Hepatocellular Carcinoma

Ebeogu Olisaeloka

Introduction Epidemiology Aetiology Pathophysiology Clinical features Differential Diagnosis Staging systems Investigations Treatment Prevention Conclusion

Outline

It is a malignancy arising from the parenchyma of the liver. Thought to arise from the hepatic stem cells. Different from metastatic liver disease

It is the 6th most common primary tumor and the 3rd leading cause of cancer related deaths.

Morphologically, can be classified as◦ Unifocal◦ Multifocal◦ Diffusely infiltrative

Introduction

Microscopically, the tumours are classified histologically as:◦ Fibrolamella◦ Pseudoglandular◦ Pleomorphic◦ Clear cell

It usually disseminates into the vasculature, notably the portal vein.

May involve the lymph nodes, lung and bone in terminal cases.

It usually occurs in the background of cirrhosis( about 80% of cases) and the remainder occurs without cirrhosis.

Incidence is highest in Asia and Africa where the endemic high prevalence of hep B and C predisposes to the development of chronic liver disease and subsequent HCC. It is also more common among men.

Worldwide the age adjusted incidence in men was 17.43/100,000 in developing countries compared to 8.7/100,000 in the US. For women, it was 6.77 vs 2.8/100,000 between developed and developing countries.

Epidemiology

Incidence over the past 20 years in the US has doubled from 2.6 to 5.2%/100,000. Among African, increase is from 4.7 to 7.5/100,000.

Highest incidence is in East Asia with rates in men of 35/100,000 followed by Africa and the Pacific Islands.

The M:F ratio is about 5:1 in Asia and 2:1 in the US.

Incidence increases with age with mean age at presentation of 53 in Asia and 67 in the US.

In a study done by Okonkwo UC et al from June 2007 to May 2008 in NAUTH Nnewi, prevalence was about 2.4%. The male female ratio was 2:1. Mean age at presentation was 50.64 +/- 17.54.

Mortality rate was found to closely mirror incidence rate.

The combination of viral hepatitis and alcohol significantly increases the risk of cirrhosis and subsequently HCC.

In the developing world, viral hepatitis, primarily hep B, continues to represent the major risk factor.

Among patients with cirrhosis, the incidence of HCC is 1 – 6%.

May be cirrhosis related or non-cirrhosis related Cirrhosis from any cause accounts for about

80% of cases Hepatitis B

◦ Increases risk by 100 – 200 times◦ 90% of HCC are positive for HbsAg

Hepatitis C Toxins like alcohol, tobacco, aflatoxin and other

mycotoxins Autoimmune hepatitis NAFLD/NASH

Etiology

Others include Primary biliary cirrhosis Hemochromatosis α₁-antitrpsin deficiency Glycogen storage diseases Citrullinemia Porphyria cutanea tarda Hereditary tyrosinemia Wilson’s disease

In the developing world, hepatitis (primarily hep B) accounts for majority of cases.

In the developed world, hepatitis accounts for most cases in the younger populace while NASH/NAFLD accounts for majority of cases in the aging population. Among patients with cirrhosis, the incidence of HCC is about 1 – 6%.

This has not been properly elucidated. It is thought to be multifactorial

Inflammation, necrosis and fibrosis and ongoing regeneration that characterize cirrhosis are thought to contribute to HCC.

In patients with HBV whose livers are not frankly cirrhotic, fibrosis is present which suggests regeneration. HCC in the setting of HCV occurs invariably in the setting of cirrhosis.

Pathophysiology

HBV is thought to incoporate into the host genome with production of HBVX, a protein that may play a role in cirrhosis.

Recent analysis have identified some genomic pathways that are altered during hepatocarcinogenesis:◦ P₅₃◦ 171KYA◦ AY catenin genes

They appear to be mutated in patients with HCC.

Inactivating mutations of the chromatin remodelling genes, ARID2, have been identified in certain kinds of HCC.

May be asymptomatic in patients who are enrolled in a screening programe where it is detected early

In late stages, patient may present with:◦ Abdominal pain◦ Weight loss◦ Weakness◦ abdominal fullness and swelling◦ Jaundice ◦ Nausea

Clinical Features

Physical signs include◦ Hepatomegaly (in 50 – 90% of patients)◦ Abdominal bruit (in 6 – 25% of patients)◦ Ascites (in 30 – 60% of patients)◦ Splenomegaly due to portal hypertension.◦ Weight loss and muscle wasting.◦ Fever (of unknown cause) in 10 – 50% of cases.

Signs of CLD may be present including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema

Budd-Chiari syndrome can occur due to HCC invasion of the hepatic veins with tense ascites and a large tender liver.

Complications include◦ Gastrointestinal bleeding◦ Cachexia◦ Portal hypertension with oesophageal bleeding◦ Liver failure◦ Tumor rupture leading intraabdominal bleeding◦ Metastasis to nodes around the pancreas, aorta,

lungs, adrenal glands, and bones.

Paraneoplastic syndromes are associated with HCC. They include hypoglycemia, erythrocytosis, hypercalcemia, hypercholestorelemia, dysfibrinogenemia, carcinoid syndrome, increased thyroxin-binding globulin, changes in secondary sexual characteristics (gynecomastia, testicular atrophy and precocious puberty), and porphyria cutanes tarda.

Thrombocytopenia or leucopenia usually results from portal hypertension and not from infiltration of the bone marrows.

A number of staging systems have been designed to for HCC. They include:

Model for End-Stage liver Disease TNM classification Child-Pugh’s classification Okuda Cancer of the Liver Italian Programme Barcelona Clinic Liver Cancer Chinese University Prognosis index Japanese Integrated System Estrogen Receptor Classification

Staging Systems

Of all the above, the BCLC tends to more widely accepted. It considers performance, hepatic function, and in addition to tumor burden, provides both prognosis and treatment plan.

Child-Pugh’s classification offers prognosis for all forms of chronic liver disease.

Child-Pugh Classification

They include laboratory features, imaging findings and liver biopsy

α-feto protein: May be produced by the tumor (60% of HCC) or regenerating hepatocytes. Levels may also be increased by liver resection, recovery from toxic injury and seroconversion from Hep B infection.

When elevated, it is about 75 – 91% specific Levels > 400ng/mL are diagnostic of HCC. May be normal with small tumors

Diagnosis

Others include Des-γ-carboxy prothrombin Glypican-3 LFT’s INR PT WBC Electrolytes

Anemia may result from bleeding varices or other sites

Thrombocytopenia results from portal hypertension

Hyponatremia is seen in patients with cirrhosis and ascites

Creatinine may be elevated from intrinsic renal disease or from hepatorenal syndrome

Prolonged PT/INR shows deranged liver function and may preclude resection

Elevated AST/ALT reflects active hepatitis secondary to viral infection, current alcohol use or other causes

Hypoglycemia may result from end stage liver disease

Imaging studies may be with Ultrasonography, spiral CT or MRI with enhancement.

Tumors less than 2cm may be difficult to differentiate from hyperplastic nodules of cirrhosis

They are also used to stage tumors. Abdominal USS is about 60% sensitive and

97% specific. Findings should be confirmed by further imaging studies.

On CT scan, HCC generally appears as a focal nodule with early enhancement on the arterial phase with rapid washout of contrast on the portal venous phase of a 3-phase contrast scan (triphasic).

On MRI, there is high signal intensity on T2 imaging.

USS of the liver demonstrating HCC.

Arterial Phase CT Scan demonstrating Enhancement of HCC

A Modern 3T MRI

MRI of the Liver With HCC

Biopsy With lesions <1cm, less than half will be

malignant With lesions b/w 1 – 2cm, biopsy is indicated as

lesions are likely to be malignant. If positive, they are candidates for resection, transplantation or ablative surgery. Patients with lesions > 2cm, cirrhosis, characteristic imaging studies and elevated AFP can be managed without biopsy because of increased risk of tumor seeding.

Patient undergoing liver biopsy

Hyperchromatic clear cells with large red cytoplasm

Pyogenic liver abscess Amoebic liver abscess Hepatocellular adenoma Alcoholic cirrrhosis Cirrhosis from metabolic disorders:

◦ Hereditary hemochromatosis◦ Glycogen storage diseases◦ Wilson’s disease etc

Differential diagnosis

This may be medical or surgical The definitive treatment of HCC is surgery. It may be curative when lesions are found very

early. Surgery may be in the form of either resection

or liver transplantation. Patient’s with a single lesion < 5cm or upto 3

lesions with each measuring less than 3cm are candidates for surgery (Milan’s criteria).

Hepatic resection is prefered in HCC without a cirrhotic liver

Treatment

Resection may also be carried out in a selected patients with cirrhosis and preserved hepatic function (Child-Pugh’s A) who are unsuitable for liver transplantation. May be associated with a high risk of postoperative decompensation.

Recurrent rates of upto 50 – 60% in 5 years following resection have been documented.

Liver transplantation should be considered in patients who have concomitant cirrhosis.

Medical therapy is reserved for patients who are unfit for surgical intervention. They include:

Percutaneous ethanol injection (PEI): Most suitable for peripheral lesions less than 3cm. It causes necrosis of small lesions but may also damage normal tissues.

Transcathetar arterial chemoembolization (TACE): For lesions greater than 3cm but less than 4cm

PEI before and after procedure

TACE

Radiofrequency ablation: High frequency ultrasound is used to generate heat for ablation. Has no survival advantage and is usually used as bridge therapy for patients awaiting transplantation.

Cryotherapy is used intraoperatively to ablate tumors outside the planned site of resection in bilobar disease.

Chemoembolization: It is the joint use of hepatic artery chemotherapy (doxorubicin) and hepatic artery embolization.

Systemic chemotherapy: Very limited role in the treatment of

patients with HCC. Best single agent is doxorubicin. Combination chemotherapy did not increase

response. Hormonal therapy with Nolvadex, stilbestrol

and flutamide. Inteferon-α Retinoids and adaptive immunotherapy.

HCC is one of the most vascular tumor. Vascular endothelial growth factor has been implicated in its pathogenesis.

Sorafenib and Bevacizumab target VEGF in HCC.

Combination chemotherapy under investigations:◦ Bevacizumab and erlotinib◦ Sorafenib and erlotinib

Combination therapy may be the mainstay of treatment in the future.

Adverse prognostic features include Ascites Jaundice Elevated AFP Vascular invasion: Has particularly profound

effect on prognosis. Patients with Okuda III have a dire prognosis

because they cannot be curatively resected and the condition of the liver precludes chemotherapy.

Prognosis

This is achieved through screening of individuals who fall in any of these categories:

Individuals with established cirrhosis due to HBV/HCV , especially those with ongoing viral replication.

Individuals with cirrhosis due to alcohol who are abstinent and are likely to comply with treatment.

Individuals with hereditary hemochromatosis Males with a history of PBC Positive family history of HCC. Increased serum AFP levels > 20ng/mL.

Prevention

This can be achieved through ultrasound and AFP assays every 6 months.

Hepatocellular carcinoma is one of the cancers with significant mortality. Mortality is closely related to the stage at presentation, being worse at late presentation as is mostly seen in the developing world. Adequate screening program for patients who meet the criteria and early intervention is necessary for preventing its mortality.

Conclusion