Liver & intrahepatic bile ducts
Hepatocellular carcinoma
Hepatocellular carcinoma overview

Topic Completed: 1 February 2012

Minor changes: 14 January 2021

Copyright: 2003-2021,, Inc.

PubMed Search: Hepatocellular carcinoma general[TI] full text[sb]

Deepali Jain, M.D.
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Cite this page: Jain D. Hepatocellular carcinoma overview. website. Accessed January 20th, 2021.
Definition / general
  • Malignant tumor with hepatocellular differentiation
  • 85% of hepatic malignancies (30% in children); major cause of cancer death worldwide but varies by country (see below)
  • Also called liver cell carcinoma; recommended to NOT describe as hepatoma, which implies a benign process
  • #5 most common malignancy worldwide (250,000 cases worldwide), #3 most frequent cause of cancer related death; causes 20 - 40% of cancer deaths in China, Japan, sub-Saharan African
  • Highest rates of disease in Korea, Taiwan, southeast China and Mozambique and countries endemic for viral hepatitis; also high in Africa, moderately high in France and Italy; rare in North America
  • Rates vary due to differences in risk factors: chronic hepatitis B (HBV) or hepatitis C (HCV); infant HBV carriers have 200x risk; aflatoxin exposure (developing countries), smoking, cirrhosis (85% in West with HCC have cirrhosis)
  • Other less common risk factors are Thorotrast exposure (historical), androgenic steroids, tyrosinemia
  • Higher rates in blacks vs. whites (4:1); 70% male
  • Most patients are age 60+ years with cirrhosis or ages 20 - 40 years without cirrhosis, occasionally are second tumors in Wilm tumor patients
  • Aflatoxins (mycotoxins): produced by Aspergillus flavus (aflatoxin B1) and Aspergillus parasiticus, which contaminate grain, particularly peanuts stored in warm and humid conditions in tropical and subtropical regions; aflatoxin B1 is potent carcinogen activated by hepatocytes, products intercalate into DNA to form mutagenic adducts with guanosine; in sub-Saharan Africa and China, patients have mutation in hepatic enzymes that normally detoxify aflatoxin
  • Cirrhosis: major risk factor, caused by alcoholism, alpha-1-antitrypsin deficiency, HCV, hereditary tyrosinemia (40% develop HCC even with dietary control), nonalcoholic fatty liver disease, primary hemochromatosis; due to stimulation of hepatocellular division in background of ongoing necrosis and inflammation; classic HCC occurs without chronic liver disease in old age or associated with hepatocellular adenomas with β catenin gene mutations (Hepatology 2009;50:481)
  • Hepatitis B virus: HBV DNA is integrated into host cell genome, inducing genomic instability; HBV contains 4 open reading frames; HBV X protein may disrupt normal growth control by transcriptional activation of insulin like growth factor II and receptors for insulin-like growth factor I; HBV X binds to p53; associated with β catenin accumulation; cirrhosis is variable; HBV vaccination dramatically reduces HCC incidence
  • Hepatitis C virus: HCC is rare in absence of cirrhosis because HCV lacks direct carcinogenic role
Clinical features
  • Symptoms: abdominal pain, ascites, hepatomegaly and obstructive jaundice; also systemic manifestations
  • Laboratory: elevated serum AFP (70% sensitive); AFP sensitivity reduced in alcohol related cirrhosis (65% sensitive), tumors arising in noncirrhotic liver (33% sensitive), tumors 2 cm or less (25% sensitive)
  • Screening: recommended to use ultrasound and serum AFP in patients with chronic liver disease; leads to diagnosis of tumors 2 cm or less, may not reduce deaths; des-gamma-carboxy prothrombin (DCP / protein induced by vitamin K absence or antagonist II / PIVKAII): more specific than serum AFP and marker of poor prognosis; abnormal prothrombin produced by HCC, associated with early portal vein invasion, intrahepatic metastasis and capsular infiltration
  • Other causes of elevated serum AFP: chronic hepatitis, cirrhosis, fetal death, fetal neural tube defect, fetal distress, hepatoblastoma, hepatoid adenocarcinoma, massive liver necrosis, normal pregnancy, yolk sac tumors of gonads
  • Metastases: initially within liver, distant metastases late to adrenal gland, bone, lung, porta hepatis lymph nodes
  • Classification: either small (< 2 cm) or advanced (2 cm or more)
Radiology images

Case #288

Metastasis to floor of mouth - MRI

Prognostic factors
  • 5 year survival: 10% overall to 50% in tumors ≤ 5 cm with resection; death usually within 1 year from cachexia, GI bleeding, liver failure or rupture of tumor
  • Favorable: low stage, encapsulation, single lesion, tumor size < 5 cm, fibrolamellar variant, no cirrhosis, no vascular invasion and negative surgical margins; another study: low nuclear grade (grade 1 of 3) regardless of vascular invasion or intermediate nuclear grade (2 of 3) without microscopic vascular invasion
  • Poor: microscopic vascular invasion, high nuclear grade (grade 3 of 3)
  • Factors that are not prognostic: age, gender and HBV status
Case reports
  • Resection
  • Transplantation (if solitary tumor 5 cm or less or multiple nodules 3 cm or less)
  • Radiofrequency ablation / transarterial chemoembolization (causes ongoing necrosis, Mod Pathol 2002;15:110); if present, indicate degree of ablation and grade residual viable tumor
Gross description
  • Unifocal, multifocal or diffusely infiltrative soft tumor, paler than normal tissue, may be green due to bile
  • Extensive intrahepatic metastases are common
  • Snakelike masses of tumor may involve the portal vein (35 - 80%), hepatic vein (20%) or inferior vena cava (similar to renal cell carcinoma)
  • Hemorrhage and necrosis are common
  • Occasionally tumor is pedunculated (< 1%), usually on posterior and inferior surfaces of right lobe
  • Liver usually cirrhotic, often enlarged
Gross images

Images hosted on other servers:

Various images

Microscopic (histologic) description
  • Patterns are trabecular (most common) with 4+ cells surrounded by layer of flattened endothelial cells; also clear cell, giant cell, pelioid (vascular lakes), pseudoglandular (acinar with proteinaceous material or bile in lumina, may resemble thyroid follicles), sarcomatoid, solid (compact)
  • Presence of sinusoidal vessels surrounding tumor cells is an important diagnostic feature
  • Scanty stroma, from well differentiated to bizarre (often within same tumor)
  • Cells are polygonal with distinct cell membranes, abundant granular eosinophilic cytoplasm, higher N/C ratio than normal, round nuclei with coarse chromatin and thickened nuclear membrane; may have prominent nucleoli
  • Common features are portal vein thrombosis, vascular invasion, mitotic figures
  • Variable: abundant fat, bile (5 - 33%), bile canaliculi, copper, intracellular hyaline bodies (round or oval homogeneous eosinophilic hyaline bodies with surrounding halo containing p62, 9%), intranuclear pseudoinclusions, Mallory hyaline (Mallory-Denk bodies, 2 - 25%), no central veins, pale bodies consisting of fibrinogen mimicking HBsAg containing ground glass change (6%); rarely is undifferentiated
  • Minimal desmoplasia

  • Well differentiated: thin plates (1 - 3 hepatocytes thick), cells smaller than normal, abnormal reticulin network; minimal nuclear atypia, nuclear density 2x normal liver; commonly fatty change and pseudoglands; may resemble hepatocyte adenoma; common pattern for small hepatocellular carcinoma
  • Moderately differentiated: trabecular pattern with 4+ cells thick; larger tumor cells than well differentiated HCC with more eosinophilic cytoplasm, distinct nucleoli, pseudoglands, bile and tumor giant cells; most common pattern in advanced HCC
  • Poorly differentiated: large tumor cells with hyperchromatic nuclei in compact growth pattern with rare trabeculae or bile; prominent pleomorphism, may have spindle cell or small cell areas; may not appear to be hepatocellular

  • Combined hepatocellular cholangiocarcinoma: < 1% of primary liver carcinomas; unequivocal hepatocellular and cholangiocarcinoma that are intimately admixed (World J Gastroenterol 2009;15:3940); increased CA19-9 and AFP; controversy regarding behavior

  • Diffuse cirrhosis-like HCC: diffuse and extensive liver involvement by small cirrhosis-like nodules that evade clinical and radiographic detection (Am J Surg Pathol 2010;34:935); small number of reported cases

  • Steatohepatitic HCC: recently described variant associated with metabolic dysfunction such as nonalcoholic fatty liver disease (Hum Pathol 2012;43:737, Am J Surg Pathol 2010;34:1630); slightly firmer than classic HCC (due to fibrosis) and more yellow (due to steatosis); histology shows steatosis, hepatocyte ballooning, Mallory-Denk Bodies, inflammation and pericellular fibrosis within neoplastic tissue
Microscopic (histologic) images

Case #288

Core biopsy



Case #161, contributed by Dr. S. Yasir Zaidi

Images hosted on other servers:

Smaller tumor cells infiltrate normal hepatocytes

Thick cords without lobules

Pseudoglandular type - various images

Positive stains
  • Must differentiate trapped normal hepatocytes from tumor cells when interpreting stains
  • HepPar1 (80 - 90%, cytoplasmic and granular), polyclonal CEA in canalicular pattern (50 - 90%, in better differentiated tumors), AFP (15 - 70%, not in small tumors); also albumin mRNA ISH, alpha-1-antitrypsin (55 - 93%), CAM 5.2 (CK8 / 18), CD10 (52%), CEA Gold 5 (76%), copper (7 - 41%), transferrin
  • Note: polyclonal CEA in canalicular pattern is specific for hepatocellular carcinoma, probably due to cross reactivity to biliary glycoprotein I present in bile canaliculi of normal liver and hepatocellular neoplasms; only 50 - 90% sensitive for hepatocellular carcinoma; monoclonal CEA is usually negative

  • Recommended panels:
    1. To differentiate from metastatic carcinoma: arginase1+, HepPar1+ and glypican 3+ (Am J Clin Pathol 2012;138:203)
    2. To differentiate from nonmalignant lesions - positivity for 2 of 3: glypican 3 / GPC3 (cytoplasmic and canalicular), HSP70 and glutamine synthetase (Hepatology 2007;45:725, J Hepatol 2009;50:746); adding clathrin heavy chain may be helpful (Hepatology 2011;53:1549)
    3. To differentiate from nonmalignant lesions: GPC3 plus CD34 complete staining pattern (Am J Surg Pathol 2008;32:433)
Negative stains
Electron microscopy description
  • Numerous mitochondria, microbodies and abundant glycogen
  • Intracytoplasmic bile products (bile canaliculi, peroxisomes)
Molecular / cytogenetics description
  • 50 - 92% hyperploid or aneuploid
Differential diagnosis
  • Adenoma / macroregenerative nodule (difficult if small sample): no cirrhosis in adenoma, not trabecular, no extensive pseudoglandular growth pattern, different clinical history, reticulin framework slightly maintained, minimal atypia, no mitotic figures; no thick fibrous pseudocapsule; negative for GPC3 and AFP
  • Angiomyolipoma, epithelioid: spindle cell component, thick walled vessels, HMB45+, actin+, CK-
  • Focal nodular hyperplasia: no cytologic atypia, no ductular reaction, arteries are abnormally structured; note that "focal nodular hyperplasia-like nodules" may be present in cirrhotic livers and mimic HCC on imaging

Metastatic tumors or contiguous spread:
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