Liver and Gallbladder Cancer

 

Liver and gallbladder cancer are common and aggressive malignancies of the hepatic biliary system. Liver cancer is the fourth leading cause of cancer mortality and is ranked the sixth most diagnosed cancer worldwide. However, the gallbladder cancer is a rare cancer and accounts for 1.2% of all cancer diagnoses globally. The incidence of these cancers is increasing and there is a higher prevalence in developing countries.

About Liver and Gallbladder

Liver and gallbladder are two accessory organs of the gastrointestinal tract. Liver is located under the diaphragm in upper right portion of the abdomen. It aids in digestion and hemostasis. Liver secretes bile - a yellowish-green fluid that emulsifies fats. The excess bile is stored in a small sac-shaped organ – gallbladder which is located below the liver. The liver and gallbladder are interconnected by ducts. When the cells in liver or gallbladder undergo DNA changes (mutations), it may cause abnormal cell growth, leading to cancers.

Liver cancer

Liver cancer (or hepatic cancer) arises when the healthy cells in the liver undergo mutations in their DNA and grow out of control to form a mass or sheet of cells called a tumor. These tumors can be malignant (cancerous, spread to other parts of the body) or benign (non-cancerous, do not spread to nearby tissues).

Types of liver cancer

Liver cancer can be basically classified into two:

  • Primary cancer begins in the tissue of the liver.
  • Secondary cancer also known as metastatic cancer begins in other parts of the body and spread to the liver. Metastatic tumors are more common than primary tumors.

Signs and symptoms

Liver cancer in the early stage, generally have no signs or symptoms. As the cancer grows and spreads to nearby tissue the following symptoms can be observed:

  • Enlarged liver and spleen
  • Painful or painless hard lump under ribs on the right side of the body
  • Yellowing of skin and eyes (jaundice)
  • Unexplained weight loss
  • Nausea
  • Loss of appetite
  • Upper abdominal pain
  • Bloating

Causes/Risk factors

The precise cause of liver cancer is not known. However, certain factors can increase the risk of developing liver cancer. These include:

  • Long-term hepatitis B or C infection
  • Cirrhosis and long-term alcohol abuse
  • Exposure to carcinogens
  • History of non-alcoholic fatty liver disease
  • Smoking
  • Obesity
  • Type-II diabetes
  • Increased intake of anabolic steroids
  • A family history of other liver diseases

Diagnosis

If a person experiences any signs or symptoms of liver cancer, the following tests may be recommended:

  1. Blood tests: These tests help to diagnose liver function abnormalities.
    1. Liver function tests: These tests check for abnormal levels of proteins, liver enzymes and bilirubin in blood.
    2. Serum marker test: Markers are proteins secreted by cancer cells, whose presence in blood indicates cancer. Elevated level of alpha-fetoprotein (AFP) in blood indicates liver cancer.
  2. Imaging tests: Tests such as ultrasound, computerized tomography (CT) scan, magnetic resonance imaging (MRI) provide detailed information about the size and spread of the cancer. Angiogram is performed to examine the blood vessels that supply blood to the tumor.
  3. Biopsy: It involves the removal of tumor tissues using specialized needles for detailed examination. It is the most reliable way to determine cancer.

Stages

The liver cancer staging is done using the TNM staging system. It provides detailed information about:

  • Tumour (T): Whether the primary tumour has grown through the liver
  • Node (N): Whether the cancer has spread to the surrounding lymph nodes
  • Metastasis (M): Whether the cancer has spread to distant parts of the body

Based on this system, liver cancer has the following stages:

  • Stage I: Single tumor confined to the liver and has not spread to nearby lymph nodes or distant sites.
  • Stage II: Either a single tumor larger than 2cm that has spread to blood vessels OR several small tumors that all remain in the liver
  • Stage III: More than one tumor confined to the liver, with one tumor larger than 5 cm OR one tumor that has spread to a major branch of a large vein of the liver
  • Stage IV: Single tumor or multiple tumors that have spread to distant parts of the body like bones, lungs

Treatment

Once liver cancer is diagnosed, a customised treatment plan is created based on the stage of cancer at the time of diagnosis and the overall health of liver. Treatments for liver cancer include:

Surgery: The tumor and some surrounding healthy tissue are removed by surgical procedures. Surgery improves the chance of recovery for patients with early stage liver cancer. Surgical approaches include:

  1. Partial hepatectomy: This involves the removal of a portion of the liver, ranging from a smaller wedge to an entire lobe. It is recommended for stage I cancer.
  2. Liver transplantation: This involves removal of the whole liver and replacing it with a healthy one from an organ donor. It is an option for those tumors that cannot be removed with surgery.

Possible side effects are bleeding, infections, blood clots and rejection of new liver.

Ablation therapy: This therapy involves non-surgical methods to destroy the tumors without removing them and is recommended for the elderly or patients with serious conditions, where surgery cannot be considered. The procedure involves placing a needle or probe directly into the liver tumor to destroy them. Based on the methods used to destroy the cancer cells, it is classified into:

  • Radiofrequency ablation
  • Percutaneous ethanol (alcohol) ablation
  • Cryotherapy
  • Microwave ablation

Embolization Therapy: Embolization is a procedure in which certain substances are injected directly into the blood vessels in liver to block or reduce the blood flow to a tumor in the liver. Sometimes, the procedure is combined with chemotherapy (called chemoembolization) or radiation (radioembolization) for better outcomes.

Possible complications after the procedure are abdominal pain, fever, nausea, liver infections and blood clots in the main blood vessels.

Targeted therapy: This therapy uses drugs that interfere with genes or proteins that contribute to the growth and survival of cancer, and thereby destroy the cancer cells. These are different from chemo drugs and have minimal side effects.

Chemotherapy: It involves the use of specific oral or intravenous drugs to kill cancer cells. It is recommended for patients who cannot undergo surgery or have not responded to local therapies or targeted therapy. Chemotherapy is usually given in cycles and the patient may receive single or combination of drugs.

Common side effects include fatigue, nausea, vomiting, loss of appetite, hair loss and diarrhea.4

Radiation therapy:  High-energy radiations like X-rays are used to destroy tumor cells. It is not considered for patients with severe liver damage due to hepatitis or cirrhosis.

For liver cancer, stereotactic body radiation therapy is used. This method delivers high doses of radiation to a tumor while limiting the amount of radiation to nearby healthy tissue.

Major side effects may include mild skin reactions, fatigue, loss of appetite, nausea and vomiting, diarrhea, and weight loss.

Immunotherapy: This uses drugs that direct the body’s own immune system to kill cancer cells. For liver cancer, drugs like atezolizumab, pembrolizumab, nivolumab and ipilimumab are used to attack cancer cells by boosting the natural defense of the immune system.

Gallbladder Cancer

Gallbladder cancer occurs when healthy cells in the gallbladder undergo change and start to grow out of control, which slowly form a tissue mass or lump called a tumor. The tumors can be benign (non-cancerous, do not spread to nearby tissues) or malignant (cancerous, spread to other parts of the body).

Majority of the gallbladder cancers are adenocarcinomas - cancer that start in the tissue on the inside wall of gallbladder. Less common types of gallbladder cancer are adenosquamous carcinomas, squamous cell carcinomas, and carcinosarcomas.

Signs and Symptoms

There are no specific symptoms for gallbladder cancer in its early stage. Symptoms usually appear in the advanced stage when the tumor is large and/or has spread.

Common symptoms of gallbladder cancer include:

  • Abdominal pain and cramps
  • Bloating
  • Fever
  • Unintentional weight loss
  • Nausea
  • Yellowing of skin and whites of the eyes (jaundice)
  • Itchy skin

Causes/Risk factors

Like other cancers, the exact cause of gallbladder cancer is not clear. Some factors that may increase the risk of gallbladder cancer are:

  • History of gallstones
  • Older age
  • Female gender
  • Obesity
  • Abnormalities of the bile ducts
  • Gallbladder polyps (growths in the gallbladder wall)
  • Porcelain gallbladder (calcium buildup in the gallbladder)
  • Smoking

Diagnosis

There are no early screening tests used for gallbladder cancer. If a person experiences any signs or symptoms of gallbladder cancer, following tests are recommended.

  • Blood tests:
    1. Liver and gallbladder function test: Elevated levels of bilirubin in the blood indicate gallbladder cancer due to blockage of the common bile duct by a tumor.
    2. Tumor marker: Tumor markers are proteins secreted by cancer cells, whose presence in the blood indicates cancer. Gallbladder cancer patients have high CA19-9 or carcinoembryonic antigen (CEA) levels in blood.
  • Imaging tests: Tests such as ultrasound, computerized tomography (CT) scan, magnetic resonance imaging (MRI) are done to examine the suspicious area to learn how far the cancer may have spread.
  • Laparoscopy: In this procedure, a small laparoscope (thin flexible tube with a mounted video camera) is inserted through the abdomen. The camera transmits the real-time images of the bladder to examine the structures and signs of disease.
  • Biopsy: It involves removal of some tumor tissues from the suspicious area using a needle. The sample is analyzed under a microscope to determine if it is cancerous or benign. The procedure is guided by CT or MRI scanning.

Stages

Gallbladder cancer is also staged based on the TNM staging system. Based on this system, the cancer has the following stages:

  • Stage I: Cancer cells are confined to the gallbladder and have not spread to distant sites.
  • Stage II: Cancer cells have extended to the peri-muscular connective tissue but not spread to distant sites.
  • Stage III: Cancer cells have either spread beyond the gallbladder and have not spread to lymph nodes or are present in the gallbladder and have spread to lymph nodes. 
  • Stage IV: Cancer cells have either spread to nearby blood vessels or lymph nodes and have not spread to distant sites; or have spread to distant parts of the body like bones, lungs.

Treatment

Treatment approaches for gallbladder cancer depends on the stage of cancer at the time of diagnosis, possible side effects and overall health of the patient. The main types of treatments for gallbladder cancer are:

Surgery: It involves the surgical removal of the entire tumor. Surgery is the mainstay early and advanced cancers for easing the symptoms of advanced cancer.

Types of surgery:

  • Cholecystectomy: It involves the removal of gallbladder. It is recommended for stage I cancer.
  • Radical gallbladder resection: In this procedure, the gallbladder along with a wedge-shaped section of the liver, the bile duct, and lymph nodes are removed.
  • Palliative surgery: It is performed to ease the symptoms and complications of cancer such as blockage of the bile ducts. It is recommended for stage IV cancer.

Radiation therapy: Radiation therapy may be used before surgery (neoadjuvant therapy) to shrink the tumor or after surgery (adjuvant therapy) to destroy any remaining cancer cells. For advanced cancers, it is also used to ease the symptoms (palliative therapy).

For gallbladder cancer, high energy beams are delivered to the site of tumor through an external source (external beam therapy). It is an outpatient procedure that is usually given over several weeks.

Side effects from radiation therapy may include mild skin reactions, fatigue, loss of appetite, nausea and vomiting, diarrhea, and weight loss.

Chemotherapy: It involves the use of specific anticancer drugs to destroy the cancer cells. In gallbladder cancer, chemo drugs are used as:

  • A part of the main treatment for some advanced cancers
  • An adjuvant treatment after surgery to reduce the recurrence of cancer

Common side effects of chemotherapy are fatigue, nausea and vomiting, loss of appetite, hair loss and diarrhea.

Immunotherapy: It involves the use of medications that boost patient’s own immune system to recognize the cancer cells and destroy them. Most of the immunotherapy drugs for gallbladder cancer are in clinical trials.

Outlook:

Although there is no way to prevent liver and gallbladder cancers, early diagnosis and prompt treatment may reduce the risk of cancer. Patients with early-stage tumors have the best chance of long-term survival. Unfortunately, most liver and gallbladder cancers are diagnosed in the advanced stages. Follow-up care and staying positive throughout the treatment will help obtain better outcomes.

Reference:
  1. Liver cancer. https://www.cancer.net/cancer-types/liver-cancer/. Accessed on: 19-08-2020.
  2. Liver cancer. https://www.cancer.org/cancer/liver-cancer. Accessed on: 19-08-2020.
  3. Liver cancer.https://my.clevelandclinic.org/health/diseases/9418-liver-cancer/. Accessed on: 19-08-2020.
  4. Gallbladder cancer. https://www.oncolink.org/cancers/gastrointestinal/gallbladder-cancer/all-about-gallbladder-cancer. Accessed on: 19-08-2020.
  5. Gallbladder cancer. https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer. Accessed on: 19-08-2020.
  6. Gallbladder cancer. https://www.cancer.org/cancer/gallbladder-cancer/. Accessed on: 19-08-2020.
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