Liver and intrahepatic bile ducts - tumor
Hepatocellular carcinoma - General

Author: Deepali Jain, M.D. (see Authors page)

Revised: 8 October 2015, last major update February 2012

Copyright: (c) 2003-2015,, Inc.

PubMed Search: hepatocellular carcinoma general
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’s 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), non-alcoholic 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
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
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 non-cirrhotic 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)
Clinical Images

Metastasis to floor
of mouth - MRI

  • 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
Case Reports
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

Various images

Involvement of inferior vena
cava and other large vessels

Micro 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’s 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 non-alcoholic 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
Micro Images
Images on our server

Core biopsy

Left: HepPar1, Right: DPAS

Contributed by: Dr. S. Yasir Zaidi, Sinai-Grace Hospital (USA)

Images from other websites

Smaller tumor cells
infiltrate normal

Thick cords without lobules

Vascular invasion

Liver tumor and vascular invasion in lung

Pseudoglandular type - various images
Courtesy of Dr. Semir Vranic

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 (CK 8/18), 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:
    (a) To differentiate from metastatic carcinoma: Arginase1+, HepPar1+, and Glypican3+ (Am J Clin Pathol 2012;138:203)
    (b) To differentiate from nonmalignant lesions: positivity for 2 of 3: Glypican-3/GPC-3 (cytoplasmic and canalicular), HSP-70 and Glutamine synthetase (Hepatology 2007;45:725, J Hepatol 2009;50:746); adding clathrin heavy chain may be helpful (Hepatology 2011;53:1549)
    (c) To differentiate from nonmalignant lesions: GPC-3 plus CD34 complete staining pattern (Am J Surg Pathol 2008;32:433)
Negative Stains
  • Keratins: AE1-AE3, CK7 (positive in 20%), CK13, CK19 (positive in <10%, if positive, marker of adverse prognosis, Histopathology 2006;49:138), CK20, keratin903 (> 90%)
  • EMA, monoclonal CEA (positive in 0-10%), CD15, mucin (mucicarmine), MOC31 and BerEP4
Molecular / Cytogenetics Description
  • 50-92% hyperploid or aneuploid
Electron Microscopy Description
  • Numerous mitochondria, microbodies and abundant glycogen
  • Intracytoplasmic bile products (bile canaliculi, peroxisomes)
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 GPC-3 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:
  • Adenocarcinoma (hepatoid) from stomach or lung: no cirrhosis; CK7+, CK19+, CK20+, TTF1+ (lung), CDX-2+ (colorectal); HepPar1-
  • Adenocarcinoma (poorly differentiated) or cholangiocarcinoma: desmoplastic stroma, mucin+, CK7+, CK19+
  • Breast: CK7+, ER+, GCDFP15+, Mammaglobin+
  • Melanoma
  • Neuroendocrine tumors from pancreas or small bowel: no cirrhosis; similar trabecular pattern but smaller cells, inconspicuous nucleoli, stippled chromatin, CK7+, CDX2+ (small bowel)
  • Ovarian carcinomas: CK7+, ER+, WT1+
  • Prostate: PSA+, PAP+
  • Renal cell carcinoma: PAX2+, HepPar1-, RCC+; make sure biopsy is NOT from renal mass
  • Thyroid: CK7+, TTF1+, thyroglobulin+