Ken’s Pathology Guide

Hepatocellular Carcinoma (HCC)

Epidemiology and Etiology:

M > F
2^nd most common cancer in Asia

Highest incidence is in East Asia (China, Japan)

Risk factors:

Cirrhosis from any cause (70-90% of HCC patients have macronodular cirrhosis)
HBV
HCV
Aflatoxin B₁ (AFB₁) (Southern China and Subsaharan Africa)

Aspergillus species contaminating grains (esp. peanuts)
Induces a mutation in the TP53 gene
Multiplicatory effect along with HBV infection

EtOH
Smoking
Iron overload
OCP
Alpha-1-antitrypsin deficiency
Obesity, DM, NASH

Fibrolamellar carcinoma (FLC) occurs in children and young adults

North America / Europe more common
Non-cirrhotic liver
Etiology unknown

Gross features:

Unifocal or multifocal or diffusely infiltrative
White-yellow; usually paler than surrounding liver, may have a green hue
Occasionally gross invasion of portal vein
May see nodule within a nodule (HCC occurring in a hyperplastic nodule)
Encapsulated often (fibrous pseudocapsule)
Intratumoural septations
Surrounding liver is often cirrhotic
Softer than background liver typically
Fibrolamellar carcinoma:

Single large mass

appears to be composed of smaller nodules

May have a capsule
Central scar (75%)

Histologic features:

Hepatocytes in a roughly (>2-3 cells thick) trabecular pattern or in an acinar, pseudoglandular pattern
Aberrant arteries within tumour (“nontriadal” or “unpaired” arteries)

Not part of portal tracts

Cells often smaller with higher N:C ratio
Portal tracts absent (may see entrapped in the periphery)
Sinusoids lined by endothelial layer (“capillarization”)

Resemble normal capillaries

Hyaline granules
Bile (maybe)
Strong propensity for vascular invasion
Grading (WHO 2010):

Mixture of patterns often seen in larger tumours, periphery tends to be more differentiated
Well-differentiated:

< 2cm most common (not usually seen in > 3cm tumours except focally at periphery)
Rare in advanced tumours
Mild atypia
Increased n:c ratio
Thin trabecular pattern
Pseudoglandular structures often
Fatty change frequent

Moderately-differentiated:

> 3cm tumours most common
Trabecular growth of 3 or more cells in thickness
Abundant eosinophilic cytoplasm
Round nuclei with distinct nucleoli
Pseudoglandular pattern frequent

Poorly-differentiated HCC:

Extremely rare in small, early-stage tumours
Solid pattern without distinct sinusoid-like blood spaces
Slit-like blood vessels observed in large tumour nests
Increased n:c ratio
Moderate to marked pleomorphism frequently

Undifferentiated HCC:

Little cytoplasm
Spindle or round-shaped
Solid growth

Patterns:

Trabecular pattern (most common)

Trabeculae become thicker with de-differentiation

Pseudoacinar and glandular

Single layer of tumour cells moslty
Often proteinaceous fluids within

May be PASD+
Mucicarmine –
Acian blue –

Cystic dilation

Compact (poorly-differentiated pattern)

Inconspicuous slit-like sinusoids
Solid appearance

Scirrhous

Marked fibrosis along the sinusoids
Atrophy of tumour trabeculae
Note similar changes can be seen post-treatment (chemo, rads, embolization)

Undifferentiated (rare)

Based on IHC

Lymphoepithelial-like carcinoma (rare)

May or may not be EBV+

Cytology variants:

Pleomorphic cell

Pleomorphism, tumour giant cells

Clear cell (abundant glycogen)

May appear similar to clear cell renal carcinoma

Spindle cells / Sarcomatous change:

If predominantly sarcomatoid, the term sarcomatous HCC is used

Fatty change
Bile production
Mallory hyaline bodies (PAS neg, keratin pos)
Globular hyaline bodies

Small
Round
Homogenous
Strongly acidophilic
Intracytoplasmic
PAS+
Alpha-1-antitrypsin + often

Pale bodies

Intracytoplasmic
Round to ovoid
Amorphous
Lightly eosinophlic

Ground glass inclusions (rarely)

Fibrolamellar variant (young adults, non-cirrhotic):

Well-differentiated polygonal cells in sheets or small trabeculae
Abundant eosinophilic cytoplasm (oncocytic)
Large vesicular nuclei and large nucleoli
Separated by parallel lamellae of dense collagen bundles with a characteristic lamellated pattern
Gland-like formation maybe

Grading (Edmonson & Steiner) (not favoured anymore by WHO):

Grade I:

Difficult to distinguish from normal liver histology
Diagnosis rests on demonstration of more aggressive growths in parts of the neoplasm

Grade II:

Marked resemblance to normal hepatocytes
Nuclei larger and more hyperchromatic
Cytoplasm abundant and acidophilic
Cell borders sharp
Acini frequent

Lumena filled with bile or protein precipitate

Grade III:

Nuclei larger and more pleomorphic

High N:C ratio

Cytoplasm less granular and acidophilic
Acini are less frequent

Less often filled with bile or protein precipitate

More single cell growth in vascular channels

Grade IV:

Nuclei intensely hyperchromatic

High N:C ratio

Cytoplasm variable, often scanty

Contains fewer granules

Medullary growth pattern

Trabeculae difficult to find
Cell masses lie loosely without cohesion in vascular channels
Rare acini

Small cell morphology maybe

Immunophenotype:

Marker:	Sensitivity:	Specificity:
CD34 (sinusoids)
Factor-VIII-related antigen (sinusoids)
Subendoethilial laminin (sinusoids)
Type IV collagen (sinusoids)
Reticulin (trabecular pattern recognition)
HepPar1 (carbamoyl phosphate synthetase-1)	90% Less frequent in poorly differentiated or scirrhous HCCs
CEA (canalicular pattern)	Maybe
CD10 (canalicular pattern)	Maybe
ABCB1/MDR1 (canalicular pattern)	Maybe
AFP	Often
Fibrinogen	Often
CK8/18	Often
CK19 (neg)	Usually
EMA (neg)	Usually
PAS (pseudoglandular fluids)
Mucicarmine (neg)	Except FLC maybe
Alcian blue (neg)	Except FLC maybe

Molecular features:

Other features:

AFP in serum:

>500ng/mL or continuously rising levels strongly suggest HCC
Not very sensitive or specific (other liver disease)
Poor prognosis if > 100 ng/mL at diagnosis

Paraneoplastic syndrome (occasionally):

Erythrocytosis
Hypoglycemia
Hypercalcemia

Prognosis better for non-cirrhotic patients
Prognostic factors:

Poor prognosis overall
AFP level at diagnosis
Partial or complete portal vein thrombosis
TP53 gene mutation
CK19 staining in > 5% of tumour cells (poor prognosis)
Spontaneous regression rarely

References:

Robbins 2005
Lester’s Manual of Surgical Pathology
WHO Pathology and Genetics of Tumours of the Digestive System (2000)
WHO Classification of Tumours of the Digestive System, 4^th ed. (2010)