Multifocal Intrahepatic Cholangiocarcinoma: Causes, Symptoms, Diagnosis, and Treatment

Introduction:

Cholangiocarcinoma is a rare form of a group of cancer that develops in bile ducts. These bile ducts are thin tubes that connect the liver to the small intestine. The main function of these ducts is to carry a fluid called bile from the liver into the small intestine. The digestive fluid and bile helps in the digestion of fats in the food. Bile is produced by the liver and stored in the gall bladder before being released into the small intestine. It breaks down fats derived from food into fatty acids, thereby helping in digestion.

There are several subtypes of cholangiocarcinoma, which are classified according to location. They are:

• Intrahepatic Cholangiocarcinoma: When cancer develops within the bile ducts inside the liver, it is called intrahepatic cholangiocarcinoma (ICC).

• Extrahepatic Cholangiocarcinoma: Cancer that develops in the bile ducts outside the liver is called extrahepatic cholangiocarcinoma or bile duct cancer. It is further classified as:

  • Perihilar cholangiocarcinoma.

  • Distal cholangiocarcinoma.

  • Gall bladder carcinoma.

What Is Multifocal Intrahepatic Cholangiocarcinoma (ICC)?

It is a subtype of cholangiocarcinoma that develops within the ducts of the liver that connect with the small intestine. It is considered as cancer that spreads to adjacent tissues and other parts of the body. Intrahepatic cholangiocarcinoma accounts for 10 % to 15 % of all primary liver cancers (cancer that has its origin in the liver). It is most common in the elderly between the ages of 50 and 70 years. Most of the patients are asymptommatic, until the disease reaches an advanced stage. All the subtypes of this cancer remain undetected without signs and symptoms till they are spread beyond the bile ducts to the other tissues. It is due to this delay in the diagnosis of ICC that the prognosis is not favorable, even though there are many advancements in therapies. The cases of ICC have been increasing over the last ten years.

What Is the Cause for Multifocal Intrahepatic Cholangiocarcinoma?

Any cancer develops due to mutations in genes that regulate the multiplication of the number of cells. These mutations lead to abnormal proliferation of cells forming masses or tumors of abnormal cells, thereby forming cancer. In the case of cholangiocarcinoma, all the subtypes are caused due to gene mutations that are acquired. Cholangiocarcinoma is not hereditary. Most people acquire the mutations in later stages of life, hence also called somatic mutations. Somatic mutations can occur in different types of genes that are listed and explained below:

• Tumor Suppressor Genes: These genes control and restrict the growth and division of cells. Any mutation in such genes leads to abnormal proliferation of cells leading to cancer.

• Oncogenes: They are the genes that carry the ability to cause cancer. In a healthy and normal individual, these oncogenes are in inactive form. Once they are activated, they undergo mutation, causing normal cells to multiply abnormally.

• Germline Mutations: We have already learned previously that any subtype of cholangiocarcinoma is not inherited and that they are acquired. But recent studies show that some genes can be a possible risk factor for cholangiocarcinoma.

Fig 1: Classification of cholangiocarcinoma according to its location.

What Are the Symptoms of Multifocal Intrahepatic Cholangiocarcinoma?

• Jaundice: By its nature, jaundice can be considered a separate entity of disorder or a symptom, just like in the case of cholangiocarcinoma. Jaundice occurs when the liver cannot get rid of bilirubin. In a healthy individual, the liver can get rid of bilirubin on its own. But in the case of ICC, the liver is unable to excrete bilirubin. In such instances, signs of jaundice can be listed as follows:

  • Fever.

  • Chills.

  • Abdominal pain.

  • Flu-like symptoms.

  • Yellowish discoloration of the skin.

  • Dark-colored urine.

  • Clay-colored stools.

  • Loss of weight.

• Itching: An increase in bilirubin causes the skin to itch. This is one of the common symptoms of cholangiocarcinoma.

• Greasy Stools: When the bile ducts are blocked due to cancer or tumor mass, it prevents bile from reaching the intestine. It is then when the intestine is unable to digest the fat in the food. This undigested fat is the reason for greasy stools.

• Light-colored Stools: Bilirubin is the one that contributes to the brown pigment of stools. When the bilirubin is trapped inside the liver, the intestine is devoid of bilirubin which causes pale or light-colored stools.

• Dark Urine: When the bilirubin levels are high in the blood, it combines with urine, due to which it becomes darker.

• Abdominal Pain: Cholangiocarcinoma, in its early stages, may cause slight pain or no pain at all. But as the tumor size increases, cancer causes belly pain.

• Fever: Few patients become febrile due to cholangiocarcinoma.

• Nausea and Vomiting: Not all, but a few individuals who develop an infection due to blockage of the bile duct, can experience nausea and vomiting.

These symptoms are not specific to cholangiocarcinoma. There is not one clinical sign or symptom that can distinguish this cancer. Some other conditions in which similar signs and symptoms appear are gallstones, and hepatitis A. Careful investigation has to be carried out for the diagnosis of cholangiocarcinoma.

How to Diagnose Multifocal Intrahepatic Cholangiocarcinoma?

Previously, in this article, we understood that it is hard to find ICC in the initial stages. This cancer does not become obvious till it reaches its advanced stage. The bile ducts are located deep inside the body. Hence small tumors go undetected for a long duration as they are asymptomatic.

The diagnosis of ICC in its early stages is difficult due to a lack of blood tests or imaging studies for the same. However, there are tests that can diagnose multifocal intrahepatic cholangiocarcinoma.

• Medical History: A thorough medical history will be asked by the doctor to identify any risk factors.

• Physical Examination: The abdomen or belly is palpated to locate any lumps that are caused due to fluid accumulation. The doctor shall examine for pain and tenderness in the abdomen. The color of skin and eyes are also examined to identify color changes.

• Blood Tests: One can expect a nurse to draw blood from the patient to be sent to the laboratory for analysis. Blood tests normally include liver function tests (LFT) that help in evaluating liver and gallbladder functionality. These tests assess the levels of albumin, liver enzymes, and other substances in the blood.

• Tumor Markers: These are the substances produced by cancer cells. The presence of these substances in blood confirms cancer. In ICC, the blood is evaluated for two markers, namely, CEA (carcinoembryonic antigen) and CA 19-9 (carbohydrate antigen 19-9). The levels of these markers are found to be extremely high in patients with cholangiocarcinoma.

• Imaging Tests: These tests help the doctor in locating cancer, plan the treatment, perform the guided biopsy, identify if cancer has spread, and identify the recurrence of cancer. These tests include abdominal and endoscopic ultrasound, computed tomography, magnetic resonance imaging, cholangiography, angiography, laparoscopy, cholangioscopy, and last but not least, biopsy.

How Is Multifocal Intrahepatic Cholangiocarcinoma Best Treated?

There are various treatment options for treating multifocal ICC. Though, the selection of treatment depends on multiple factors like:

• Location and extent of cancer.
• If the cancer is treatable by surgery.
• Concomitant factors- other conditions of the patient.

The treatment methods are mentioned below:

• Surgical Therapy (Liver Resection): The only potentially curative therapy for ICC is surgical resection. Resection is the excision or removal of the tumor surgically. The main aim of the surgery is to remove the tumor mass, leaving healthy liver remnants inside the body. Since the disease itself is diagnosed in advanced stages, regional lymphadenectomy is usually performed. There are a total of six lymph nodes that will be planned for resection in ICC. If, in the early stages, the tumor can be removed surgically, neoadjuvant therapy can be followed, which is a new advancement in treatment modalities. This therapy helps in downgrading the tumor by slowing its progression, thereby removing the lesion.
• Median survival following a liver resection is 28 to 30 months, while disease-free survival is about 20 months. Minimally invasive liver resection is also performed but rarely since it needs a sophisticated environment. But the centers that conduct this type of liver resection showed excellent results. Though these results are promising, they did not show any positive impact on prognosis.

• Chemotherapy: Chemotherapy uses anticancer drugs that are given to the patient systemically. These drugs enter the bloodstream to kill cancer cells. Chemotherapy can be delivered in many ways:

  • Post-Surgery: After the surgery, the drugs are given to the patient to lower the recurrence risk (the risk of cancer coming back). This therapy is also called adjuvant chemotherapy.

  • Before Surgery: Few anticancer drugs are given before the surgery, only to shrink or reduce the size of the tumor to enhance the success of the surgery. This is called neoadjuvant therapy.

  • During the Liver Transplant Procedure: While a patient is waiting for a liver transplant, drugs are prescribed to control the spread of cancer.

  • First-line of Treatment: When the cancer is unresectable from the body, that is, in advanced cancer, these types of drugs are prescribed to control the spread to other parts of the body.

  • Palliative Therapy: Few drugs are given to the patient to alleviate or reduce the symptoms.

• Radiotherapy: The two main radiation therapy options available for the treatment of ICC include external beam radiation therapy and internal radiation therapy (brachytherapy). This therapy uses X-rays to treat cancer. These radiations are quite stronger than normal X-rays that are used to scan the body or parts of the body. It is a painless procedure that lasts for a short period (a few minutes) for many days to weeks.

• Targeted Drug Therapy: Sometimes, traditional chemotherapy fails to bring results. For such situations, researchers have developed a few drugs that specifically target cancer cells and destroy them. Some of them are listed as follows:

  • Fibroblast growth factor receptors.

  • IDH1 inhibitors (isocitrate dehydrogenase 1).

Conclusion:

Intrahepatic cholangiocarcinoma is difficult to diagnose because it remains asymptomatic for longer duration till it reaches an advanced stage. Although with many technologies upfront in diagnostician therapeutic measures, prognosis remains to be unfavorable. However, liver resection remains to be the only curative option, even in the most advanced stages.