
- Palliative therapy: Chemotherapeutic drugs are given as a palliative therapy to relieve the patients from symptoms and shrink the tumors
How chemotherapy is given?
Chemotherapy is given in cycles, depending on the drugs used, each cycle contains one or more treatment sessions followed by a rest period for the patient to recover and prepare themselves for the next cycle. Chemotherapy can be given in many ways:
These drugs have a protective coating which is breakable by the stomach and is absorbed by the organs.
Most chemotherapeutic drugs are given intravenously, which makes it the most commonly deliverable method. Here, the medication is injected into the veins and sometimes into the larger muscle. This injection of the drug will help in its rapid circulation in the bloodstream.
- Cannula: A small, thin tube or cannula is inserted in the veins of the forearm which is fixed temporarily.
Portable infusion pump: These are small pressure pumps which are used to deliver the drug at a slower pace.
- Port-a-cath: This is also known as an implantable port or a subcutaneous port. It is used for patients who require constant or frequent administration of chemotherapy. This system is used to eliminate the discomfort caused by other systems.
- Central lines (tunnelled catheters): These are placed through the skin in the middle of the chest. They are pushed through the subcutaneous tissue and inserted into the superior vena cava. The catheters have lumens or entrances that facilitate extraction of blood samples and giving the drugs simultaneously.
Types of chemotherapy for gallbladder cancer:
Depending on the diagnostic results, chemotherapeutic drugs are prescribed to the patient. Following the chemotherapeutic drugs used for treating gallbladder cancer.
It is an antimetabolite drug used in treating gallbladder cancer. It is given intravenously into the blood. Gemcitabine cannot be taken orally.
Cisplatin is an anticancer drug which is given intravenously to eliminate the cancer or symptoms of cancer. This drug has to be given under strict monitoring of experienced and skilled doctors because it is an irritant and can cause inflammation or redness with pain. Before and after the drug is given, IV fluids are prescribed to the patients to ensure hydration to protect the kidney functioning.
It is one of the most common chemotherapeutic drugs used for treating gallbladder cancer. Fluorouracil if an antimetabolite drug which is infused in the body to treat the cancer.
This is a chemotherapeutic drug which is classified as an antimetabolite used to treat gallbladder cancer. It is taken orally and within 30 minutes after a meal.
Oxaliplatin is an anticancer drug used to treat gallbladder cancer in advanced stages. It is often given in combination with 5-fluorouracil. This drug is often infused in the vein.
Side effects of chemotherapy for gallbladder cancer:
Chemotherapy aims to destroy cancer cells, in this process healthy cells can be killed too and this is what leads to side effects of this treatment. Read about the side effects of chemotherapy for gallbladder cancer here
Dosage and survival rate for gallbladder cancer:
Each cycle is followed by a rest period for the patients to recover with the side effects. The dosage of each cycle depends on the type of drug used, for which cancer it is used, tolerance and overall health of the drug. Chemotherapeutic drugs alone cannot completely treat gallbladder cancer. This treatment when combined with other treatments like surgery, targeted therapy, immunotherapy and radiation therapy will help increase the survival rate of the cancer post chemotherapy.
The five year survival rate of cancer is the number of people out of 100, who have survived cancer for five years after treatment. The survival rate of gallbladder cancer is 19% because it is often diagnosed in the advanced stages.
Radiation Therapy Treatment For Gallbladder Cancer
How radiation therapy works for gallbladder cancer?
Strict monitored doses of high energy beams are projected in the areas that are affected by the cancer. Radiation is given externally to treat gallbladder cancers using x-ray machines known as linear accelerators which project the beams of radiation. The advantage of using radiation therapy to treat gallbladder cancer is that it minimizes the risk of damage to the healthy cells. It is often used in treating metastasized gallbladder cancer. Radiotherapy can be used for treating gallbladder cancer in the following ways:
- After surgery: Post surgical removal of the gallbladder tumours, radiation is given to the patients to eliminate the remaining cancer in the body as an adjuvant treatment.
- As the main treatment: Radiation therapy is used as a main treatment for advanced stages of gallbladder cancer.
- Palliative therapy: Radiation is given to the patients to relieve them from pain and other symptoms of gallbladder cancer in advanced stages where the patient cannot be cured and improving the quality of life is the aim of the treatment.
Types of radiation therapy for gallbladder cancer:
For treating gallbladder cancer, the radiation is mainly aimed at the gallbladder and abdomen region to kill the cancer cells and shrink the tumours. Following are the types of radiotherapy therapies used for treating gallbladder cancer:
External beam radiation therapy (EBRT):
To treat gallbladder cancer, external beam radiation treatment uses X rays to treat the cancer tumours. This treatment aims at killing the malignant cells by directing beams of radiation externally using an X ray machine called the linear accelerator. The procedure involves projecting the radiation when the patient is laid down on a table and the linear accelerator moves around him/her to project radiation in different angles. During the procedure, the patient is left alone in a room and is monitored from the cameras fixed in the room to avoid exposure. Higher and more accurate doses are given in order to avoid the side effects caused by damaging the healthy blood cells.
Three-dimensional conformal radiation therapy (3D-CRT):
This treatment is a more advanced type of EBRT. It uses specialized computers which accurately map the location of the tumours. The radiation beams that are projected are shaped similar to the tumours and are given in different angles. This treatment minimizes the damage to the healthy tissues.
Intensity modulated radiation therapy (IMRT):
IMRT is an advanced form of 3D-CRT. This procedure involves the usage of computer driven machines which move the patient as the accelerator delivers radiation. During this treatment, the radiation is shaped and is given in many angles. Doctors can adjust the intensity of the radiation during the treatment.
Radiation therapy is often given along with other treatments, especially chemotherapy to treat gallbladder cancer. The success rate of EBRT when given in combination with chemotherapeutic drugs is much higher than either of them alone. However, the patients have to be able to cope up with the side effects of both the treatments. This treatment is often suggested for patients who have metastasized gallbladder cancer.
Side effects of radiotherapy for gallbladder cancer:
Radiotherapy aims to destroy localized cancer cells, in this process healthy cells can be killed too and this is what leads to side effects of this treatment. Read about the side effects of radiotherapy for gallbladder cancer here
Depending on the type and stage of gallbladder cancer, the patients have to share their medical history along with useful medical information and allergies for the oncologist to prescribe the type and dosage of radiation. Early diagnosis of gallbladder cancer can help in successful treatment. For advanced stages of cancer, high doses of radiation is given with accuracy to reduce the damage to the remaining healthy cells.
Radiation therapy for gallbladder cancer alone does not show successful results, it is often combined with other treatments to increase the survival rate. It is given to patients who have advanced stages of gallbladder cancer which cannot be eliminated by one treatment alone.
Drugs Used in the Treatment of Gallbladder Cancer
Drugs in the treatment of gallbladder cancer:
The most drugs used for treating gallbladder cancer in combination with other treatments and as a part of targeted therapy are as follows:
It is an antineoplastic drug which inhibits the growth and division of the malignant cells. Cytidine analog targets the gene mutations and DNA of the cells after intracellular metabolism to active nucleotide. This drug is given intravenously only.
- Flu-like symptoms
- Mild nausea
- Poor appetite
- Skin rash
- Low blood counts leading to anemia, infections and easy bleeding
This anticancer drug is a platinum containing compound that affects the growth of the cells by causing denaturation of double helix in the DNA. It covalently binds the DNA of the cells with preferential binding to N-7 position of guanine and adenine. The platinum complex in the drug activates the bifunctional alkylating agent to aquated form in cell and binds to the DNA, resulting in intrastrand cross-linking and denaturation of double helix.
This affects the growth and division of the cells, eventually killing the cancer. Cisplatin has adverse effects on the kidney and hence the patients have to take a lot of fluids during and after the treatment.
- Severe nausea and vomiting
- Temporary hair loss
- Loss of appetite
- Dry mouth
- Dark urine
- Dry skin
This antineoplastic drug is a prodrug of fluorouracil that forms active moiety after undergoing hydrolysis in the liver and tissues. On inhibiting thymidylate synthetase, it turns blocks methylation of deoxyuridylic acid to thymidylic acid, which interferes the functioning of the DNA.
This restricts the growth and division of the cancer cells in the body. It is often taken orally after 30 minutes of having a meal.
- Severe nausea and vomiting
- Abdominal pain
- Bone, joint and muscle pain
- Skin problems
- Sleeping troubles
The above drugs are used alone or in combination with other treatments or drugs for gallbladder cancer. The patients have to take utmost care and have strict follow up in order minimize the impact of the side effects. Read about the follow up of gallbladder cancer treatment here
How To Prevent Gallbladder Cancer
Prevention of gallbladder cancer:
There are no specific ways to prevent gallbladder cancer only avoid the risk factors, though early detection significantly increases the survival chances of the patient. To read about the signs and symptoms of gallbladder cancer, click here. Following are the tips to reduce the risk of developing gallbladder cancer:
The patients are advised to gradually reduce weight. This helps them prevent gallstones. Also, since obesity is a major risk factor of gallbladder cancer, reducing weight will minimize the risk. Regular exercising will help patients reduce weight and maintain a healthy lifestyle.
Following a healthy diet and not pressurizing the liver much will help in minimizing the risk of developing gallbladder cancer. Following are the do’s and don’ts to maintain a healthy diet:
- Reduce foods that are high in carbohydrates
- Have foods that are rich in healthy fats
- Consume high fibre foods
- Avoid sugars
Protecting your liver
The liver is responsible for the detoxification of the food that is consumed by the person. In case the liver is over pressurized or does not function properly, there is a high risk of damage to the gallbladder, which can cause gallbladder cancer.