Hepatocellular Carcinoma and Variants

Hepatocellular Carcinoma in Cirrhotic Liver
Autopsy specimen shows a large, central mass with small satellite tumor nodules image. The latter may represent intrahepatic spread due to vascular invasion or independent primaries. The nonneoplastic liver shows cirrhosis.

Hepatocellular Carcinoma in Noncirrhotic Liver
This image shows a unifocal, yellow-tan, well-circumscribed tumor in the background of a normal liver. Of hepatocellular carcinoma (HCC), 10-30% arise in noncirrhotic liver.

Trabecular Pattern
Neoplastic cells resemble hepatocytes and have a high nuclear:cytoplasmic ratio. The tumor cells are organized in thick, disordered trabeculae.

Pseudoacinar Pattern
Pseudoacinar or pseudoglandular pattern is common in HCC and can mimic adenocarcinoma. Unlike true glands, there is no basement membrane, and the nuclei do not have a basal location.



• 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, ataxia-telangiectasia, Abernethy malformation, and genetic diseases such as bile salt export protein (BSEP) deficiency

Environmental Exposure

• Aflatoxin B1 (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

• Recent studies have implicated diabetes, obesity, and metabolic syndrome as risk factors


• 70-90% of HCC arises in cirrhosis

• Prognosis is significantly worse compared to HCC in noncirrhotic liver

• Macronodular cirrhosis is more strongly associated with HCC than micronodular

Progression of Benign Tumor

• HCC can arise in preexisting hepatocellular adenoma



• Incidence
image 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 ∼ 4 per 100,000

• Age
image 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

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

• Sex
image 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
image 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
image 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
image Resection is possible if sufficient reserve liver function

image Transplantation is option if patient meets Milan criteria of single tumor < 5 cm, or < 4 tumors, none > 3 cm

image Less stringent UCSF criteria have been proposed: Solitary tumor < 6.5 cm, or < 4 tumors, none > 4.5 cm and total tumor diameter up to 8 cm, without gross vascular invasion

image Histologic differentiation as selection criterion has been implemented in certain centers, as poor differentiation has been shown to be associated with high recurrence

• Drugs
image HCC is resistant to chemotherapeutic agents

image Sorafenib
– Tyrosine kinase inhibitor that has proven to be at least somewhat effective in advanced cases

• Ablation therapy
image Radiofrequency or microwave ablation, or direct percutaneous ethanol injections are options for small tumors

image Transarterial embolization (TEA) and transarterial chemoembolization (TACE) can prolong survival


• Favorable prognostic factors
image Age < 50 years, female gender

image Resectable tumor

image Noncirrhotic liver

image Encapsulated tumor, early HCC

image Well or moderately differentiated

image Absence of vascular invasion

• In USA, 5-year survival is 30% for localized disease, 10% for regional disease, and < 5% for metastatic disease

• For early cancers that receive transplant, 5-year survival is 60-70%


Radiographic Findings

• Characteristic features on contrast-enhanced study (dynamic CT scan or MR)
image HCC enhances more intensely than surrounding liver in arterial phase

image HCC enhances < surrounding liver in venous phase (washout)

• Biopsy not required for diagnosis if findings typical of HCC are seen in cirrhotic liver of lesions > 2 cm

• For lesions 1-2 cm, typical radiology findings on 2 techniques increases sensitivity and specificity of diagnosis

• All suspicious lesions in noncirrhotic liver as well as ones in cirrhotic liver with atypical imaging features should be biopsied

• Liver Imaging Reporting and Data System (LI-RADS) is now being used
image Combines arterial enhancement with size, venous washout, presence of capsule and growth compared to prior imaging to yield 5 diagnostic categories
– LR-1: Definitely benign

– LR-2: Probably benign

– LR-3: Moderate probability of benign or malignant

– LR-4: Probably malignant

– LR-5: Definitely malignant


General Features

• Variable hemorrhage and necrosis, can be bile-stained
• Solitary ± satellite nodules, or multiple discrete tumors

• Multiple small, indistinct tumor nodules can mimic cirrhosis on imaging and gross examination (cirrhosis-like variant)

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

image Encapsulated tumors are usually solitary tumors that arise in cirrhotic livers and have better prognosis

• Gross venous or bile duct invasion may be seen


Histologic Features

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

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

image Compact pattern: Trabeculae grow compressed together

image Spindle cell pattern: Often referred to as sarcomatoid HCC

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

image Inclusions can be seen in tumor cells: Mallory hyaline, ground-glass inclusions, hyaline globules, pale bodies

image Clear cells may be present and even numerous due to accumulation of glycogen or fat

image Bizarre mono- or multinucleate tumor giant cells, rarely osteoclast-like giant cells

image Cytoplasmic fat can be present, often diffuse in small, well-differentiated tumors

image Bile can be present in dilated canaliculi, helpful in distinguishing HCC from its mimics

Cytologic Features

• Neoplastic cells resemble hepatocytes but with enlarged nuclei, nuclear membrane irregularity, coarse chromatin, and prominent macronucleoli
image May have dispersed cell pattern with numerous stripped, atypical nuclei

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Apr 20, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hepatocellular Carcinoma and Variants

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