Hepatocellular Carcinoma

Lecture 27

HCCHepatoma

HCC,,,.2,28,28

Epidemiology• The fifth most common cancer worldwide and the

third most common cause of cancer mortality.• Because of its high fatality rates, the incidence

and mortality rates are almost equal..

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About 82% of HCC cases occur in developing countries with high rates of chronic HBV infection (& HCV), such as in southeast Asian and African countries;

52% of all HCC cases occur in China.

• There is a clear predominance of males with a ratio of 2.4 : 1.

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Risk factors The main risk factors for hepatocellular carcinoma

are;• Alcoholism• Hepatitis B• Hepatitis C (25% of causes globally)• Aflatoxin (Mycotoxin) B1 produced by Aspergillus

flavus• Cirrhosis of the liver• Hemochromatosis• Wilson's disease• Type 2 Diabetes (probably aided by obesity)HCC

• Alpha 1 antitrypsin deficiency• Chemical carcinogens: butter yellow,

nitrosamines• Prolonged immunosuppressive therapy• Other types of viral hepatitis• Tobacco smoking• Parasitic infestations: clonorchiasis,

schistosomiasis

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Pathogenesis

• Hepatocellular carcinoma develops when

there is a mutation to the cellular machinery that causes the cell to replicate at a higher rate and/or results in the cell avoiding apoptosis.

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UNCERTAIN

PathogenesisFour major etiologic factors associated with

HCC have been established:1. Chronic viral infection (HBV, HCV),2.Chronic alcoholism, 3.Food contaminants (primarily aflatoxins). 4.Non-alcoholic Steatohepatitis (NASH),

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Other conditions include:

• Tyrosinemia, 40%• Glycogen storage disease, • Hereditary hemochromatosis,• Non-alcoholic fatty liver disease, and• α1-antitrypsin deficiency.

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Many factors interact in the development of HCC, including:

• Genetic factors, • Age, • Gender, • Chemicals,• Hormones, and • Nutrition, HCC

Cirrhosis seems to be a prerequisite contributor to the emergence of HCC in Western countries.

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Pathogenesis

• Repeated cycles of cell death and regeneration, in chronic hepatitis damage DNA repair mechanisms and eventually transform hepatocytes &

HCC develops.

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Developing countries (endemic areas)

•Aflatoxin can bind covalently with cellular DNA and cause a specific mutation in p53.

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HCC may appear grossly as (1) unifocal(2) multifocal, (3) diffusely infiltrative/spreading

cancer,

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1.Unifocal tumorAKA Expanding type, most frequently, it forms a

single, yellow-brown, large mass, most often in the right lobe of the liver with central necrosis, hemorrhage and occasional bile-staining. It may be deceptively encapsulated.

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2.Multifocal type• Less often, multifocal, multiple masses, 3-5 cm in

diameter, scattered throughout the liver are seen.

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3. Infiltrating (Spreading) type

• Rarely, the HCC forms diffusely infiltrating tumor mass.

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• All three patterns may cause liver enlargement, particularly the large unifocal and multinodular patterns.

• The diffusely infiltrative tumor may blend imperceptibly into a cirrhotic liver background.

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Liver removed at autopsy showing a unifocal, massive neoplasm replacing most of the right hepatic lobe in a noncirrhotic liver;

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• Lymph node metastases to the perihilar, peripancreatic, and para-aortic nodes above and below the diaphragm are found in fewer than half of HCCs that spread beyond the liver.

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• HCC spreads extensively within the liver by obvious contiguous growth and by the development of satellite (outpost) nodules, which can be shown by molecular methods to be derived from the parent tumor.

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•Metastasis outside the liver is primarily via vascular invasion, especially into the hepatic vein system, but hematogenous metastases, especially to the lung, tend to occur late in the disease.

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• HCCs are usually PALER than the surrounding liver, and sometimes take on a GREEN hue when composed of well-differentiated hepatocytes

capable of secreting BILE.

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• All patterns of HCCs have a strong propensity for

invasion of vascular structures. Extensive intrahepatic metastases ensue (develop), and occasionally, long, snakelike masses of tumor invade the portal vein (with occlusion of the portal circulation) or inferior vena cava, extending even into the right side of the

heart. HCC

• If HCC with venous invasion is identified in explanted livers at the time of liver transplantation, tumor recurrence is likely to occur in the transplanted donor liver.

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• HCCs range from well-differentiated to highly anaplastic undifferentiated lesions.

I. In well-differentiated and moderately differentiated tumors, cells that are recognizable as hepatocytic in origin are disposed either in a trabecular pattern or in an acinar, pseudoglandular pattern.

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Microscopy

• In the better differentiated variants,

globules of bile may be found within the cytoplasm of cells and in pseudocanliculi between cells.

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Microscopy

• Acidophilic hyaline inclusions within the cytoplasm may be present, resembling Mallory bodies. There is surprisingly scant stroma in most HCCs,

explaining the soft consistency of these tumors.

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II. In poorly differentiated forms, tumor cells can take on a pleomorphic appearance with numerous anaplastic

giant cells, can be small and completely undifferentiated, or may even resemble a spindle cell sarcoma.

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Important diagnostic features are:

1.Histologic patterns2.Cytologic features

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Histologic patterns

i) Trabecular or sinusoidal patterns- is the most common.

The trabecullae are made up of 2-8 cell wide layers of tumors cells separated by vascular spaces or sinusoids which are endothelium-lined.

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Histologic Patterns• ii) Pseudo glandular or acinar

patterns is seen sometimes. The tumor cells are disposed around central cystic space formed by degeneration and breakdown in the trabeculae.

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Histologic Patterns

• iii) Compact pattern resembles trabecular

pattern but the tumor cells form large solid masses with conspicuous sinusoids.

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• iv) Scirrhous pattern is characterised by more abundant fibrous stroma.

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2. Cytologic features:

• The typical cytologic features in the HCC consist of

cells resembling hepatocytes having

vesicular nuclei with prominent nucleoli.

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• The cytoplasm is granular and eosinophilic but becomes increasingly basophilic with

increasing malignancy.

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Aside from these features, a few others cytologic variants are:

• Pleomorphism, • Bizarre giant cell formation, • Spindle-shaped cells,• Tumor cells with clear cytoplasm, • Presence of bile within dilated canaliculi, and• Inracytoplasmic mallory’s hyline.

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Microscopic view of a well-differentiated lesion; tumor cells are arranged in nests, sometimes with a central lumen. HCC

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Fibrolamellar Carcinoma

• This variant constitutes 5% of HCCs. It occurs in young male and female adults (20 to 40 years of age) with equal incidence.

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• Patients usually do not have underlying chronic liver diseases, and so the prognosis is better than the conventional HCC.

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• The etiology of fibrolamellar carcinoma is unknown.

• It usually presents as • single large, hard “scirrhous” tumor with

fibrous bands coursing through it.

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On microscopic examination it is composed of well-differentiated polygonal cells growing in nests or cords, and separated by parallel lamellae of dense collagen bundles. The tumor cells have abundant eosinophilic cytoplasm and prominent nucleoli .

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Fibrolamellar carcinoma. A, Resected specimen showing a demarcated nodule in an otherwise normal liver

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B, Microscopic view showing nests and cords of malignant-appearing hepatocytes separated

by dense bundles of collagen.

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•Part II,• Lecture 28

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Recap

• The main primary tumor is HCC• More common (82%) in Asia & Africa.• The main etiologic agents for HCC are

hepatitis B, C, alcoholic cirrhosis, hemochromatosis, and more rarely, tyrosinemia.

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• In the western population about 90% of HCC develop in cirrhotic livers;

• In Asia almost 50% of cases develop in noncirrhotic livers.

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• The chronic inflammation and cellular regeneration associated with viral hepatitis may be predisposing factors for development of carcinomas.

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• Hepatocellular carcinomas may be unifocal or multifocal, tend to invade blood vessels, and recapitulate normal liver architecture to varying degrees.

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Clinical Features

• The clinical manifestations of HCC are seldom characteristic and,

• in the Western population, often are masked by those related to the underlying cirrhosis or chronic hepatitis.

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• In areas of high incidence such as tropical Africa, patients usually have no clinical history of liver disease, although cirrhosis may be detected at autopsy.

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• In both populations most patients have• ill-defined upper abdominal pain,• malaise, • fatigue, • weight loss, and • sometimes awareness of an abdominal mass

or abdominal fullness.

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• In many cases the enlarged liver can be felt on palpation, with sufficient

irregularity or nodularity to permit differentiation from cirrhosis.

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• Jaundice,• fever, and • gastrointestinal or esophageal variceal

bleeding are inconstant findings.

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Diagnosis Lab Study

• Elevated levels of serum α-fetoprotein are found in 50% of persons with HCC

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• Recently, staining for Glypican-3 has

been used to distinguish early HCC from dysplastic nodules.

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Imaging studies• Most valuable for detection of small tumors

are imaging studies:• Ultrasonography, • Hepatic angiography, • Computed tomography, and • Magnetic resonance imaging.

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PrognosisOverall, death usually occurs from (1) cachexia, (2) gastrointestinal or esophageal variceal

bleeding, (3) liver failure with hepatic coma, or, rarely, (4) rupture of the tumor with fatal

hemorrhage.

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• The 5-year survival of large

tumors is dismal, with the majority of patients dying within the first 2 years.

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• With implementation of screening procedures and advances in imaging, the detection of HCCs less than 2 cm in diameter has increased in countries where such facilities are available. These small tumors can be removed surgically with good prognostic outcomes.

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Treatment

• Radiofrequency ablation is used for local control of large tumors, and chemoembolization can also be used, according to a clinical algorithm that has been widely adopted.

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• Recent findings show that the kinase

inhibitor sorafenib can prolong the life of individuals with advanced-stage HCC.

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Primary billiary cirrhosisSecondary billiary cirrhosis

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Primary Billiary Cirrhosis

• PBC is an inflammatory autoimmune disease mainly affecting the intrahepatic bile ducts. The primary feature of this disease is a nonsuppurative, inflammatory destruction of medium-sized intrahepatic bile ducts. It is accompanied by portal inflammation, scarring, and eventual development of cirrhosis and liver failure

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Secondary billiary cirrhosis

• Secondary biliary cirrhosis is a condition resulting most often from uncorrected obstruction of the extrahepatic biliary tree.

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