Neoplasm of liver-II
Hepatocellular carcinoma- HCC
DR.ASHRAF ABDELFATAH DEYAB
Assistant Professor of Pathology
Neoplasm of liver-II
(Objectives)
• Describe hepatocellular carcinoma
• Discuss etiopathogenesis
• Discuss morphological features of
hepatocellular carcinoma
• Enlist clinical features, spread, and
complications of hepatocellular carcinoma
• Suggested reading: Robbin’s Basic Pathology, 8th Ed. Page-663-666 &
671-672
Hepatocellular carcinoma- HCC
• Primary liver cancer, almost all being HCC,.
• HCC- third most frequent cause of cancer deaths.
• 626,000 new cases per\yr of primary liver neoplasm
all being HCC .
• The third most frequent cause of cancer deaths.
• HCC- 82% of cases occur in developing countries with
high rates of chronic HBV infection (AFRICA, SOUTH
ASIAN countries,), 52% of all cases in China, 25%-of all
ca.- USA due to HBV&HCV.
• There is a clear predominance of males with a ratio of
2.4 : 1.
HCC- Global variations in incidence rates of liver cancer, prevalence of chronic HCV infection
and chronic HBV infection
HCC-ETIOLOGY& PATHOGENESIS
ETIOLOGY\Risk factors for development of HCC
• Four major etiologic factors associated with HCC
have been established:
• 1- Chronic viral infection (HBV, HCV).
• 2. Chronic alcoholism,.
• 3. Non-alcoholic steatohepatitis (NASH).
• 4. Food contaminants (primarily aflatoxins).
• Prevention: Vaccination of children against HBV ,
as one of measures, mention other measures??
Risk factors for development of HCC
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Other conditions include:
1- Cirrhosis.
2- Non-alcoholic fatty liver disease (NFLD).
3- Glycogen storage disease,.
4- Tyrosinemia.
5- Hereditary Hemochromatosis.
6- α1-antitrypsin deficiency.
7-Oral contraceptive use
8- Radiation exposure
9- Tobacco smoking
10- Genetic factors, gender, nutrition, hormones
HCC- pathogenesis
The precise mechanisms of carcinogenesis are unknown,
several events have been implicated:
1- Chronic hepatitis-( repeated cycle of regeneration lead to
accumulation of mutation) during continuous cycles of cell
division > this may damage DNA repair mechanisms > >>>>
transform hepatocytes> progression to HCC through point
mutation (e.g. KRAS and p53) e.g. Chronic Hepatitis due to
following cellular death.
2- HBV –induced carcinogenesis by disruption of cells genome by
virus integration>> also lead to activate proto-oncogenes that
contribute to tumorigenicity.
* Vertical transmission of HBV – length of hepatocytes exposure
too long>> by age of 20 to 40 can develop HCC , 50% of them
not develop cirrhosis.
• toxins)
HCC- pathogenesis
The precise mechanisms of carcinogenesis are unknown.
3- HCV infection- mechanism is even more uncertain, (HCV
core+ other proteins) participate in the development of HCC.
(persistent inflammation with development of cirrhosis-western).
4- Cirrhosis seems to be a prerequisite contributor to HCC- in
EUROPE
5- Exposure to contaminated food- e.g. aflatoxin, a toxin
produced by fungus Aspergillus flavus, contaminates peanuts
and grains. This bind covalently with cellular DNA and cause a
specific mutation in p53 (CHINA, AFRICA) in HBV endemic areas
Summary- HCC pathogenesis
Possible Pathogenic Mechanisms in the Development of HCC
Risk factor
1-Hepatitis B :
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2-Hepatitis C :
Possible mechanism
Integration into host genome lead to
disruption& activation proto-oncogenes
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Persistent inflammation & cirrhosis
HCV core induced genetic modulation.
3- Aflatoxin B1:
Genetic, mutation of p53 gene.
4- Male gender :
?? Androgenic stimulation of
transforming growth factor α
HCC- morphology
HCC- morphology
• HCC may appear grossly as: ENLARGED LIVER
• (1) Unifocal (usually large) mass – e.g. fibrolamellar
type, hard “scirrhous”.
• (2) Multifocal, widely distributed nodules of variable
size (multi-nodular\multi-centric).
• (3)Diffusely infiltrative cancer- involve entire liver.
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• Color: Paler than adjacent tissue or Green due to
bile secretion (well-differentiated).
Hepatocellular carcinoma- GROSS
Neoplasm is large and bulky and has a greenish cast because
it contains bile. To the right of the main mass are smaller
satellite nodules.
Liver Metastasis
Origin of HCC
1- Cirrhotic liver
• All causes
2- Noncirrhotic liver
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Hepatitis B
Fibrolamellar variant
Rare metabolic diseases
(eg, glycogenosis, porphyria)
Hepatitis C (rare)
Other
HCC- morphology-2
• Microscopic appearance: HCCs range from :
• 1. Well-differentiated 2. Moderate- differentiated
= (trabecular, acinar, pseudoglandular pattern)
• 3. Highly “anaplastic” undifferentiated lesions =
(pleomorphic, anaplastic giant cells, small
undifferentiated, or mimic a spindle cell sarcoma.)
• 4. HCC- fibrolamellar : Unknown, < 5% of HCC,
young male& female (20-40y), do not have chronic
hepatitis, prognosis is better > conventional HCC.
Hepatocellular carcinoma
A, a unifocal, nodular neoplasm
B. well-differentiated tumor cells are arranged in nests\acinar
Hepatocellular carcinoma
Branching trabeculae
HEPATOCELLULAR CARCINOMA (HCC)
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Histological features:
1) Tumor cells : Trabecular or Acinar pattern
2) Fibro-lamellar pattern of growth.
3) The tumor cells grow in columns, well-differentiated
polygonal cells: abundant eosinophilic cytoplasm &
prominent nucleoli.
4) Functional activity (bile secretion).
HCC metastasis :
• strong propensity for vascular invasion
• 1. Extensive intra-hepatic metastases- contiguous spread
development of satellite nodules.
• 2. - Invasion of vascular structures: Intrahepatic (Snake-like lesion
to involve Hepatic vein, Portal vein (occlusion) and IVC &
extending to the Right heart .
• 3- Extrahepatic mets: Lungs, bone, adrenal
• 3 Lymph nodes “peri-hilar, peri-aortic, peripancreatic”
HCC-Fibrolamellar carcinoma
A specimen showing a demarcated hard, Scirrhous nodule
B, nests& cords of malignant polygonal hepatocytes
separated by dense bundles of collagen
Clinical features& complications
Clinical features
• HCC seldom characteristic, Asymptomatic discovered late.
• HCC masked by cirrhosis or chronic hepatitis.
HCC symptoms:
• 1. ill-defined upper abdominal pain, mainly RUQ.
• 2. Abdominal mass or abdominal fullness• 3. Malaise, fatigue, weight loss, +\- Fever.
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Examination findings:
• 1. Enlarged liver on palpation: irregularity or nodularity.
• 2. Hepatic Decompensation Jaundice, Ascites.
• 3. Gastrointestinal Hemorrhage: GIT or esophageal variceal
bleeding (RARE)+ Peptic ulcer disease.
• 4. Tumor ruptur “Hemoperitoneum”
• 5 . Paraneoplastic Syndromes
HCC- systemic effect
• Systemic (paraneoplastic) manifestations
• Hypoglycemia- from defective processing by malignant cell of
the precursor of insulin-like growth factor II.
• Hypercalcaemia(probable cause is secretion of
parathyroid hormone-related protein ).
Polycythaemia (due to production of erythropoietin).
HTN – ectopic synthesis of angiotensinogen
Prognosis:
The 5-year survival of large tumors is dismal, with the majority of
patients dying within the first 2 yrs.
Treatment:
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Radiofrequency ablation&
chemoembolization+ Ethanol injection
Surgery- small tumor + transplantation
No surgery – only palliative management.
Diagnosis
• Clinical history and presented signs& symptoms.
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Laboratory studies : rarely conclusive:
1. AFP- exclude other sources (>500ug\ml).
2. CEA- less conclusive.
3. Others: Viral markers, LFT, CBC, PT.
4. Image studies (USG, CT, MRI).
4. Liver-biopsy: ( Glypican-3, Liver stains, AFP).
5. Molecular analysis: classifications& Therapy.
6. Exclude metastatic nodular metastasis.
HCC complications
1) Death due to severe cachexia, liver failure.
2) Liver failure with hepatic coma.
3) Complications of portal hypertension GIT or
esophageal variceal bleedin g.
4) Rupture of the tumor with fatal hemorrhage- Massive
intraperitoneal haemorrhage
5) Complications due to metastasis.
Questions?
• Mention the Four major etiologic factors
associated with HCC?
• Describe the morphologic features of HCC bases?
• How is HCC Diagnosed?
• Mention the diagnostic value of Alpha-fetoprotein
Levels?
• How do we screen for HCC?
“Thank you”