What Is Gallbladder Cancer?

Gallbladder cancer facts by John P. Cunha, DO, FACOEP:

• Gallbladder cancer is a rare disease in which malignant (cancer) cells form in the tissues of the gallbladder.
• Risk factors for gallbladder cancer include being female and Native American.
• Symptoms of gallbladder cancer include jaundice (yellowing of the skin and whites of the eyes), pain, fever, nausea, and vomiting, bloating, and lumps in the abdomen.
• Gallbladder cancer is difficult to detect and diagnose because there often are no noticeable signs in the early stages. When there are symptoms, they often resemble other illnesses, and the gallbladder is hidden behind the liver.
• Ultrasound, liver function tests, carcinoembryonic antigen or CA 19-9 assay, CT scan, MRI, X-ray, biopsy, and blood tests can help diagnose gallbladder cancer.
• Gallbladder cancer can be cured only if it is found before it has spread and when it can be removed by surgery. Other treatments include radiation and chemotherapy.

The type of gallbladder cancer is determined by the cell type infiltrating the organ. Individuals should be aware that various cell variants might cause gallbladder cancer.

Types of gallbladder cancer

Adenocarcinoma: Adenocarcinoma of the gallbladder begins in the cells lining the interior of the digestive tract. This is the most prominent type, usually affecting 85 out of every 100 people diagnosed with gallbladder cancer.

Adenocarcinoma is further classified into three types:

• Nonpapillary carcinoma: Develops in the gland cells in the gallbladder lining; the most common type of the three subtypes.
• Papillary adenocarcinoma: Develops in the connective tissues that hold the gallbladder in place. It accounts for about six percent of all gallbladder cancer cases. Cells resemble finger-like projections when seen under a microscope. Rarely spread to the liver or surrounding lymph nodes. Because the "fingers" block the bile ducts and cause symptoms, they may appear early in this subtype. Considered to be a more treatable form of gallbladder cancer. 
• Mucinous adenocarcinoma: Develops in the cells that produce mucin, the primary ingredient of mucus. Rarest of the three subtypes.

Some rarer types of gallbladder cancer affect 15 out of every 100 patients diagnosed with gallbladder cancer:

• Squamous cell cancer
  • Develop from the skin-like cells that surround the gallbladder's lining, as well as gland cells. Contribute to about five percent of all gallbladder malignancies.
• Adenosquamous carcinoma
  • Contains both squamous and glandular cancer cells. 
• Small cell carcinoma
  • Known as “oat cell” carcinoma because cancer cells have an oat-like shape when seen under a microscope.
• Sarcoma
  • Affects the body's supporting or defensive tissues, which are generally referred to as connective tissues. Muscles, blood vessels, and nerves are examples of connective tissues. 
  • Cancer begins in the gallbladder's muscular layer.
• Neuroendocrine tumor
  • Develops from hormone-producing cells in the digestive system. The most common type of neuroendocrine tumor is a carcinoid tumor.
• Lymphoma and melanoma of the gallbladder
  • Very rare. Not always treated in the same manner as other types.

The early the gallbladder cancer is diagnosed, the better its prognosis. Squamous cell carcinoma and adenosquamous carcinoma are thought to account for 2 to 10 percent of all cases. These types of cancer typically have a poorer prognosis than adenocarcinoma.

In its early stages, gallbladder cancer might be asymptomatic. It is sometimes identified incidentally during regular gallstone surgery or documented in the final biopsy of the gallbladder excised for gallstones. It is occasionally found during routine abdominal ultrasounds or when an ultrasound is performed for another underlying reason. These do not show any signs in the early stages, and the symptoms do not appear until the advanced stages. However, few patients do have symptoms, which they tend to ignore.

Signs and symptoms of gallbladder cancer include:

• Abdominal pain, especially in the upper right quadrant
• Nausea and vomiting
• Fatigue
• Unexplained weight loss or losing weight without trying
• Loss of appetite
• A sense of fullness, even if a person only eats a small amount
• Jaundice (yellow eyes, skin, and urine)
• Lump in the abdomen or abdominal mass on the right side
• Itchy skin
• Fever
• Dark urine
• Greasy or light-colored stools
• Abdominal bloating

Gallbladder cancer is frequently diagnosed in advanced stages before symptoms appear. Symptoms appear when the tumor becomes big or has migrated outside of the gallbladder to other organs or lymph nodes.

If gallbladder cancer spreads (metastatic/stage IV gallbladder cancer), patients may experience symptoms such as:

• Severe jaundice
• Ascites (fluid in the abdomen)
• Cough/breathlessness
• Bone pain

If a patient has any of the symptoms listed above that are persistent and chronic, they should consult their doctor to determine the underlying reason. These symptoms can be caused by various disorders and are not always connected to gallbladder cancer alone. Knowing the cause of this cancer will also assist them to decide on a treatment plan.

The physician will examine the patient and inquire about their symptoms. If they suspect gallbladder cancer, they may refer the patient to a gastroenterologist or an oncologist. Moreover, the physician may conduct the following tests to confirm or rule out gallbladder cancer:

• Blood tests
  • Can be used to examine the patient’s overall health; determine whether they have an infection; determine how well particular organs, such as the liver and kidneys, are functioning, and screen for genetic problems and underlying medical issues.
• Liver function tests
  • The doctor can identify suspected liver damage caused by gallbladder cancer by examining a blood sample that may have the usual quantities of several enzymes secreted by the liver.
• Abdominal CT scan
  • Detailed pictures inside the body and organs can identify some problems.
• Ultrasound
  • Uses sound waves instead of radiation to identify abnormal areas in the gallbladder or nearby organs.
• Carcinoembryonic antigen (CEA) and CA 19-9 assays
  • Assess CEA and CA 19-9 in the blood, which are chemicals produced in the circulation by both cancer and normal cells. They might be a symptom of gallbladder cancer if discovered in higher than usual concentrations.
• Percutaneous transhepatic cholangiography
  • This X-ray of the liver and bile ducts requires introducing a tiny needle through the skin below the ribcage and into the liver. Before the X-ray is taken, dye is injected into the liver or bile ducts. 
  • If a blockage is discovered, a thin, flexible tube called a stent is occasionally left in the liver to drain bile into the small intestine or a collecting bag outside the body.
• Endoscopic retrograde cholangiopancreatography
  • Involves taking an X-ray of the ducts (tubes) that transport bile from the liver to the gallbladder and from the gallbladder to the small intestine. 
  • Sometimes, gallbladder cancer causes these channels to constrict and obstruct or delay the flow of bile, resulting in jaundice. 
  • If the ducts are obstructed by a tumor, a thin tube may be placed and kept in place to maintain the duct open. 
  • Tissue samples may be obtained and examined under a microscope for symptoms of malignancy.
• Laparoscopy
  • Determines if the cancer is limited to the gallbladder or has spread to adjacent tissues and whether it can be removed surgically. 
  • A pathologist can examine any tissue sample collected under a microscope to look for symptoms of malignancy. The biopsy may be performed following surgery to remove the tumor.

Clinical symptoms, biochemical tests, and tumor markers (CA 19-9, CEA) are used for diagnosis. Other tests may help know the malignancy and type of cancer. Early detection is a crucial aspect of detecting this aggressive cancer. Treatment, when started early, has the best prognosis.

The exact etiology of gallbladder cancer has yet to be determined. When the DNA of healthy gallbladder cells mutates, gallbladder cancer develops. These mutations or alterations cause the cells to proliferate uncontrollably and develop a tumor, which can migrate beyond the gallbladder and into other parts of the body. Cancer normally develops in the epithelial cells of the gallbladder's inner lining and spreads to other regions of the body.

Although the exact cause of gallbladder cancer is unknown, some people are more susceptible to acquiring it than others. Certain risk factors may trigger gallbladder cancer. Having a risk factor does not guarantee that a person will get cancer; it simply means that their chances are higher than the average person's.

• Gallstones
  • Gallstones (clumps of cholesterol) are the largest risk factor for gallbladder cancer, most likely because the stones suggest persistent inflammation. About 75 to 90 percent of patients with gallbladder cancer have a history of gallstones; however, not everyone who has them develops cancer.
• Other gallbladder disorders and conditions
  • Abnormal growths, porcelain gallbladder, abnormal bile ducts, swelling of the gallbladder or bile ducts, and diabetes are some conditions that increase the risk of gallbladder cancer.
• Inflammation of bile ducts
  • A condition called primary sclerosing cholangitis can cause inflammation and drainage of bile from the gallbladder and liver, thereby increasing the risk of cancer.
• Pancreatic and bile duct abnormalities
  • Patients with abnormal bile duct–pancreas connections and bile duct outgrowths are more likely to develop gallbladder cancer. 
  • These bile ducts and pancreas malformations develop during pregnancy but do not manifest until later in life.
• Gender
  • Gallbladder cancer is more common in women than in men. Seven out of 10 cases of gallbladder cancer are women.
• Age
  • The risk of gallbladder cancer is higher in adults older than 65 years. Risk increases with age, especially after 50 years.
• Family
  • Gallbladder cancer is more common in people whose ancestors had gallstones. A genetic mutation known as BRCA2 increases the risk of gallbladder cancer.
  • People who have a family member (parent, brother, or sister) with this cancer are at high risk.
• Smoking
  • Tobacco use in daily life increases the probability of gallbladder cancer.
• Ethnicity and geography
  • Native Americans
  • Mexican Americans
  • Asian American
  • Alaskan natives
  • American Indians
  • African Indians
• Obesity
  • Gallbladder cancer is more often found in individuals who are overweight or obese. Those consuming unhealthy, junk foods are at an increased risk of obesity and gallbladder cancer.
• Infectious conditions
  • According to research, Salmonella and Opisthorchis viverrini infections may trigger gallbladder cancer.
• Others
  • Exposure to substances such as nitrosamines induces DNA alterations. These compounds are commonly found in the rubber, textile, and metal industries.
• Hormone replacement therapy
  • The risk of gallbladder cancer is increased by hormone replacement or transfusion. 
  • During these therapies, women are exposed to high levels of estrogen, which increases their risk of cancer.
• Certain medical conditions
  • Ulcerative colitis
  • Gallbladder polyps
  • Occasionally occurs in patients with Lynch syndrome or familial adenomatous polyposis
  • Congenital abnormalities of the bile duct, such as choledochal cyst

Although not many Americans have gallbladder cancer, the condition is still a major health concern in the country. This is primarily because cancer is only discovered after it has advanced, making treatment challenging. Only a third of cases are detected early enough to be treated before they eventually spread outside the gallbladder.

Depending on the size, metastasis (whether cancer has spread to other parts of the body), and the appearance of the cancer cells under a microscope, gallbladder cancer can be staged and graded. Oncologists can determine the best course of treatment for a patient based on cancer's staging and grading.

Staging of gallbladder cancer is ranked 0 through IV and recurrent. 

1. Stage 0 or carcinoma in situ
   • Gallbladder cancer detected in its very early stages is called carcinoma in situ.
   • Cancerous cells are only present in the tissue layer lining the gallbladder. Some doctors might not think this is true cancer because the cancer cells are only in the lining. 
   • The likelihood of cancer spreading, as a result, is extremely low. As gallbladder cancer has few or no symptoms at this point, early detection is rare but will have the best prognosis.
2. Stage I or invasive cancer
   • Still considered early-stage cancer.
   • Cancer has only been detected in the inner layers of the gallbladder's tissues.
   • It may not have spread to nearby tissues, lymph nodes, or organs.
3. Stage II
   • Detected cancer may have spread through the gallbladder wall’s muscle layer and into the connective tissue beneath.
   • However, it may not have spread outside of the gallbladder.
4. Stage III or localized cancer: Cancer might become large and grow deeper into nearby tissue. This stage can be divided into the following:
   • IIIA
     • Cancer has developed through the gallbladder wall but may not have migrated to the lymph nodes.
   • IIIB
     • Cancer has spread to nearby lymph nodes or has broken through the gallbladder's outer layer.
5. Stage IV or advanced or metastatic cancer: This may indicate that the malignancy has progressed to other tissues and organs in the body. Further divided into two stages that include:
   • IVA
     • Cancer has spread to one of the liver's main blood arteries or two or more organs other than the liver. It is also possible that it has spread to neighboring lymph nodes.
   • IVB
     • Cancer has spread to lymph nodes other than the gallbladder and can be of any size. In some cases, it may or may not have reached distant organs.

Grades of gallbladder cancer

Cancer can also be graded based on the rate of growth and propensity to spread.

1. Grade I or low grade
   • Cancer cells usually appear slightly abnormal and grow slowly.
2. Grade II or intermediate-grade tumor
   • Cancer cells appear abnormal and grow more quickly than grade I tumors.
3. Grade III or high-grade tumor
   • Cancer cells appear abnormal and may grow rapidly.

After the tumor has been staged and graded, the doctor may suggest genetic testing, which analyzes the DNA of the tumor and can help determine which treatment has the best chance of success. They will then discuss the best treatment option for the patient.

Treatment options for gallbladder cancer may depend on age, underlying health conditions, stage, and grade of cancer. 

Multidisciplinary approach

A team of specialists (gastroenterologists, medical oncologists, radiation oncologists, surgical oncologists, pathologists, radiologists, palliative care physicians, and dedicated nursing, nutrition, and social work staff) works closely together from initial diagnosis through the entire treatment, ensuring that care is coordinated.

Treatment options depending on different stages of gallbladder cancer include:

Stage I

Surgery is the most effective treatment of early gallbladder cancer. Treatment beyond cholecystectomy may not be required in early-stage I gallbladder cancer. An extended cholecystectomy is preferred if cancer has spread to the muscle layer or is in a part of the gallbladder close to the liver.

Cholecystectomy: Cholecystectomy is a common surgical procedure used to remove the gallbladder, and there are two methods:

1. Laparoscopic cholecystectomy involves making small incisions in the abdomen and removing the gallbladder pieces with fine surgical instruments.
2. Open cholecystectomy involves a single large incision to access and remove cancer-affected tissues and organs.

Extended cholecystectomy or radical cholecystectomy

• If there is a risk of cancer returning after a simple cholecystectomy, an extended or radical cholecystectomy will be performed.
• This includes removing the gallbladder, an inch or more of liver tissue adjacent to the gallbladder, and all lymph nodes in the area.
• Depending on the extent of the cancer and the patient's health, additional organs or parts may be removed as well.

Stage II

Depending on the extent of the spread and risk of recurrence, an extended cholecystectomy may be required, followed by a round of radiation therapy or chemotherapy.

Extended cholecystectomy

• Removal of the gallbladder, 2 cm or more of liver tissue adjacent to the gallbladder, and all lymph nodes in the region.
• Depending on the extent of cancer's spread and the patient's health, additional organs or parts may be removed as well.

Chemotherapy

• Chemotherapy, which uses drugs to kill cancer cells, is used to treat stage II gallbladder cancer if recurrence is a possibility.

Radiotherapy

• Involves killing cancer cells with high-intensity radiation and is used if the tumors are to be targeted.
• However, due to the risks of radiation, it is only used if cancer has spread locally or has the potential to recur.

Stage III

Surgery can still be performed at this stage due to recent and advanced radical surgical methods. It can, however, improve the patient's chances of survival if not cure cancer. As cancer progresses, other treatment options for the patient may include surgery followed by chemotherapy or clinical trials.

Extended cholecystectomy: This entails removing the gallbladder, an inch or more of liver tissue adjacent to the gallbladder, and all lymph nodes in the region. Depending on the extent of cancer and the patient's health, removal of surrounding organs or parts such as the following may also be required:

• Part of the liver or a whole lobe of the liver 
• Common bile duct
• Removal of a portion or the entire ligament between the liver and intestines
• Lymph nodes near the pancreas and major blood vessels
• Pancreas
• Duodenum

Chemotherapy

• Chemotherapy is used to treat stage III gallbladder cancer if there is a likelihood of recurrence or if the disease has progressed too far, and it is often suggested following surgery to remove any leftover cancer cells.

Stage IV

Has a poor prognosis; cancer cannot be cured at this stage, and treatment focuses on relieving symptoms and making the patient as comfortable as possible.

Palliative surgery: The goal is not to treat cancer but to relieve the patient of the problems caused by the disease, and following are some of the procedures that can be used as palliative care:

Biliary stent or a catheter

• If bile cannot move from the gallbladder or liver into the small intestine due to a cancer-related blockage, bile buildup can cause jaundice. To allow bile movement, a stent or catheter may be placed through the blockage.

Biliary bypass

• Depending on the location of the tumor, surgery can be used to create a bypass to remove the blockage and allow bile to drain from the liver and gallbladder. 
• A bypass lasts longer than a stent or catheter, but the patient must be healthy enough to tolerate the procedure.

Alcohol injection

• Doctors may use alcohol injections to neutralize the nerves that transport pain signals from the gallbladder and the intestinal region to the brain. 
• This can be done during surgery or as a separate operation using a CT scan.

Chemotherapy

• Chemotherapy is used in the treatment of gallbladder cancer if there is a risk of recurrence or if the disease has progressed too far, and it is often suggested after surgery to eradicate any leftover cancer cells in this stage.

Radiotherapy

• Only used if the disease has spread or is likely to return. It can be used to eliminate tumors that are causing difficulties and to alleviate symptoms.

Clinical trials and genetic screening

• Specialists are actively involved in research and apply the most recent findings to ongoing care. 
• All patients have access to genetic testing and clinical trials.
• Targeted medicines from these trials are part of the therapy process, and many patients prefer to participate as a hope for treatment or cure.

Supportive resources

To address a patient’s physical and emotional needs, doctors recommend a comprehensive range of support services and complementary and integrative therapies. They recommend

• Family Counseling
• Rehabilitation and physical therapy
• Pain and symptom management
• Acupuncture
• Massage
• Information to the nearest support groups

Surgery is the most commonly used option in the early stages to contain the chances of malignancy. Because it is unknown whether cancer will return after surgery or total removal of the gland, doctors may recommend chemotherapy and radiotherapy either after or before the surgical procedures. Surgical options may not cure cancer in its later stages; as a result, the doctor chooses specific treatments and procedures to alleviate pain and keep the patient comfortable.

There are no specific ways to prevent gallbladder cancer; instead, avoid the controllable risk factors. However, early detection significantly increases the patient's chances of survival. 

Common methods for staying healthy and avoiding gallbladder cancer include:

• Reduce weight
  • Patients are advised to lose weight gradually—this aids in the prevention of gallstones.
  • Furthermore, losing weight will reduce the risk because obesity is a major risk factor for gallbladder cancer. 
  • Regular exercise will assist patients in losing weight and maintaining a healthy lifestyle.
• Diet
  • Following a healthy diet and not putting too much strain on the liver will help reduce the risk of gallbladder cancer. The following are some dos and don'ts for eating a healthy diet:
    • Reduce the intake of carbohydrate-rich foods.
    • Consume foods high in healthy fats.
    • Consume foods high in fiber.
    • Limit or avoid sugar and artificial sugar products.
• Protecting the liver
  • The liver is in charge of detoxifying the person's food. If the liver is overly stressed or does not function properly, there is a high risk of gallbladder damage, which can lead to gallbladder cancer. Protect the liver by maintaining a healthy lifestyle.

Maintaining a healthy weight and eating a healthy diet rich in fruits, vegetables, and whole grains are recommended. Avoid smoking and drinking. When long-term disease results in porcelain gallbladders or severe gallstones, doctors may recommend organ removal as part of prevention. Individuals with a family history of cancer should maintain regular checkups for early cancer diagnosis. This will prevent a patient from reaching stage IV gallbladder cancer.

Although the exact course of the disease cannot be predicted, the doctor can give the patient a general idea about tumor growth, sensitivity to treatment, and medical history. Gallbladder cancer in its early stages typically has a better prognosis and survival rate. The prognosis is less favorable, and the risk of cancer recurrence increases if the cancer has spread and advanced. To better understand the prognosis, discussing specific circumstances with the doctor is crucial for patients.

According to Surveillance, Epidemiology, and End Results, the average five-year survival rate of various stages of gallbladder cancer is 19 percent.

When discussing patient cases, doctors can find the gallbladder cancer survival rate to be a useful point of reference, but it shouldn’t be an absolute indicator. This is so because various factors can affect a person's outcome.