Hepatocellular Carcinoma and Variants

Hepatocellular Carcinoma and Variants

Joseph Misdraji, MD

Laura Webb Lamps, MD

Gross photograph shows a large bile-stained tumor nodule image in a background of cirrhosis. This is a classic presentation of hepatocellular carcinoma.

Hepatocellular carcinoma is typically composed of neoplastic cells resembling hepatocytes with a high nuclear to cytoplasmic ratio, which are organized into thick, disordered trabeculae.



  • Hepatocellular carcinoma (HCC)


  • Hepatoma


  • Primary malignant neoplasm of liver with hepatocytic differentiation


Developmental Anomaly

  • HCC can occur in patients with various congenital anomalies, including Alagille syndrome, ataxiatelangiectasia, Abernethy malformation, and bile salt export protein (BSEP) deficiency

Environmental Exposure

  • Aflatoxin B1, a mycotoxin produced by fungi of Aspergillus genus that contaminates food, is major cause of HCC in China and southern Africa

  • Alcoholic cirrhosis is major cause of HCC in western populations

  • Other exposures linked to HCC include anabolic steroids, Thorotrast, oral contraceptives, and smoking

Infectious Agents

  • Chronic viral hepatitis (hepatitis B and hepatitis C) is leading cause of HCC worldwide

Metabolic Disorders

  • Various metabolic disorders, including hemochromatosis, tyrosinemia, hypercitrullinemia, α-1-antitrypsin deficiency, and fructosemia, are associated with increased risk of HCC


  • 70-90% of HCC arises in cirrhosis

  • Macronodular cirrhosis is more strongly associated with HCC than micronodular

Progression of Benign Tumor

  • HCC can arise in preexisting hepatocellular adenoma



  • Incidence

    • Varies widely depending on geography in parallel with prevalence of hepatitis B and C and aflatoxin exposure

      • East Asia and southern Africa have highest incidence worldwide, up to 150 per 100,000

      • In USA, annual incidence is approximately 4 per 100,000

  • Age

    • Incidence increases with advancing age and then falls off in elderly; however, average age varies depending on geography

      • In parts of world with high incidence, average age is 35 years

      • In USA, average age is 60 years

    • Can occur in children, particularly in those with metabolic or genetic disorders

  • Gender

    • More common in men


  • Abdominal pain due to stretching of Glisson capsule

  • Malaise, weight loss, hepatomegaly

  • Decompensation of previously stable cirrhotic patient with jaundice and rapidly accumulating ascites

  • Fever, leukocytosis, and liver mass mimicking hepatic abscess

  • Increasingly, small asymptomatic tumors are being found during surveillance of cirrhotic patients

Laboratory Tests

  • α-fetoprotein (AFP) is elevated in 70-90% of patients

Natural History

  • Metastasis occurs in 40-60% of patients

    • Most common locations are lymph nodes in porta hepatis, around pancreas, and celiac axis

  • HCC has tendency for intravascular spread with involvement of hepatic and portal veins

    • Hematogenous spread most commonly occurs to lungs, but also adrenal glands, bone, stomach, heart, pancreas, kidney, spleen, and ovary

  • Tumor seldom breaches Glisson capsule, and therefore dissemination throughout peritoneal cavity is rare


  • Surgical approaches

    • Resection is possible if sufficient reserve liver function

    • Transplantation is option if patient meets “Milan criteria” of single tumor < 5 cm, or fewer than 4 tumors, none > 3 cm

  • Drugs

    • Sorafenib

      • Tyrosine kinase inhibitor that has proven to be at least somewhat effective in advanced cases

  • Ablation therapy

    • Radiofrequency or microwave ablation or direct percutaneous ethanol injections are options for small tumors

    • Angiographic embolization of hepatic artery can infarct tumor and prolong survival


  • Better prognosis associated with age < 50 years, female gender, resectable tumor, better differentiated tumor, low mitotic index, absence of vascular invasion, encapsulated tumor, and absence of cirrhosis

  • In USA, 5-year survival is 75% for tumors < 5 cm and 30-40% overall


General Features

  • Soft tumor that can be bile-stained, with variable hemorrhage and necrosis

  • Can be solitary tumor, solitary tumor with “satellite nodules,” multiple discrete tumors, or multiple small indistinct nodules throughout portion of liver or entire liver

    • Pedunculated tumors are rare, more easily resected, and have better prognosis

    • Encapsulated tumors are rare, usually solitary tumors that arise in cirrhotic livers, and have better prognosis

  • Gross venous or bile duct invasion may be seen and should be sought


Histologic Features

  • Architectural patterns

    • Trabecular pattern: Tumor cells grow as thickened hepatic plates separated by sinusoids without desmoplastic stroma

    • Pseudoglandular or acinar pattern: Tumor cells grow in solid nests with central degenerative changes

    • Compact pattern: Trabeculae grow compressed together

    • Scirrhous pattern: Resemble trabecular HCC but with abundant stroma

    • Giant cell pattern: Multinucleate giant cells

    • Spindle cell pattern is often referred to as sarcomatoid HCC

  • Tumor cell morphology

    • Tumor cells resemble hepatocytes with polygonal shape, round vesicular nuclei, and prominent nucleoli

      • Inclusions can be seen in tumor cells, including Mallory hyaline, hyaline globules, and pale bodies

      • Clear cells may be present and even numerous due to accumulation of glycogen, water, or fat

    • Presence of bile pigment in dilated canaliculi is helpful in distinguishing HCC from its mimics

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hepatocellular Carcinoma and Variants
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