History

A concise and complete history-taking should be done by the physician to obtain valuable pieces of information such as occupation, a history of hepatitis, jaundice, intravenous drug use, blood transfusion, multiple unprotected sexual partners, exposure to possible carcinogens and family history of HCC.

Symptoms

• Abdominal Pain

The most frequent complaint among HCC patients is abdominal pain. It may present with jaundice if the intrahepatic ducts are obstructed.

• Weight Loss, anorexia, and fever

Weight loss is defined as unintentional weight loss of more than 10% of body weight over a span of 6 months.

Weight loss, anorexia, muscle wasting, and fever occur as a consequence of rapid – growing or large tumors.

The tumor necrosis factor or cachexin is responsible for chronic inflammation and weight loss. It also induces fever in 10-15% of patients [2].

•  Hematemesis

Hematemesis may be seen if there is portal hypertension involved [2].

Portal hypertension leads to utilization of collateral hepatic blood supply and subsequently esophageal varices.

• Bone pain

Bone pain may also be present in up to 12% of patients [2].
The tumor can involve bone metastasis by way of the Baston’s plexus of veins running along the vertebrae.

Physical Signs

• Hepatomegaly is the most common physical examination finding in 50-90% of HCC patients.
• Splenomegaly may arise too as a consequence of portal hypertension.
• Ascites occurs on 30-60% of patients.

Ascites may occur due to a concomitant liver disease or compression of structures by a fast-growing tumor.
If the ascites is tense with a large and tender liver , a superimposition of Budd-Chiari syndrome should be suspected. The syndrome can occur due to invasion of the hepatic veins by HCC.

• Stigmata of chronic liver disease may be present.

This includes jaundice, caput medusa, spider angiomata, asterixis , palmar erythema, peripheral edema, gynecomastia, and testicular atrophy.

• Neurologic changes

Neurologic changes may occur with liver disease associated-encephalitis.

• Paraneoplastic Syndromes

Paraneoplastic syndromes are a cluster of symptoms that arise due to the expression of cytokines by tumor cells or an immune reaction of the body against the tumor. It is not a direct effect of the tumor’s presence. It may precede the diagnosis of malignancy.

 Paraneoplastic syndromes of HCC do not produce clinical symptoms. They are often biochemical abnormalities with no clear cause. The common biochemical abnormalities include:

Hypoglycemia
Hypoglycemia occurs as part of late-stage HCC. Destruction or incompetent hepatocytes alter the liver’s important capability of regulating glucose levels in the body.

Erythrocytosis
Erythrocytosis occurs in 3–12% [2] of patients. This may be a consequence of hypersplenism.

Hypercholesterolemia
10–40% of HCC patients have hypercholesterolemia. It may be a consequence of increased de novo synthesis of cholesterol, which primarily takes place in the liver.

Staging

The CLIP staging is a very useful staging system for HCC. It is more accurate than both the Okuda and Child-Pugh staging systems [10].

The CLIP staging involves 4 parameters namely Child-Pugh score, tumor morphology, α-fetoprotein [AFP], and portal vein thrombosis. A linear scoring is added with cumulative score of the 4 parameters ranging from 0 being the lowest to 6 being the highest.

• Child-Pugh score

The Child-Pugh scoring system gauges the prognosis of chronic liver disease with cirrhosis. It is based on 5 parameters namely serum albumin, total bilirubin, INR, hepatic encephalopathy, and ascites. Staging is based on the assessment of each parameter. The score ranges from 3 to 15. A score of 5-6 represents Stage A, a score of 7-9 indicates stage B, and 10-15 points is classified under Stage C. The two-year survival rates for Stages A, B, and C are 85%, 57%, and 35%, respectively. 

The Child-Pugh staging is related to the CLIP staging as follows:
Stage A = CLIP 0
Stage B = CLIP 1
Stage C = CLIP 2

• Tumor cell morphology

The histopathologic classification of tumor cell in relation to CLIP scoring is as follows:
Uninodular; < 50% extension = CLIP 0
Multinoudlar; < 50% extension = CLIP 1
Massive; extension > 50% = CLIP 2

• AFP

The AFP is a serum glycoprotein marker that has been used to screen and detect HCC. The AFP normally remains at < 10 ng/ml after approximately the 10th month of life. Elevations of AFP should give suspicion of an underlying malignancy.
The AFP level in relation to the CLIP scoring is as follows:
• < 400ng/ml = CLIP 0
• > 400 ng/ml = CLIP 1

Portal vein thrombosis
Absence of portal vein thrombosis = CLIP 0
Presence of portal vein thrombosis = CLIP 1

Biochemical markers

• AFP

The AFP is a serum marker for HCC. Elevations of AFP > 400ng/ml is considered diagnostic of HCC. The marker is non-specific though as carcinoma arising from the stomach, pancreas and biliary tree can induce AFP elevations as well.

• Des-gamma-carboxy prothrombin (DCP)

DCP levels become elevated in 80% [2] of patients with HCC due to the absence of vitamin K. However, DCP becomes elevated with warfarin use and frank Vitamin K deficiency as well.

• Routine liver function tests such as prothrombin time (PT), partial thromboplastin time (PTT), albumin, transaminases, gamma-glutamyl transpeptidase, and alkaline phosphatase should be performed to have a better picture of the liver’s health status.
• Complete blood count may reveal thrombocytopenia and leukopenia. Both can indicate an underlying portal hypertension problem.

Hepatitis serologic markers

HBV and HCV serology testing should be done.

Liver Ultrasound

Ultrasound of the liver is an excellent screening tool [2]. Hypervascularity of the tumor can be seen due to neovascularization. Invasion or thrombosis of the portal veins should also be checked.
Ultrasound of the liver, gallbladder, pancreas, and spleen (LGBPS) can also be done to verify involvement of the other organs.

CT scan

Abdominal CT scan
A triphasic abdominal CT scan is requested to determine tumor size and extent of tumor involvement [2]. Tumor invasion of the portal vein is also assessed with the CT scan.

Chest and Pelvic CT scan
These scans are requested as part of a metastatic work-up.

Tumor Biopsy

The sensitivity of liver biopsy is70-90% regardless of tumor size [11]; however, a negative tumor biopsy result does not rule out malignancy since stromal invasion (pathognomonic of HCC) may be difficult to identify [12]. Tumor morphology alone poses difficulty in distinguishing the stage of HCC especially for tumors <2cm in size [13].

An ultrasound-guided core liver biopsy is done. Care must be observed as the tumor is rich in blood supply as a result of neovascularization. There may also be associated clotting factor reduction due to the absence of vitamin K or thrombocytopenia as a result of hypersplenism. Both of these factors pose higher bleeding risk compared to other tumors.

HCC Screening

High risk populations should enter a surveillance program for HCC. High-risk individuals include those with:

• Liver cirrhosis
• History of HBV or HCV infection
• Intravenous drug users
• HIV patients
• Family history of HCC
• Alcohol abuse problems

Liver ultrasound every 6 to 12 months is suggested in this group. Ultrasound of the liver has a diagnostic specificity of 58 to 89% [14][15] and sensitivity of >90% [14][15] when used to screen HCC.

AFP determination is also done every 6 months.

Surgical Excision

A liver parenchyma –sparing approach is the treatment of choice for HCC without underlying cirrhosis [8]. Cirrhotic livers may not tolerate loss of significant hepatic parenchyma with surgical excision [2] and result in liver failure.
A preoperative occlusion of the portal vein permits a safer outcome by inducing a compensatory hypertrophy of the unaffected lobe [2].

Radiofrequency ablation (RFA)

RFA induces tumor necrosis with the use of heat. RFA is nonselective and can injure normal structures as well. This limits the use of the treatment in tumor near intrahepatic blood vessels and ducts. The technique offers a 7 cm zone of necrosis [2] which is suitable for tumors up to 3 cm in size.

Transcatheter Arterial Chemoembolization (TACE).

TACE allows delivery of chemotherapeutic drugs directly to the liver by way of the hepatic artery using embolizing agents [2] such as cellulose and ethanol (PEI). The status of the liver must be considered prior to TACE as embolizing agents are hepatotoxic [16]. PEI is non-selective and will cause lysis of normal hepatocytes as well. Degradable starch microspheres and gelatin sponge particles reduce the hepatotoxic effects of the procedure with 50–60% response rates.
The maximum size of tumor that can be treated effectively even with multiple injections is 3 cm in diameter [2]. One of the main concerns with TACE is that cirrhotic liver cannot tolerate the hepatotoxic effects. As a result, liver failure occurs.

Orthotopic Liver Transplantation (OLTX)

OLTX is recommended for patients who cannot benefit from surgical resection (e.g. advanced HCC or underlying liver cirrhosis). The main issue with OLTX is that patients are kept on the waiting list for a long time. TACE and RFA are now anecdotally used to counter the long waiting time prior to liver transplantation. The pre-transplant treatment approach is not yet well-documented on its success and safety.

Disease Prognosis

• HCC with underlying liver cirrhosis yields a very poor prognosis because of very limited treatment options.
• The Cancer of the Liver Italian Program (CLIP) scoring system allows guidance of treatment and prognostication. The scoring system will be discussed further below in the disease presentation section. The prognosis becomes poor as CLIP score increases. The following survival rates are based on CLIP scoring:

CLIP 0 - 31 months
CLIP 1 – 27 months
CLIP 2 – 13 months
CLIP 3 – 8 months
CLIP 4-6 – 2 months

• High α-fetoprotein (AFP) concentration (> 400 ng/ml), a tumor marker for HCC, is associated with a poor prognosis [8].

Treatment prognosis

• Transcatheter Arterial Chemoembolisation (TACE)

TACE allows extensive local exposure of the tumor to chemotherapy. The median survival rate with this type of treatment is >2 years [9].

• Surgical resection

Possibility of malignancy recurrence is high with resection with a rate of 50-60% after 5 years [2].

• Orthotopic Liver Transplantation (OLTX)

OLTX has a disease-free survival of ≥70% at 5 years with patients who have either a single lesion ≤5 cm or three or fewer nodules, each ≤3 cm [2].

Chemical Carcinogens

Aflatoxin B1 is a mycotoxin produced by the fungi Aspergillus flavus and parasiticus. It is a well-documented carcinogen that can be absorbed systemically through skin penetration. Once it enters the body, the liver tries to degrade the mycotoxin to less harmful compounds. Chronic exposure to aflatoxin B1 taxes the liver on its role of metabolizing the mycotoxin. Failure of the liver to convert it to non-harmful compounds leads to harmful liver reactions that can potentially induce oncologic changes.

Persistent aflatoxin B1 exposure is a major risk factor to developing HCC. There is a strong relation between the dietary intake of aflatoxin B1, TP53 mutations and incidence of HCC, specifically in HBV-infected individuals [3]. It often lurks in endemic areas that are known to store staple foods (e.g. grains and peanuts) without refrigeration.

Hepatitis

A history of infection with either the HBV or HCV poses a risk factor for HCC.

HBV

• 54% of HCC cases are associated with HBV [4].
• The risk is 98 times greater for those who are serologically positive with the hepatits B surface antigen (HBsAg) positive individulas. Alternating episodes of hepatocyte destruction and subsequent proliferation may be the underlying reason for developing HCC in HBV patients. 

HCV

• 31% of HCC cases stem from HCV infection [4].
• HCV-induced HCC is attributable to dietary aflatoxin B1 exposure and other mycotoxins. This is clearly evident in endemic areas where 85% of HCC arises.

Liver cirrhosis

HCC development occurs in up to 85% of liver cirrhosis cases [2].
It is still inconclusive as to whether it is cirrhosis or the underlying liver condition such as alcohol abuse, hepatitis, no nonalcoholic steatohepatitis (NASH) that plays a role in carcinogenesis.

HIV infection

HIV infection depresses the immune system and augments the risk of HCC in HBV or HCV patients [5].

Cigarette smoking

Smoking is a clear co-factor to developing HCC [6]. The tremendous amount of stress and free radical generation with cigarette smoking increases the risk of HCC.

The male-to-female ratio of HCC is 4:1 [2].

• This may be attributable to the higher tendency of male individuals to indulge in risky habits such as chronic alcohol intake, promiscuity, drug use, and smoking.
• Males are more likely to be exposed to harmful carcinogenic occupation than females in their occupation.

The death rate increases linearly with the incidence rate.

• Non-endemic areas have low death rates of 1.9 per 100,000 cases per year [2].
• Endemic areas have death rates of 23.1-150 per 100,000 per year [2].

The incidence rate of HCC rises at the age of 70 years old regardless of geographic location[7].

• This can be attributed to a high age-dependent penetrance of HCC. Nonetheless, there is a younger age of onset of HCC in people living in endemic areas [7].

5% of patients who suffer from liver cirrhosis with concomitant HCV infection are likely to develop HCC.

The main pathophysiology of HCC is still unknown at this time. The most common accepted theory is the cellular changes involved with cirrhosis lead to tumor genesis. Alternating bouts of inflammation, necrosis, and regeneration play a role in uncontrolled hepatocyte proliferation. This is not consistent though as approximately 20% of HCC patients do not have an underlying liver cirrhosis problem [4].

HBV and HCV infections put a person at risk for HCC due to two proposed reasons. First, the chronic inflammatory processes in the liver may lead to primary malignancy as a result. Lastly, the viral infections can induce liver cirrhosis open link problem, which contributes to HCC in majority of cases.

Immunosuppression due to a concomitant HIV infection can play a role in HCC development. Uncontrolled tumor growth with downregulation of tumor suppressor genes can ensue due to a weakened immune system.

Risky lifestyle behaviors such as chronic alcohol consumption, intravenous drug use, smoking, and unprotected coitus with multiple sexual partners can lead to HCC.

Alcohol consumption and smoking induce the accumulation of free radicals in the liver. These noxious chemicals in turn induce chronic inflammatory conditions to the liver.

Parenteral route of drug use increases the chance of acquiring HBV, HCV,and HIV.

Promiscuity leads to a higher risk of HIV infection.

• HBV vaccination

Universal vaccination of the newborn drastically caused a reduction of HBV-related HCC cases in endemic areas [2] [17]. The first dose of HBV vaccine is given immediately after birth to decrease the chance of perinatal or early postnatal transmission of HBV [18].

• Alcohol consumption in moderation

Chronic alcohol consumption or binge drinking can induce liver failure. Limiting alcohol intake to a maximum of 2 drinks will help prevent alcohol-related liver problems.

• Monogamy

Monogamy is highly tantamount to prevent risk of acquiring HIV infection. HIV depresses the immune system and leaves the body vulnerable to liver damage and HCC development.

• Stop drug abuse

Avoiding parenteral use of drugs keeps a person safe from blood-related illnesses such as HBV, HCV, and HIV infections, all of which are risk factors for HCC.

Hepatocellular carcinoma (HCC) accounts for majority (90%) of primary hepatic malignancies. It ranks 6th on the list of most common malignancies worldwide [1]. HCC is the 3rd [1] leading cause of cancer mortalities as treatment becomes limited when coupled with underlying cirrhosis or an advanced stage.

The most common predisposing factors to development of HCC are Hepatitis B virus (HBV), Hepatitis C virus (HCV), and cirrhosis. Other factors include human immunodeficiency virus (HIV) infection, intravenous drug use, chronic excessive alcohol consumption, and a family history of HCC.

85% of cases arise from East Asia, sub-Saharan Africa and Melanesia [2]. The endemic areas have a high disease occurrence because of two factors. First is the high rate of HBV carriers in the area. Second is the contamination of food and water with known mycotoxins such as aflatoxin b1The growing incidence of HCC worldwide may be attributed to the migration of people from endemic regions to non-endemic area.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. It is the 6th most common types of cancer and the 3rd leading cause of death from all types of cancer. HCC is highly associated with liver disease and persistent infection of the liver (e.g. hepatitis B virus (HBV) and hepatitis C virus (HCV).

Risk Factors:

• HBV infection

54% [4] of HCC cases is associated with a history HBV infection.

• HCV infection

31% [4] of HCC arises from HCC infection.

• Human Immunodeficiency Virus (HIV) infection

HIV weakens the body’s defense against harmful chemicals. The liver becomes easily vulnerable to damages from external factors such as infection and alcohol abuse. Persistent liver infection and damage can lead to HCC.

• Exposure to carcinogens

Aflatoxin B1 is a type of carcinogen that comes from fungi. Exposure to this carcinogen is highest in areas where staple food is stored unrefrigerated such as in East Asia and Africa. Prolonged exposure to aflatoxin b1 is documented to cause HCC as evidenced by the cluster of cases in the aforementioned region.

• Drug use

Using needles to infuse drugs is a very risky way of attracting needle-prick related infections such as HBV, HCV, and HIV. Once any of these infections is acquired, HCC may commence.

• Alcohol abuse

Alcohol abuse leads to extensive liver damage. Though a person may not feel the harmful effects initially, extended abuse will lead to irreversible liver damage and failure. Damage of the liver increases the chance of developing HCC.

Symptoms

• Abdominal pain

Abdominal pain is the most frequent symptom complained by HCC patients.
Sudden unintentional weight loss, Fever, and Loss of appetite
The three symptoms are often caused by a harmful chemical named cachexin. This chemical promotes muscle wasting and fever. The main trigger for release of the chemical is chronic liver damage and the cancer itself.

• Vomiting of blood

Vomiting of blood can occur as a result of wounds in the food pipe. Presence of wounds in the food pipe is a sign of liver problem.

• Bone Pain

Bone pain occurs when the cancer spreads to the bones.

Treatment

• Removal of tumor

Surgical removal of the tumor is feasible if the disease is caught in the early stages. It cannot be done in patients with impending liver failure. The chance of recurrence of a tumor is 50% after 5 years.

• Radiofrequency Ablation (RFA)

RFA melts the cancer cells by using heat. The downside of this technique is that it kills normal liver cells as well. Moreover, it can only be effective in treating tumors with a size of 3cm in diameter or less.

• Chemotherapy

Transcatheter Arterial Chemoembolization (TACE) is a technique that uses the artery within the liver to infuse chemotherapeutic drugs directly to the tumor. This technique cannot be done in patients with impending liver failure. The technique prolongs the survival of a HCC patient by an average of 2 years.

• Liver Transplant

Liver transplant is the ideal choice for HCC since the liver is almost always severely damaged with the disease. It is highly recommended for patients who have an impending liver failure or overlapping infection with HBV or HCV. A patient who undergoes liver transplant has a 70% chance of becoming disease free after 5 years.

Prevention

• HBV vaccines

Universal vaccination of babies immediately after birth against HBV has dramatically decreased the number of HCC cases related to HBV.

• Moderate drinking

Alcohol drinking should be kept to a maximum of 2 drinks to avoid sudden or chronic liver disease.

• Monogamy

Monogamy is the best protection against acquiring HIV infection

• Say no to drugs

The use of drugs, especially through the veins, places a person at a very high risk of acquiring HBV, HCV, and HIV. These three infections can ultimately lead to HCC.

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