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Liver and intrahepatic bile ducts - tumor

Hepatocellular carcinoma - General

Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 24 April 2014, last major update February 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.


● 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)


● 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

● 22 year old woman with focal hepatic glycogenosis after 6 years of azathioprine therapy (Hum Pathol 2000;31:874)
● 48 year old man with lymphangitis carcinomatosis in lung (Arch Pathol Lab Med 2003;127:e11)
● 65 year old man with large mass in the floor of the mouth (Case of the Week #288)

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

Left to right: trabecular, pseudoglandular and acinar, trabecular and pseudoglandular patterns

Smaller tumor cells   Thick cords without    Vascular invasion      Liver tumor and vascular
infiltrate normal     lobules                      invasion in lung

H&E and HepPar1   pCEA           AFP           H&E and CD10

pCEA in hepatocellular carcinoma         Post radiofrequency ablation
vs. cholangiocarcinoma

Acinar (pseudoalveolar) pattern        Solid pattern with loss of cell
resembling cholangiocarcinoma         plate architecture (reticulin stain)

Adenocarcinoma staining             MOC31 in hepatocellular
with MOC31, pCEA and CD10         carcinoma vs. cholangiocarcinoma

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

Metastasis to floor of mouth -


Core biopsy

Left: HepPar1, right: DPAS

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 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+

End of Liver and intrahepatic bile ducts - tumor > Hepatocellular carcinoma > General

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