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PA24.{5,7} | Portal Hypertension & Hepatocellular Carcinoma — SDL Guide (Part 4)

Microscopic Patterns of HCC

Four-panel histology diagram comparing normal liver plates with trabecular, pseudoglandular, and solid microscopic patterns of hepatocellular carcinoma. — **Panel A:** Normal liver plates 1-2 cells thick, trabecular HCC plates 3 or more cells thick, sinusoidal spaces, diagnostic plate-thickness bracket.. **Panel B:** Well-differentiated HCC with thickened trabecular plates, sinusoid-like vascular channels, endothelial lining, bile canaliculi, hepatocyte-like tumour cells.. **Panel C:** Pseudoglandular or acinar HCC with gland-like spaces containing bile or proteinaceous fluid and surrounding neoplastic hepatocytes.. **Panel D:** Poorly differentiated solid HCC with compact sheets, compressed sinusoids, pleomorphic tumour cells, atypical mitoses, giant cells, clear-cell change, and hyaline globules..

Histological examination shows neoplastic hepatocytes arranged in various patterns, recapitulating (imperfectly) normal liver architecture.

Trabecular (sinusoidal) pattern — commonest; tumour cells form plates 2–3 (or more) cells thick, separated by sinusoid-like vascular channels lined by endothelial cells. Normal liver plates are only 1–2 cells thick — thickened plates are a diagnostic clue.

Pseudoglandular (acinar) pattern — tumour cells form gland-like spaces containing bile or proteinaceous fluid.

Solid (compact) pattern — sheets of cells with compressed sinusoids; seen in poorly differentiated tumours.

Cytological features:
• Cells resemble hepatocytes: abundant eosinophilic cytoplasm, central nucleus, prominent nucleolus.
• Bile production within tumour cells — pathognomonic of hepatocellular origin (distinguishes from metastatic adenocarcinoma, cholangiocarcinoma).
• Intracellular hyaline globules (α1-antitrypsin or fibrinogen), Mallory hyaline.
• In poorly differentiated HCC, cells may be pleomorphic, giant, or clear-cell type.

Two-panel H&E-style histology diagram comparing well-differentiated trabecular hepatocellular carcinoma with poorly differentiated solid hepatocellular carcinoma. — **Panel A:** Well-differentiated HCC with thickened trabecular plates, sinusoid-like vascular channels, endothelial lining, and bile canaliculi; includes bracket showing 3-5 cell plate thickness.. **Panel B:** Poorly differentiated HCC with solid sheets of tumour cells, pleomorphic nuclei, atypical mitotic figures, and compressed sinusoids..

SELF-CHECK

A liver biopsy in a 55-year-old man shows thickened hepatocyte plates (3–4 cells thick) separated by sinusoid-like channels. Tumour cells have abundant eosinophilic cytoplasm and some contain greenish intracellular deposits. AFP is 1,200 ng/mL. The microscopic finding that MOST specifically confirms hepatocellular origin of this carcinoma is:

A. Prominent nucleoli in tumour cells

B. Intracellular bile production

C. Elevated serum AFP

D. Trabecular growth pattern

Reveal Answer

Answer: B. Intracellular bile production

Intracellular bile production is pathognomonic of hepatocellular differentiation — no other tumour type produces bile. Trabecular pattern and prominent nucleoli are characteristic but not exclusive to HCC. Elevated AFP supports the diagnosis but is a serum marker, not a histological finding. AFP can also be raised in germ cell tumours and, less markedly, in hepatic metastases.

Alpha-Fetoprotein, Screening, and Complications

Infographic showing AFP biology, HCC screening in cirrhosis, diagnostic AFP thresholds, and major local and systemic complications of hepatocellular carcinoma. — **Panel A:** Adult liver, cirrhotic background, hepatocellular carcinoma nodule, serum AFP, fetal yolk sac, fetal liver, normal adult AFP less than 10 ng/mL. **Panel B:** Cirrhosis of any cause, 6-monthly ultrasound, AFP optional, early HCC detection, potentially curative stage. **Panel C:** AFP less than 10 ng/mL normal, AFP greater than 20 ng/mL abnormal but nonspecific, AFP greater than 400 ng/mL plus cirrhosis plus liver mass suggests HCC. **Panel D:** Superficial HCC rupture, haemoperitoneum, bloody ascites, portal vein tumour thrombus, acute portal hypertension, variceal haemorrhage. **Panel E:** Hypoglycaemia from IGF-II or insulin-like activity, hypercalcaemia from PTHrP, polycythaemia from erythropoietin, hypercholesterolaemia, lung metastasis, bone metastasis, adrenal metastasis.

Alpha-fetoprotein (AFP) is a glycoprotein normally produced by the fetal yolk sac and liver; it is virtually absent in adults (normal < 10 ng/mL). In HCC, AFP is elevated in ~70% of cases.

Diagnostic thresholds:
• AFP > 400 ng/mL in a cirrhotic with a liver mass = HCC until proved otherwise (Barcelona BCLC criteria).
• AFP > 20 ng/mL is abnormal but not specific (also elevated in germ cell tumours, hepatic regeneration, hepatitis).

Screening protocol in cirrhotics: 6-monthly ultrasound ± AFP in all patients with cirrhosis (any cause). This detects HCC at an earlier, potentially curative stage. Cost-effective even in resource-limited settings.

Complications of HCC:
• Tumour rupture → haemoperitoneum — spontaneous rupture of a superficial HCC causes acute abdominal pain, circulatory collapse, and bloody ascites; mortality > 50% without emergency intervention.
• Portal vein invasion — PVTT precipitates acute portal hypertension, variceal haemorrhage.
• Paraneoplastic syndromes — hypoglycaemia (ectopic IGF-II or insulin-like activity), hypercalcaemia (ectopic PTHrP), polycythaemia (ectopic erythropoietin), hypercholesterolaemia.
• Metastases — haematogenous to lungs, bone, adrenals.

Fibrolamellar Variant of HCC

A four-panel medical diagram contrasts fibrolamellar HCC with conventional HCC, highlighting its characteristic lamellar fibrosis, young adult presentation, non-cirrhotic liver background, normal AFP, and DNAJB1–PRKACA fusion. — **Panel A:** Large polygonal tumour cells, dense granular eosinophilic cytoplasm, central nuclei, prominent nucleoli, dense lamellar collagen fibrosis bands, abundant mitochondria inset. **Panel B:** Conventional HCC in cirrhotic liver of older adult versus fibrolamellar HCC in non-cirrhotic liver of young adult. **Panel C:** DNAJB1 gene, PRKACA gene, DNAJB1–PRKACA fusion kinase, pathognomonic molecular driver. **Panel D:** Young adults 20–40 years, no cirrhosis, AFP normal or mildly elevated, relatively better prognosis.

The fibrolamellar HCC is a distinct clinicopathological entity — not a subtype of conventional HCC but a separate tumour with different biology, demographics, and prognosis.

Key distinctions from conventional HCC:

Feature	Conventional HCC	Fibrolamellar HCC
Age	Middle-aged/elderly	Young adults (20–40 yr)
Cirrhosis background	Yes (>80%)	No
AFP	Elevated ~70%	Normal or mildly elevated
Morphology	See above	Large polygonal cells with dense granular eosinophilic cytoplasm (abundant mitochondria), separated by dense lamellar fibrosis bands
Molecular driver	TP53, TERT, HBx	DNAJB1–PRKACA fusion (pathognomonic)
Prognosis	Poor (overall 5-yr <15%)	Relatively better if resectable

Pathognomonic molecular feature: The DNAJB1–PRKACA fusion gene (created by a focal deletion on chr 19) is present in virtually 100% of fibrolamellar HCC and absent in conventional HCC — diagnostic on molecular testing when histology is ambiguous.

SELF-CHECK

A 24-year-old non-drinker with no viral hepatitis markers presents with a solitary 8 cm liver mass and a normal AFP. Histology shows large polygonal hepatocytes with deeply eosinophilic granular cytoplasm arranged in nests separated by parallel bands of dense fibrous stroma. The molecular alteration MOST characteristic of this tumour is:

A. TP53 codon-249 mutation

B. TERT promoter mutation

C. DNAJB1–PRKACA fusion

D. HBx protein integration

Reveal Answer

Answer: C. DNAJB1–PRKACA fusion

The clinical and histological description is classic for fibrolamellar HCC — young patient, no cirrhosis, normal AFP, lamellar fibrosis. The DNAJB1–PRKACA fusion gene, created by a focal deletion on chromosome 19, is present in virtually 100% of fibrolamellar HCCs and is absent in conventional HCC. TP53 R249S is the aflatoxin signature; TERT promoter mutation is the commonest alteration in conventional HCC; HBx integration is the HBV-related carcinogenesis mechanism.