Intrahepatic Cholangiocarcinoma: An Overview

Introduction:

Any liver inflammation increases the chance of developing intrahepatic cholangiocarcinoma. Most of cholangiocarcinoma are adenocarcinomas. About 90 percent of cases show elevated serum levels of alpha-fetoprotein. Cholangiocarcinoma does not contain bile pigment within it, unlike other tumor cells.

What Is Intra Hepatic Cholangiocarcinoma?

Intrahepatic cholangiocarcinoma is caused by abundant fibrous stroma deposition (desmoplasia) in the liver. They appear firm and gritty in consistency. They have well-defined structures similar to those of glands and tubules. These structures are lined by anaplastic cuboidal to low columnar cells. However, bile pigment and hyaline inclusion bodies are absent in such cases. It shows metastatic properties spreading to nearby tissues like the lymph nodes, bones, adrenal glands, and other sites.

What Is the Epidemiology of Intra Hepatic Cholangiocarcinoma?

Intrahepatic cholangiocarcinoma is distributed globally, with geographic variation in the following percentage. The United States of America has one or two percent affecting per thousand of the population. In north-eastern Thailand, it is seen as an epidemic, with almost 85 percent affecting a thousand population. In Thailand, liver fluke cases are high, contributing to many cholangiocarcinoma cases. In China, eight in every thousand people are affected by cholangiocarcinoma.

What Are the Causes of Intra Hepatic Cholangiocarcinoma?

• Liver infections.

• Oxidative stress is caused in the liver due to excessive fat deposition.

• Obesity or overweight.

• Genetic mutations and non-somatic mutations are seen in 62 percent of cases. The most common mutations observed are K-RAS and B-RAF. Other mutations like IDH1 and IDH2 combined have shown 20 percent cases of intrahepatic cholangiocarcinoma.

What Are the Risk Factors Associated With Intra Hepatic Cholangiocarcinoma?

The following are the risk factors involved in cholangiocarcinoma.

• Chronic illness involving the biliary tree. For example, clonorchis sinensis is caused due to parasitic infections, which are seen among Asians.

• People over 50 years are prone to develop this condition.

• Primary sclerosing cholangitis.

• Stones in the bile ducts or liver (hepatolithiasis) can also be risk factors.

• Blackish material or biliary sludge seen within the tubules of bile ducts can cause cholangiocarcinoma.

• Alcohol consumption.

• Other infections.

• Diabetes.

• Obesity.

• Fatty liver causes fibrosis and cirrhosis and eventually leading to cancer.

• Chronic ulcerative colitis or Chron’s disease.

• Smoking.

• Hepatitis B and C.

• People exposed to toxic, carcinogenic agents.

What Are the Symptoms of Intrahepatic Cholangiocarcinoma?

Most of the patients are asymptomatic. Symptoms of the disease depend upon the progression and site of the lesion. Some of the presenting signs are as follows:

• Loss of appetite.

• Weight loss.

• Fatigue.

• Fever.

• Chills.

• Abdominal pain.

• Dark-colored urine.

• Itchy skin.

• Nausea and vomiting.

• Jaundice.

What Are the Diagnostic Tests Conducted to Check for Intrahepatic Cholangiocarcinoma?

Based on the existing symptoms, various tests are performed. Such as

• Liver Function Test: High value of alpha-fetoprotein above 1000 ng/mL is solely encountered in extrahepatic cholangiocarcinoma. Liver function tests giving high values to tumor markers are a distinctive feature of cholangiocarcinomas. But about 20 percent of cases show negative results in tumor markers despite active cholangiocarcinomas. Especially, CEA is elevated in 25 percent of cases, CA 19-9 is elevated in 50 percent of cases, and AFP is elevated in less than five percent of cases. CEA and CA 19-9 are not sensitive enough to diagnose cholangiocarcinomas in half of the population.

• Ultrasound: This imaging technique helps identify abnormal mass growth inside the liver and gall bladder.

• Computed Tomography (CT): A higher diagnostic value that gives a better contrast image of the internal organs to study any malignancies if present. It is captured in a cross-sectional panoramic view.

• Magnetic Resonance Imaging (MRI): High magnetic field is used to capture the three-dimensional view of the internal structures.

• Mammogram or Gynaecologic Exam: This is done to rule out any metastasis if present.

• Upper and Lower Endoscopy: This is done predominantly in the colon and rectal areas. It is done to evaluate for any ulcerations or plaque formation. The gut and the esophageal region are visualized using a fiber optic camera.

• Positron Emission Tomography (PET) Scan: It helps to rule out cancer depending on the site of occurrence, for example, rectal cancer or bile duct cancer. The other thing is that it helps in lighting up the nodal disease. This helps in planning the treatment accordingly. If it has already spread to the nodal region, as in the case of occult metastatic disease, the first line of treatment will be to give chemotherapy before proceeding with surgery.

Is Intrahepatic Cholangiocarcinoma Treatable, and How to Take Preventive Measures Against This?

Various clinical trials are being conducted to study the scope of treatment for this condition, specifically targetting the IDH1 mutations and inducing molecular therapy. Genomic studies are undertaken to understand the mutation at the genetic level, and in particular, immunotherapy like PD1 and FGFRO1 receptors are done. Another treatment option is immunizing the high-risk world population against the hepatitis B virus (HBV). The small tumors can be surgically removed. All of the extrahepatic biliary tree is removed. If the tumor is big, removing eighty percent of the liver is required. These are tough tumors, and getting a negative margin postoperatively is very difficult therefore a positive margin gets left behind. Adjuvant therapy like chemotherapy and radiotherapy can be given. Vascular invasion of disease indicates lymph node metastasis. Around six lymph node stations should be evaluated in order to understand the staging of the disease. Half of the population post-operatively shows reoccurrence in less than two years.

How Is the Prognosis of Cholangiocarcinoma?

The staging of the disease decides the probable outcome of the disease. The mutations caused due to K-RAS and B-RAF gene has a median survival rate of seven months to one year, with death caused by cachexia (death of muscle cells), internal bleeding, liver failure with hepatic coma, and rarely rupture of the tumor followed by fatal hemorrhage. The survival rate of cholangiocarcinoma caused due to IDH gene mutation is two years. However, the overall prognosis is very poor.

Conclusion:

Patients suffering from cholangiocarcinoma may be present with silent hepatomegaly. Most tumors are associated with underlining conditions like liver cirrhosis which worsens into ascites, fever, and pain. However, tumor markers lack specificity due to similar symptoms in other illnesses like liver cirrhosis, hepatitis, and pregnancy. But values of serum alpha-fetoprotein above 1000 ng/mL are a unique diagnostic feature of cholangiocarcinoma.