Hepatoma (Hepatocellular carcinoma)


5th-6th leading malignancy in the world.

Worldwide hepatitis B and hepatitis C other to most common causes of hepatocellular cancer, count was 78% of cases (Perz JF et al).

Accounts for the majority of primary liver cancers (90%).

Hepatoma is the second or third leading cause of cancer related deaths worldwide.

Incidence on the rise both in US and abroad.

The annual incidence of liver cancer increased from 3 to 9.4 per hundred thousand in the US between 1985 and 2015.

Average five-year survival rate of 18%.

In 2023 it is anticipated there will be 41,210 cases of liver cancer.

Approximately 80% of cases of occur in sub-Saharan Africa and east Asia, with chronic hepatitis B and aflaxatoxin B1 exposure or the main risk factors for its development.

Approximately 40% of patients with liver cancer do not have known risk factors.

In 98,786 post menopausal women followed for a median of 20.9 years those consuming three servings or less of sugar sweetened beverages per month compared to those consuming one or more servings per day had a higher rate of liver cancer, 18 versus 10.3/100,000 persons and chronic disease mortality.

With a five-year survival of 18% it is the second most lethal tumor, after pancreatic cancer.

Five-year survival in the US is approximately 2% in patients with metastatic disease.

Affects 7 per 100,000 Americans, and has increased in incidence threefold in the US over the past 20-30 years.

Incidence in US increase can be accounted for by an increase in immigration from epidemic areas, development of cirrhosis and patients with hepatitis C virus and an increase in nonalcoholic fatty liver disease.

Approximately 700,000 new cases reported per year worldwide, with 600,000 deaths.

in 2020 there was an estimated 42,810 new cases and 30,160 deaths related to liver cancer in the US.

Incidence is highest among Asians, followed by blacks, Hispanics, and whites.

Men have a higher propensity for developing HCC owing to a higher incidence of cirrhosis.

Smoking is one of the most common environmental risk factors.

Some variants of HCC are more common in women: fibrolamellar is driven by estrogens.

Incidence rate approximates the death rate.

Five-year survival rates in the United States are approximately 26%

Survival is dependent on both the degree of hepatic dysfunction as well as tumor biology.
Its major risk factor is liver cirrhosis.
It is rare for hepatoma to develop without cirrhosis which can be due to nonalcoholic fatty liver disease, alcohol, hepatitis viruses, autoimmune liver diseases, and rare metabolic storage diseases.
Other risk factors is exposures to carcinogenic chemicals such as vinyl chloride, anabolic steroid use and some naturally occurring toxins such aflatoxin found in fungus and can contaminate legumes, beans, rice, and wheat.

Patients with early HCC achieved five-year survival rates near 70% with resection and transplantation, whereas patients with advanced disease have a median survival of less than 1 year.

This majority of cases occur in the setting of chronic liver disease such as viral hepatitis, alcohol abuse, and or nonalcoholic steatohepatitis (NASH).

With a chronic liver disease there is a sustained hepatic inflammation, fibrosis, and aberrant hepatocyte regeneration: causing cirrhosis and genetic and epigenetic events that form due plastic nodules with your preneoplastic lesions.

These dysplastic cells undergo proliferative, invasive, and survival advantages and transition to hepatocellular carcinoma.

It can arise in patients who have chronic liver disease but who do not have established cirrhosis or more inflammation.

Hepatocellular carcinoma accumulate somatic DNA alterations, including mutations and chromosomal aberrations.

Mutations in the TERT promoter are the most frequent genetic alterations and accounts for approximately 60% of cases.

The TERT promoter is a recurrent insertion site for the genome of HBV.

Other risk factors include aflatoxin exposure, type two diabetes, fatty liver disease and hemachromatosis.

Viral hepatitis accounts for roughly 75% of cases.

Most cases of liver cancer can be prevented through vaccination, antiviral treatment, safe blood transfusion and injection practices, as well as interventions to reduce excessive alcohol use.

5th most common malignancy in men and the eighth most common in women, worldwide.

Second most common pediatric liver malignancy.

Estimated 748,000 deaths in 2008 (Yang JD, Roberts LR).

Greater than 80% of cases worldwide occur in developing parts of the world.

The incidence rose in the U.S. by more than 90% by 1976 and 2000.

Incidence has tripled in the last 3 years in the United States, due to be incidence of hepatitis C epidemic.

Incidence has tripled in the US in the past 3 decades from 1.6-4.6 cases per 100,000 person-years (Alterkuse SF et al).

In 2013 there were an estimated 30,640 new cases diagnosed.

The primary risk factor for development of HCC in liver disease is the development of cirrhosis, with more than 80% of patients developing the disease having cirrhosis.

Patients with cirrhosis should have surveillance every 6 months with AFP and ultrasonography, with the combination equating to a 90% sensitivity in developing HCC.

A 5 year risk of development of HCC in patients with cirrhosis ranges from 5-30% (Fattovich G et al).

The risk for hepatocellular carcinoma is 15-20 times higher in persons infected with hepatitis C, then in persons noninfected with this virus.

In western societies 30-40% of patients are not infected with HBV or HCV suggesting other risk factors for the development of HCC.

Age-adjusted incidence rate has doubled in recent decades (Altekruse SF).

Age is a risk factor, with an average age at diagnosis 65 years in the US.

Incidence amng the elderly is progressively increasing (El-Serag SA).

The incidence is approximately 3 cases per 100,000 people in the US.

African-Americans have a greater than 3-fold risk compared to whites.

Blacks and Hispanics are at higher risk of death, even after adjusting for the stage, time of diagnosis and therapy.

Higher incidence in men by a factor of 2 to 6, among various ethnic groups.

Increased incidence and mortality among American Indians and Alaska natives.

Asian-Americans have the highest death rate due to HCC.

In developing countries, HBV is the most common cause of HCC, whereas HCV is more common in developing countries.

Prevention is focused on hepatitis B and C viral transmission and efforts to reduce the prevalence of obesity.

Most effectively treated when diagnosed at an early stage, and the best chance for early diagnosis results from surveillance of patients at high risk.

Associated with nonalcoholic steatohepatitis and diabetes.

NCCN guidelines recommend screening high-risk patients with serum alpha-fetoprotein levels and liver ultrasound every 6 to 12 months.

A rising alpha-fetoprotein level associated with the liver nodule of greater than 1 cm raises the suspicion for hepatocellular cancer and warrants evaluation with special imaging.

In a setting up chronic liver disease, lesions greater than 1 cm in the liver that and imaging characteristics on triple phase CT or contrast enhanced MRI of early arterial enhancement and venous phase washout are classified as hepatocellular carcinomas.

Hepatic carcinoma has hypervascularity supplied predominantly by branches of the hepatic artery, while normal liver tissue is mostly supplied by the portal vein.

Lesions suspicious for HCC appear darker then background liver on T1 weighted imaging.

5 year overall survival rate is 10-12% in the United States, and an even lower survival rate in developing countries.

Asian immigrants to the US have a higher incidence than do Asians born in the US.

Women tend to have longer survival than men, suggesting that biological features of the tumor and host environment may differ between the sexes.

Surveillance versus no surveillance with patient’s infected with HBV, or HCV ultrasonography and alpha-fetoprotein every 6 months showed a survival benefit, with a 37% reduction in HCC mortality and surveillance arm (Zhang BH et al).

Recurrence rate after resection of HCV related hepatocellular carcinoma 70-80% at 5 years.

Risk factors for chronic hepatitis B-related hepatocellular carcinoma include gender, age, cigarette smoking exposure, chemical carcinogens, alcohol consumption hormonal factors and genetic susceptibility.

Common association with viral hepatitis, alcohol, non-alcoholic steatohepatitis associated with diabetes and morbid obesity.

In a retrospective study comparing patients above and below 70 years: older group have a lower M:F ratio, fewer HCV infections, and less advanced underlying liver disease, worse performance status than the younger group, but hepatoma specific survival was similar (Kozyreva ON et al).

RAS/Raf/MEK/ERK pathway is dysregulated and overexpression of Raf kinase occurs in hepatocellular carcinoma.

VEGF, platelet-derived growth factor (PFGF), and basic fibroblast growth factor are expressed in this tumor.

Seropositivity for hepatitis B surface antigen (HBsAg associated with a 5-98 fold risk.

Majority of cases of hepatocellular carcinoma cases worldwide are associated with hepatitis B.

Risk increases with hepatitis B viral load and with genotype C of hepatits B.

Elevated levels of HCV RNA and ALT and genotype 1 are independent risk predictors for hepatocellular carcinoma 5 or more years before it’s diagnosis (Lee M-H et al).

The risk of hepatocellular carcinoma for anti-HCV seropositive patients with undetectable serum HCV RNA levels is much lower than for individuals with detectable levels: Implying that patients with chronic HCV may be benefited from lowering serum HCV RNA to undetectable levels by effective treatments.

In patients with undetectable serum HCV RNA levels, the incidence of hepatocellular carcinoma is moderately high for those who have had elevated serum ALT levels, suggesting that the serum ALT level is an important serum marker.

Gene polymorphism associated with risk for development of hepatocellular carcinoma in cirrhosis via modulation of epidermal growth factor levels.

Cirrhotic nodules become hyperplastic than dysplastic and ultimately transform into cancer cells.

Angiogenesis seen in early stage disease and correlates with disease progression.

Associated with erythrocytosis in fewer than 10% of cases.

Tumors with microRNA 26 low expression have a shorter survival were more likely to have a response to interferon therapy, as compared to patients with tumors with high microRNA-26 expression (Junfang).

The expression of micro RNA 26A and micro RNA 26B and non-tumor hepatic tissues is higher in women than in men.

SALL4 an oncoprotein that is expressed in fetal human liver, and silenced in the adult liver: when reexpressed in hepatocellular carcinoma is an expression of an aggressive phenotype (Yong KJ et al$.

Because of late presentation, impaired liver reserve in the nontumorous, cirrhotic liver and high rate of recurrence, the prognosis of patients with Hepatoma remains poor.

5-year survival rates for patients with metastatic disease, regional or distant, less than 10%.

Therapy options: resection, liver transplant, and locoregional measures radiofrequency abation, percutaneous ethanol injection, ytrium 90, transarterial chemoembolization and systemic chemotherapy and targeted agents.

In a nationwide Swedish study the use of low-dose aspirin was associated with a significantly lower risk of hepatocellular carcinoma and lower liver related mortality than  no use of aspirin in patients with chronic viral hepatitis.
Treatment options depend on the disease, burden, hepatic, reserve, functional status, and goals of therapy.

Surgical resection and liver transplantation are preferred management procedures because they are potentially curative, however only 10 to 15% of patients are candidates for these approaches.

Surgical resection is associated with tumor recurrence rates of 50% at three years and 70% at five years.

Combination chemotherapy has not improved overall survival in advanced disease, but is used for possible palliation.

Considered a chemotherapy resistant malignancy

Liver transplantation offers the best prognosis for patients with small hepatoma.

Liver transplantation allows for resection of the tumor and potentially corrects the underlying liver disease.

Transplant selection criteria for candidates include one nodule less than 5 cm or two or three nodules less than 3 cm in the absence of detectable vascular invasion associated determined by imaging with Doppler ultrasound, CT scanning and MRI.

5-year survival rates for transplant candidates as noted by the above criteria is as high as 70%.

Hepatic resection can be used as a bridge to transplantation, particularly for lesions in the upper part of the right liver that can be removed with a thoracic incision.

Hepatic resection can be performed for early stage cancer in patients without cirrhosis or with well compensated disease.

Resection of substantial liver in a patient with cirrhosis can be fatal.

Superficial tumors can be resected by laparoscopy and can improve selection of possible liver transplant patients.

Alpha-fetoprotein (AFP) is an oncoprotein produced by liver cancer cells.

Alpha-fetoprotein is a validated surveillance tool to follow patients with hepatitis B or hepatitis C and with ultrasound is associated with a 37% reduction in hepatoma related mortality (Mazzaferno V et al).

Elevated AFP levels are detectable in 60 to 70% of patients with hepatocellular carcinoma.

AFP useful to monitor treatment responsiveness and tumor recurrence.

Lens culinaris agglutinin-reactive AFP and protein induced vitamin K absence or antagonist-II (PIVKA-II) are other serological tests was used to follow hepatoma as a surveillance and monitor of treatment.

High dose alpha interferon induces significant tumor suppression in approximately 30% of patients with inoperable hepatoma.

Surgical resection feasible in <25% of patients.

Many factors affect hepatocellular carcinoma recurrence risk after resection including: tumor size and stage, serum alpha-fetoprotein level, the presence cirrhosis, hepatitis B e antigen status and hepatitis B virus viral load.

Higher HBV viral load is an independent risk factor for hepatocellular carcinoma recurrence in patients with HBV related hepatoma.

For patients with tumors or greater than 4 cm in diameter transarterial chemoembolization is an option since the liver is perfused both by the portal vein and hepatic artery and hepatocellular carcinoma’s blood supply is almost entirely from the hepatic artery.

Median survival for patients with unresectable hepatoma who receive transcatheter arterial chemoembolization estimated at 13-18 months.

Transcatheter arterial catheter embolization effective treatment method in patients with unresectable hepatoma.

Transcatheter arterial chemoembolization (TACE) can improve three-year survival rates from 10% to 40-50% with a median survival duration of 16-20 months(Cabrera R, Nelson DR).

TACE in hepatoma associated with a two-year improved overall survival compared with conservative treatment.

Radiofrequency ablation has a use in small HCC in less than 3 cm, with a three-year disease control rate of up to 80-90% in most series.

TACE standard of care for patients with intermediate stage disease with multinodular lesions but without vascular invasion.

TACE exploits the difference in blood supply to the normal liver with the normal liver being perfused by both the portal vein and the hepatic artery.

Hepatoma derived its blood supply almost entirely from the hepatic artery.

Transarterial radio embolization (TARE) is the use of selectively, delivering radioactive isotopes conjugated to microparticles via tumor feeding arteries to the liver.

The most commonly employed isotope in TARE is yttrium-90.

Yttrium-90., trim 90 is a beta particle with penetrance 2.5 mm with maximum penetrance of 11 mm.

TARE has demonstrated utility for early, intermediate,  and late stage hepatoma.

Treatment goals include curative intent, bridging to transplant, and downsizing disease facilitating resection.

Postoperative alpha interferon decreases recurrence after resection of hepatitis C virus-related hepatocellular carcinoma.

Most common solid organ tumor worldwide.

In the US the major cause of HCC is hepatitis C, and it accounts for 50% of cases.

In the US hepatitis B accounts for 15% of cases of HCC.

Other causes of HCC include nonalcoholic steatohepatitis, hemochromatosis, autoimmune hepatitis, and alpha1 antitrypsin deficiency.

Most patients who are not treated die within 3-6 months of hepatic failure.

Rarely occurs in the absence of cirrhosis or advanced fibrosis.

Most common sites of metastases are regional lymphnodes of the liver, the lung and bones.

The frequency of bone metastases in patients with extra hepatic metastases is estimated to be 38%.

Somatostatin receptors have been identified in hepatocellular carcinoma cells (Reubi).

A study of best supportive care with short acting octreotide resulted in a overall survival of 4 months vs. 11 months. (Kouroumalis E), while other randomized controlled studies revealed no improvement.

Inherently chemoresistant due to the presence of drug resistance genes.

Phase II study of cisplatin, doxorubicin, fluorouracil and interferon a with a 21% response rate compared to doxorubicin alone with a response rate of 10% (Yeo).

Sorafenib approved for advanced unresectable disease.

400 mg bid of sorafenib in a phase 2 trial of 137 patients with inoperable hepatocellular carcinoma associated with a median time to progression and median overall survival of 4.2 months and 9.2 months, respectively.

SHARP trial, phase 3 trial Sorafenib HCC Assessment Randomized Protocol compared sorafenib 400 mg bid to placebo in 602 patients with unresectable disease without prior treatment: median overall survival 10.7 months for sorafenib and 7.9 months for placebo, 71% of patients with stable disease 2.3% had a partial response.

Sorafenib has a three-month survival advantage over a nontreated group in HCC.

Sorafenib not effective in an adjuvant setting in hepatocellular carcinoma following resection or ablation.

In a study population of > 1000 patients with hepatocellular cancer, patients randomized to sunitinib had a significantly worse median overall survival (7.9 months vs 10.2 months) compared with patients in the sorafenib arm, mainly related  to inferior outcome with sunitinib in the subgroup of patients with hepatitis C, median overall survival, 9.2 months vs 17.6 months).

Objective response rates with sorafenib around 2%, most of the effect is associated with stable disease rate of 35% to 70% in phase 2 and three trials, respectively.

Pembrolizumab approved for the treatment of patients with hepatocellular carcinoma who have previously received sorafenib.

Response rate to liver directed therapy is approximately 70%.

Regorafenib a second line choice.

The oral, multi-kinase inhibitor regorafenib (Stivarga) is approved for the second-line treatment of hepatocellular carcinoma (HCC), the first new drug for this disease in a decade, for patients who have previously received sorafenib.

The approval of regorafenib was based on results of a randomized multicenter trial that included 573 HCC patients whose disease had progressed on sorafenib.

In the trial patients received best supportive care plus either 160-mg oral regorafenib once per day or placebo for 21 days of a 28-day cycle.

Results of the trial showed that patients receiving regorafenib had an improvement in progression-free survival with a median progression-free survival of 3.1 vs 1.5 months with placebo.

Overall survival was also improved in patients on regorafenib with a median overall survival of 10.6 months vs 7.8 months with placebo.

The overall response rate based on modified RECIST was 11% vs 4% in favor of regorafenib.

The recommended dose for regorafenib is 160 mg daily, taken in four 40-mg tablets, for the first 21 days of each 28-day cycle.

REFLECT trial compared lenvatinib to sorafenib in unresectable hepatocellular carcinoma: lenvatinib had improved progression free survival, time to progression, and overall response rate.

FDA Approves Ramucirumab for Hepatocellular Carcinoma

The US Food and Drug Administration (FDA) has approved ramucirumab (Cyramza) as a single agent treatment for hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein of ≥400 ng/mL and have been previously treated with sorafenib.

Approval was based on REACH‑2, a multinational, randomised, double-blind, placebo-controlled, multicentre study.

Patients were randomised 2:1 to receive ramucirumab 8 mg/kg plus best supportive care or placebo plus best supportive care every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity.

The study found that the estimated median overall survival was 8.5 months for patients receiving ramucirumab and 7.3 months for those receiving placebo.

The most common adverse reactions observed in patients with HCC receiving single-agent ramucirumab were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites.

The recommended ramucirumab dose is 8 mg/kg administered intravenously every 2 weeks.

CheckMate-040 trial demonstrated nivolumab and ipilimumab have an objective response rate of 33% in  patients who have previously failed sorafenib.
Atezolizumab combined with Bevacizumab resulted in better overall and progression free survival outcomes than sorafenib, and may be the treatment of choice for advanced hepatocellular cancer: it is the first line therapy in advanced hepatocellular carcinoma.
Regorafenib demonstrated overall survival benefit for hepatocellular carcinoma over placebo: 10.6 versus 7.8 months.
Other approved agents include cabozantinib and ramucirumab.
Fibromellar hepatocellular cancer is a rare variant, accounting forbapproximately 1% the primary liver cancers in  the US.
Fibromellar hepatocellular cancer occurs frequently in young individuals less than 40 years of age with no history of cirrhosis of chronic liver disease. 
A large portion of such patients are asymptomatic or present with vague and nonspecific symptoms. 
Fibrolamellar hepatocellular rarely has elevated alpha-fetoprotein levels. 
Elevated levels of serum vitamin B 12 and unsaturated vitamin B 12 binding capacities have been describe
Fibrolamellar hepatocellular appears as a well-defined mass on CT scan.
Fibrolamellar hepatocellular  Is commonly associated with calcifications of 40-68%, with a stalemate score in 65-70% of cases.
Fibrolamellar hepatocellular Is characterized by monotonous proliferation of neoplastic cells with abundant eosinophilic  cytoplasm.
Fibrolamellar hepatocellular has a favorable prognosis compared to other forms of hepatocellular carcinoma.
A large primary tumor and lymph node metastasis suggests a poor prognosis.
Hepatic tumor resection the treatment of choice with overall survival rates post resection 26-76% at five years, and median survival of 32-174 months.
Liver transplant for Fibrolamellar hepatocellular there’s an alternative curative therapy for those not amenable to recection.

Leave a Reply

Your email address will not be published. Required fields are marked *