What is Hepatocellular Carcinoma ?
Hepatocellular carcinoma (HCC) is a type of cancer that begins in the liver, accounting for more than 90% of liver cancers. It’s estimated to occur in about 85% of patients who have been diagnosed with cirrhosis, a serious condition that causes scar tissue to replace healthy liver tissue. HCC is currently the fifth most common type of cancer worldwide and the second leading cause of cancer-related deaths in men, just behind lung cancer.
The chances of surviving for five years after being diagnosed with HCC are around 18%, making it almost as deadly as pancreatic cancer. Several major risk factors can increase the likelihood of developing HCC. These include viral infections like hepatitis B and hepatitis C, alcoholic liver disease, and non-alcoholic liver steatohepatitis or non-alcoholic fatty liver disease, conditions characterized by inflammation and damage in the liver that aren’t caused by alcohol. Among people with cirrhosis, 80%-90% will develop HCC, and the number of new cases diagnosed in these patients each year is between 2-4%.
What Causes Hepatocellular Carcinoma ?
Hepatocellular carcinoma, a type of liver cancer, can be caused by a number of health issues including Hepatitis B, Hepatitis C, alcohol-related liver disease, and non-alcoholic liver diseases such as steatohepatitis and fatty liver disease.
Viral Hepatitis
Chronic infections of Hepatitis B and Hepatitis C are responsible for over 70% of liver cancer cases. Hepatitis B is an infectious disease that affects over 250 million people worldwide. This virus can embed its DNA into the human host’s DNA, which is the main way it causes cancer. Some specific alterations in human DNA account for 60% of liver cancer cases. Other DNA changes can also play a role in the development of liver cancer. Hepatitis B virus infection accounts for 56% of liver cancer cases globally while Hepatitis C accounts for 20%.
Though it is most common for liver cancer to develop in patients with cirrhosis (a liver condition characterized by irreversible scarring), it can occur without cirrhosis in those suffering from Hepatitis B virus infection. Certain factors like high levels of HBV DNA and Hepatitis B e-antigen in the blood, along with co-infections with Hepatitis C or Hepatitis delta viruses, increase the risk of developing liver cancer.
Hepatitis C, like Hepatitis B, is also a major cause of liver cancer. Hepatitis C is an RNA virus with many different types and subtypes. Certain types of Hepatitis C are more frequently linked to liver cancer. Liver cirrhosis, chronic inflammation, and subsequent fibrosis (tissue thickening and scarring) and necrosis (cell death) contribute to cancer development in Hepatitis C patients. Coinfection with the Hepatitis B virus further increases the risk of liver cancer.
Non-Alcoholic Liver Disease
Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), conditions characterized by the accumulation of excessive fat in the liver cells, can also lead to liver cancer, especially in the context of metabolic syndrome. Metabolic syndrome links issues like insulin resistance, high blood pressure, high blood triglycerides, and abdominal obesity, which all increase the risk of heart disease. NAFLD is a leading cause of liver cancer, especially in Western countries. Liver cancer cases are expected to surge by 122% in the U.S between 2016 and 2030 due to the rise in obesity and diabetes rates.
Alcohol Consumption
In the United States, about 30% of liver cancer cases are linked to excessive alcohol intake. Alcohol can cause liver cancer indirectly by causing liver cirrhosis, while high daily consumption increases the risk of liver cancer by up to five times.
Exposure to Aflatoxins
Aflatoxin B1, a toxin produced by certain types of fungi and found in grains, is associated with an increased risk of liver cancer in patients with chronic Hepatitis B. This is particularly prominent in Sub-Saharan Africa and Southeast Asia.
Other risk factors for liver cancer include conditions such as iron overload, glycogen storage disease, Wilson’s disease, alpha one antitrypsin deficiency, hypercitrullinemia, Alagille syndrome, and acute intermittent porphyria.
Risk Factors and Frequency for Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC), a type of liver cancer, is the fifth most common cancer around the world. In 2018, approximately 841,000 new cases were diagnosed, and it was responsible for 780,000 deaths. Men are three times more likely to get HCC than women. Most new cases of this cancer (over 80%) are found in developing areas, including Sub-Saharan Africa, Southeast Asia, and China, where hepatitis B virus infections are high.
Non-alcoholic fatty liver disease (NAFLD) has become a major cause of HCC, particularly in Western countries. In fact, the number of HCC cases in the United States is projected to increase by 122% between 2016 and 2030 due to a rise in obesity and diabetes rates.
The average age of HCC diagnosis in the US is 64. HCC primarily affects those who had a Hepatitis C (HCV) infection, particularly people born between 1945 and 1965. Unfortunately, the survival rate for this cancer is low, with only 18% of patients surviving past five years after their diagnosis. This is only slightly higher than the survival rate for pancreatic cancer, the deadliest form of cancer.
Signs and Symptoms of Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC), a type of liver cancer, can present itself differently depending on the stage of the tumor and the presence of cirrhosis, a liver disease marked by scarring.
Patients without cirrhosis may not show symptoms in the early stages of HCC. The typical age when symptoms begin appearing for these patients is around 69 years old.
- Asymptomatic in early stages
- Typical onset at around 69 years old
On the other hand, HCC patients with cirrhosis might exhibit symptoms associated with severe liver disease. These can include:
- Yellowing of the skin (jaundice)
- Itchy skin (pruritus)
- Confusion and drowsiness (hepatic encephalopathy)
- Fluid build-up causing swollen belly (ascites)
- Felt lump in the upper abdomen
- Fever
- Feeling unwell (malaise)
- Unintended weight loss
- Feeling full quickly when eating (early satiety)
- Bloated belly (abdominal distension)
- Extreme thinness (cachexia)
- Abdominal pain
Additionally, HCC can cause a range of “paraneoplastic” symptoms – these are symptoms triggered by the body’s response to the cancer, not by the tumor itself:
- Low blood sugar (hypoglycemia)
- Excess red blood cells production (erythrocytosis)
- High calcium blood levels (hypercalcemia)
- Diarrhea
- Skin disorders like pemphigus foliaceous, pityriasis rotunda, dermatomyositis, and Leser-Trelat sign
Some symptomatic patients might present with complications like variceal bleeding, internal abdominal bleeding, obstructive jaundice, pyogenic liver abscess, or hepatic encephalopathy. Lastly, it’s important to remember that the most common sites for HCC to spread outside the liver are the lung, intra-abdominal lymph node, bone, and adrenal gland.
Testing for Hepatocellular Carcinoma
If your doctor is trying to determine if you have an advanced liver condition, such as hepatocellular carcinoma (HCC), they may request specific tests that examine how well your liver is functioning. These tests include measuring the levels of bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin in your blood. High levels of these substances may indicate a severe liver disease.
Your doctor may also conduct tests to assess your blood clotting ability, check for low blood platelets count and anemia, and verify levels of sodium and glucose in your blood. In advanced or chronic liver diseases like HCC, these tests may produce abnormal results. However, if you are in the early stages of a liver disease that is not related to cirrhosis, these tests could appear normal.
Part of the examination process might also involve testing for possible causes of HCC, like hepatitis B or C, abnormal copper levels, or abnormal iron saturation. Additionally, alpha-fetoprotein (AFP) blood levels might be checked, as high levels of this protein could indicate advanced HCC.
However, AFP levels don’t always correlate with the size of the tumor or whether it has spread to blood vessels. They might remain normal in the early progression of non-cirrhosis-related HCC. Furthermore, it’s worth noting that not all small HCC tumors produce AFP, and its levels could also increase due to other conditions like chronic hepatitis, pregnancy, and other types of tumors.
Your doctor might also employ imaging techniques such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) to diagnose HCC. While a regular ultrasound helps determine the size, shape, and location of the liver tumor, it has limited detection capabilities for tumors smaller than 2 cm. Contrast-enhanced ultrasound uses a special dye for better visualization.
CT scans give more detailed information and are especially helpful in detecting tumors 2 cm or larger in size. MRI provides excellent sensitivity for diagnosing HCC, with the technique showing variations in brightness depending upon the tumor type and stage.
The American radiology association (ARA) has developed a liver imaging reporting and data system (LI-RADS) for categorizing liver nodules. According to their criteria, liver lesions showing certain characteristics could indicate HCC.
While liver biopsy can provide definite proof of HCC, it’s not always used due to the risk of tumor spreading and bleeding, and the chance of not obtaining tissue from the right place. If the imaging tests are not clear, a biopsy may be recommended.
Treatment Options for Hepatocellular Carcinoma
Surgery
People with early stages of liver cancer (known as very early (0) and early-stage (A) in the BCLC classification) are usually the best candidates for surgery. Very early stage refers to those who have no symptoms but have a single, small (2 cm or less) cancer growth. Early stage patients also have no symptoms but have a single, slightly larger (more than 2 cm) tumor.
Patients who have a healthy liver and no significant issues with their blood pressure in the vein that supplies the liver, can expect good results from surgery. For those with small tumors under 5 cm in size, chances of surviving for 5 years are about 70%. However, the cancer can return after surgery, especially if the tumor has spread within the liver, the tumor cells are not well developed, or there are multiple small cancerous growths.
Liver Transplant
In some cases, opting for a liver transplant can remove tumors entirely, potentially curing the patient. Appropriate candidates are those who fit the Milan criteria: a single tumor smaller than or equal to 5 cm, or a maximum of three tumors, none of which are larger than 3 cm, and no spread of the cancer beyond the liver. The survival rate is 60-80% at 5 years and 50% at 10 years for individuals meeting these criteria, with a return of the cancer in less than 15% of cases. While waiting for a transplant, certain treatments can be beneficial by slightly extending life expectancy.
Tumor Ablation
If surgery isn’t the right option for a patient, another possible treatment is known as ablation. This involves modifying the temperature of the tumor using techniques such as radiofrequency ablation, cryotherapy, microwave or laser therapy, or injecting substances like ethanol, boiling saline or acetic acid into the tumor. This is proven to have fewer complications as compared to surgery.
Transarterial Therapies
Transarterial therapies or procedures to block the blood supply to the tumor are considered for patients with preserved liver function, no symptoms, and multiple, not large tumors not spread further. In such a procedure, cytotoxic agents (that kill cancer cells) are used to block the artery supplying the tumor, which is known as transarterial chemoembolization (TACE). Another method uses an isotope known as Yttrium-90, which is sent to the tumor site to deliver radiation.
Chemotherapy
If liver cancer has advanced to stage C (spread beyond the liver or affecting the blood vessels), sorafenib is the typical first-line treatment. It’s a drug that inhibits the growth of cancer cells. Clinical trials have shown that people taking sorafenib had an average survival of 10.7 months. Another option, lenvatinib, showed as much effectiveness as sorafenib, but patients on this drug had less symptoms of skin irritation and redness but more significant weight loss. For patients who can’t tolerate sorafenib or in case the cancer continues to progress, other drugs like regorafenib, cabozantinib, ramucirumab, and nivolumab are considered as alternatives.
What else can Hepatocellular Carcinoma be?
When trying to identify liver cancer, or hepatocellular carcinoma (HCC), doctors need to consider several other conditions that could display similar symptoms.
- Cholangiocarcinoma
- Fibrous nodular hyperplasia
- Dysplastic/Regenerative nodules related to cirrhosis
- Hepatic adenoma
- Primary hepatic lymphoma
- Cirrhosis
- Cancer spread from another part of the body (metastatic cancer)
Doctors often use an ultrasound to help them determine what the problem might be. This test highlights patterns in blood flow that can differentiate between different conditions. For example, in HCC, the blood vessels tend to be more numerous and faster-flowing than in other diseases.
In addition to this, HCC tends to show elevated blood supply during the arterial phase of blood flow with subsequent washout in the portal venous phase. On the other hand, regenerative nodules arising from cirrhosis usually look the same or less visible compared to the rest of the liver.
Cholangiocarcinoma, another type of liver cancer, may show increased blood supply in both the arterial phase and delayed phase on a special type of CT scan.
What to expect with Hepatocellular Carcinoma
The five-year survival rate for liver cancer, known as hepatocellular carcinoma (HCC), is about 18%, making it the second deadliest cancer after pancreatic cancer. The patient’s prognosis or likely course and outcome of HCC depend on several factors. These include the size of the tumor, the grade or severity of the tumor based on lab examination, the severity of the underlying liver disease, whether the cancer has spread to other body parts, and if the tumor has extended to nearby structures.
Patients with HCC and high levels of alpha-fetoprotein, a protein produced by the liver, tend to have a poor prognosis because this indicates that the cancer cells are poorly differentiated, meaning they appear less like normal cells. Similarly, patients with HCC who have active hepatitis B virus infection (indicated by a positive hepatitis B e-antigen blood test) tend to have a grim prognosis and higher recurrence of HCC.
High levels of hepatitis B virus DNA in the blood are linked with a higher risk for HCC and its recurrence. It’s also important to note that diabetes is a risk factor that increases the chances of someone developing HCC and, additionally, it is associated with a worse prognosis.
Possible Complications When Diagnosed with Hepatocellular Carcinoma
Liver cancer, specifically hepatocellular carcinoma, can cause a number of complications within the liver. These issues can include liver disease that affects the brain (hepatic encephalopathy), blood clot in the liver’s main vein (portal vein thrombosis), increased fluid in the abdomen (worsening ascites), stomach and esophagus vein rupture resulting in bleeding (variceal bleeding), bloated belly and yellowing of skin (obstructive jaundice), and pus-filled areas in the liver (pyogenic liver abscess).
Bleeding within the abdomen can occur as a complication of this cancer, and can pose a risk to life. Symptoms may include an enlarged and painful belly, low blood pressure, and anaemia. An emergency procedure called angiography, involving the injection of dye to identify bleeding areas, and potentially surgery, may be required to stop the bleeding. To diagnose this, a scan of the abdomen without contrast is required, and a scan with contrast is necessary if the angiography procedure is needed.
The most common spread of liver cancer outside the liver (metastasis) occurs in the lungs, followed by lymph nodes in the abdomen, the bones, and then the adrenal glands. It’s rare, but the cancer has been found to spread to the brain as well.
Common Complications:
- Hepatic encephalopathy
- Portal vein thrombosis
- Worsening ascites
- Variceal bleeding
- Obstructive jaundice
- Pyogenic liver abscess
- Internal bleeding in the abdomen
- Metastasis to lungs, lymph nodes, bones, and adrenal glands
- Rare occurrence of brain tumor
Preventing Hepatocellular Carcinoma
Hepatocellular carcinoma, a type of liver cancer, is the fifth most common cancer in the world and the number two cause of cancer deaths for men.
There are several risk factors for developing this liver cancer. These include long-term infection with hepatitis B or hepatitis C, heavy alcohol use, and a condition called non-alcoholic fatty liver disease (NAFLD).
NAFLD is becoming a major reason why people are getting this type of liver cancer, especially in Western countries. This is linked to the rise in a health issue called metabolic syndrome. Metabolic syndrome is a term for a group of risk factors that raises your risk for heart disease. These factors include high blood pressure, unhealthy cholesterol levels, excess body fat around the waist, and insulin resistance, which means your body can’t use insulin properly.
Hepatocellular carcinoma is diagnosed through various methods. These can include blood tests to measure certain biomarkers like alpha-fetoprotein, images from an ultrasound or a contrast CT or MRI scan, and sometimes a biopsy, which involves taking a small sample of liver tissue for testing.
Unfortunately, the five-year survival rate for this liver cancer is only 18% and it’s considered the second deadliest after pancreatic cancer.
