Hepatic Tumours

Hepatic Tumours

Overview

Metastatic >> primary tumours in liver. Primary arise from hepatocytes/bile duct epithelium/mesoderm.

Tumour-like lesions

Cysts (3 types):

1. CONGENITAL — small(<1cm), biliary epithelium. Single or polycystic (±polycystic kidney). Fibrous+ductal variant=congenital hepatic fibrosis
2. SIMPLE(non-parasitic) — solitary, middle-aged WOMEN, large(up to 20cm), subcapsular, serous. Palpable mass, ±jaundice. Wall=fibrous, low columnar/cuboid epithelium
3. HYDATID — see elsewhere

FOCAL NODULAR HYPERPLASIA — unknown etiology, ↑OCP users. Gross: well-demarcated subcapsular, ~5cm, tan-yellow/bile-stained, CENTRAL FIBROUS SCAR. Micro: collagenous septa radiating from scar, normal-hepatocyte nodules WITHOUT portal triads/central veins, septa=lymphocytic infiltrate.

Benign tumours

LIVER CELL ADENOMA — rare, reproductive-age women+OCP/hormones/pregnancy. Mimics HCC clinically; may RUPTURE→intraperitoneal haemorrhage. Gross: usually single(10% multiple), encapsulated, lighter/bile-stained, few cm-30cm. Micro: hepatocyte sheets/cords, normal-slight variation, NO MITOSES. ↑glycogen, ±fatty change. LACKS portal tracts+bile ducts (key differentiator from normal liver/FNH). Vascular, ±thrombosis→infarction→rupture.

BILE DUCT ADENOMA(cholangioma) — rare, small acini or larger cystadenomas, biliary epithelium.

HAEMANGIOMA — COMMONEST benign liver tumour. Usually asymptomatic/incidental. Rare rupture. Gross: circumscribed red-purple, subcapsular, mm-cm, cavernous(spongy cut surface). Micro: large cavernous blood-filled spaces, single endothelial layer, connective tissue septa. ±fibrosis+calcification over time.

Malignant tumours

HCC~85% > cholangiocarcinoma 5-10% > rare(hepatoblastoma, angiosarcoma, embryonal sarcoma).

HCC (hepatoma) — COMMONEST primary malignant liver tumour

Geographic variation tracks HBV/HCV: <1% US/Europe vs 2-8% sub-Saharan Africa/SE Asia(China). M:F=4:1. Peak 5th-6th decade (earlier in high-HBV/HCV regions). Supervenes on CIRRHOSIS in 70-80%.

Etiopathogenesis:

1. HBV — Taiwan HBsAg+ carriers = >200x risk (esp early-life infection). 95% African/Asian HCC = anti-HBc+. Direct HBV-DNA genome integration into tumour cells
2. HCV — major factor after >30yrs infection. Japan shifted HBV→HCV-dominant; developing countries still HBV-dominant. anti-HCV+anti-HBc together = 3x risk of either alone. HCV-HCC=usually cirrhotic first; HBV-HCC=half cirrhotic/half chronic-hepatitis-only. Possible HBV+HCV synergy
3. Cirrhosis — ALL types, but MACRONODULAR post-necrotic MOST frequent. Mechanism: chronic regenerative activity/vulnerability. Liver cell dysplasia: 60% cirrhotic+HCC vs 10% non-cirrhotic
4. Alcohol — 4x risk, likely CO-carcinogen with HBV/HCV, not direct carcinogen alone
5. Mycotoxins — AFLATOXIN B1 (Aspergillus flavus, poorly-stored wheat/groundnuts, hot humid) — co-acts with HBV or suppresses immunity
6. Chemical carcinogens — butter-yellow, safrole, nitrosamines; pyrrolizidine/tannic acid plants; pesticides
7. Misc: haemochromatosis, α1-AT deficiency, immunosuppression(transplant), other hepatitis, NASH, smoking, clonorchiasis/schistosomiasis, glycogen storage diseases

Molecular: p53 inactivation by HBV; HBxAg binds p53; K-RAS mutations; c-MYC/c-MET receptor mutations; WNT/AKT activation.

Morphology — Gross patterns (↓frequency): EXPANDING(single, large, yellow-brown, right lobe, central necrosis, deceptively encapsulated — COMMONEST) > MULTIFOCAL(multiple 3-5cm) > INFILTRATING(rare, diffuse).

Micro: hepatocyte-like, well-diff→anaplastic. TRABECULAR pattern MOST common (2-8 cell-wide trabeculae, endothelium-lined vascular spaces); also pseudoglandular/acinar, compact, scirrhous. Cytology: vesicular nuclei+prominent nucleoli, eosinophilic→basophilic cytoplasm(↑malignancy), pleomorphism, giant cells, bile in canaliculi, Mallory hyalin. IHC: AFP+, EMA+, keratin+.

FIBROLAMELLAR CARCINOMA — variant, YOUNG patients either sex, single mass, NO cirrhosis (opposite of typical HCC profile). Micro: eosinophilic oncocytes in cords/nests + fibrous stroma bands. BETTER prognosis than conventional HCC.

Clinical: often masked by underlying cirrhosis. Hepatomegaly+palpable mass, RUQ pain, ±jaundice/fever/variceal bleed. Ascites w/ RBC+malignant cells ~50%. Rare paraneoplastic: hypercalcaemia, hypoglycaemia, gynaecomastia, porphyria.

Labs: nonspecific anaemia, ↑ALP. AFP: SPECIFIC(>500ng/ml in 70-80% HCC) but NOT SENSITIVE(also ↑ in yolk sac tumour/cirrhosis/chronic hepatitis/massive necrosis/normal pregnancy) — modest elevation ≠ HCC confirmation. Ultrasound MORE sensitive than AFP. Des-γ-carboxy prothrombin also ↑, correlates with AFP.

Spread: reproduces primary structure. Intrahepatic=haematogenous, multiple mets. Extrahepatic=hepatic/portal veins→lungs+bones; lymphatic→porta hepatis/mediastinal/cervical nodes. Death: cachexia, variceal bleeding, hepatic failure/coma. Survival typically <2yrs.

Cholangiocarcinoma

From INTRAHEPATIC bile duct epithelium (peripheral type; hilar/extrahepatic = separate “bile duct carcinoma”). NONE of HCC’s etiologic factors apply. Distinct factors: thorotrast dye, anabolic steroids, clonorchiasis, fibrocystic disease. OLDER patients, resembles HCC clinically but prominent JAUNDICE.

Morphology: Gross=firm, hard, whitish. Micro: glandular, biliary-epithelium-like cells WITHOUT bile secretion, tubular/ductular/papillary patterns, fibrous stroma, little capillary formation. ±mucinous/signet-ring/adenosquamous patterns. Variant: combined HCC-cholangiocarcinoma.

Hepatoblastoma (embryoma)

Rare, primitive hepatic cells, presents BEFORE AGE 2, more common in BOYS. Progressive distension, anorexia, failure to thrive, fever, jaundice. High AFP. Rapidly fatal.

Morphology: Gross=circumscribed lobulated, 5-25cm, cystic/haemorrhagic/necrotic. Micro: EPITHELIAL component(embryonal=small dark hyperchromatic; fetal=larger, more cytoplasm; trabeculae/ribbons/rosettes) + MESENCHYMAL component(fibrous tissue, cartilage, osteoid, ±extramedullary haematopoiesis).

Secondary (metastatic) tumours

MORE COMMON than primary liver tumours. Blood-borne regardless of drainage route. Sources(↓frequency): stomach>breast>lung>colon>oesophagus>pancreas>melanoma>haematopoietic. Sarcomas rarely metastasise here. Hepatic dysfunction usually LATE in course.

Morphology: Gross=multiple spherical variable-size nodules, enlarged heavy liver(≥5kg), white well-demarcated/soft/haemorrhagic deposits, characteristic UMBILICATION (central necrosis). Micro: reproduces primary structure.

Clinical relevance

AFP specificity-vs-sensitivity trade-off (specific>500ng/ml but false-positive prone at lower levels) = most tested nuance — modest elevation doesn’t confirm HCC, ultrasound beats AFP for detection. HCC-macronodular/viral cirrhosis link (more than alcoholic/micronodular) = basis for differential surveillance intensity. Fibrolamellar = “exception proving the rule” — young, no cirrhosis, BETTER prognosis, opposite typical-HCC profile. Metastases >> primaries + dual portal/systemic blood supply = why hepatic met screening matters even for non-portal-draining primaries.

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Hepatic Tumours

Overview

Metastatic >> primary tumours in liver. Primary arise from hepatocytes/bile duct epithelium/mesoderm.

Tumour-like lesions

Cysts (3 types):

1. CONGENITAL — small(<1cm), biliary epithelium. Single or polycystic (±polycystic kidney). Fibrous+ductal variant=congenital hepatic fibrosis
2. SIMPLE(non-parasitic) — solitary, middle-aged WOMEN, large(up to 20cm), subcapsular, serous. Palpable mass, ±jaundice. Wall=fibrous, low columnar/cuboid epithelium
3. HYDATID — see elsewhere

FOCAL NODULAR HYPERPLASIA — unknown etiology, ↑OCP users. Gross: well-demarcated subcapsular, ~5cm, tan-yellow/bile-stained, CENTRAL FIBROUS SCAR. Micro: collagenous septa radiating from scar, normal-hepatocyte nodules WITHOUT portal triads/central veins, septa=lymphocytic infiltrate.

Benign tumours

LIVER CELL ADENOMA — rare, reproductive-age women+OCP/hormones/pregnancy. Mimics HCC clinically; may RUPTURE→intraperitoneal haemorrhage. Gross: usually single(10% multiple), encapsulated, lighter/bile-stained, few cm-30cm. Micro: hepatocyte sheets/cords, normal-slight variation, NO MITOSES. ↑glycogen, ±fatty change. LACKS portal tracts+bile ducts (key differentiator from normal liver/FNH). Vascular, ±thrombosis→infarction→rupture.

BILE DUCT ADENOMA(cholangioma) — rare, small acini or larger cystadenomas, biliary epithelium.

HAEMANGIOMA — COMMONEST benign liver tumour. Usually asymptomatic/incidental. Rare rupture. Gross: circumscribed red-purple, subcapsular, mm-cm, cavernous(spongy cut surface). Micro: large cavernous blood-filled spaces, single endothelial layer, connective tissue septa. ±fibrosis+calcification over time.

Malignant tumours

HCC~85% > cholangiocarcinoma 5-10% > rare(hepatoblastoma, angiosarcoma, embryonal sarcoma).

HCC (hepatoma) — COMMONEST primary malignant liver tumour

Geographic variation tracks HBV/HCV: <1% US/Europe vs 2-8% sub-Saharan Africa/SE Asia(China). M:F=4:1. Peak 5th-6th decade (earlier in high-HBV/HCV regions). Supervenes on CIRRHOSIS in 70-80%.

Etiopathogenesis:

1. HBV — Taiwan HBsAg+ carriers = >200x risk (esp early-life infection). 95% African/Asian HCC = anti-HBc+. Direct HBV-DNA genome integration into tumour cells
2. HCV — major factor after >30yrs infection. Japan shifted HBV→HCV-dominant; developing countries still HBV-dominant. anti-HCV+anti-HBc together = 3x risk of either alone. HCV-HCC=usually cirrhotic first; HBV-HCC=half cirrhotic/half chronic-hepatitis-only. Possible HBV+HCV synergy
3. Cirrhosis — ALL types, but MACRONODULAR post-necrotic MOST frequent. Mechanism: chronic regenerative activity/vulnerability. Liver cell dysplasia: 60% cirrhotic+HCC vs 10% non-cirrhotic
4. Alcohol — 4x risk, likely CO-carcinogen with HBV/HCV, not direct carcinogen alone
5. Mycotoxins — AFLATOXIN B1 (Aspergillus flavus, poorly-stored wheat/groundnuts, hot humid) — co-acts with HBV or suppresses immunity
6. Chemical carcinogens — butter-yellow, safrole, nitrosamines; pyrrolizidine/tannic acid plants; pesticides
7. Misc: haemochromatosis, α1-AT deficiency, immunosuppression(transplant), other hepatitis, NASH, smoking, clonorchiasis/schistosomiasis, glycogen storage diseases

Molecular: p53 inactivation by HBV; HBxAg binds p53; K-RAS mutations; c-MYC/c-MET receptor mutations; WNT/AKT activation.

Morphology — Gross patterns (↓frequency): EXPANDING(single, large, yellow-brown, right lobe, central necrosis, deceptively encapsulated — COMMONEST) > MULTIFOCAL(multiple 3-5cm) > INFILTRATING(rare, diffuse).

Micro: hepatocyte-like, well-diff→anaplastic. TRABECULAR pattern MOST common (2-8 cell-wide trabeculae, endothelium-lined vascular spaces); also pseudoglandular/acinar, compact, scirrhous. Cytology: vesicular nuclei+prominent nucleoli, eosinophilic→basophilic cytoplasm(↑malignancy), pleomorphism, giant cells, bile in canaliculi, Mallory hyalin. IHC: AFP+, EMA+, keratin+.

FIBROLAMELLAR CARCINOMA — variant, YOUNG patients either sex, single mass, NO cirrhosis (opposite of typical HCC profile). Micro: eosinophilic oncocytes in cords/nests + fibrous stroma bands. BETTER prognosis than conventional HCC.

Clinical: often masked by underlying cirrhosis. Hepatomegaly+palpable mass, RUQ pain, ±jaundice/fever/variceal bleed. Ascites w/ RBC+malignant cells ~50%. Rare paraneoplastic: hypercalcaemia, hypoglycaemia, gynaecomastia, porphyria.

Labs: nonspecific anaemia, ↑ALP. AFP: SPECIFIC(>500ng/ml in 70-80% HCC) but NOT SENSITIVE(also ↑ in yolk sac tumour/cirrhosis/chronic hepatitis/massive necrosis/normal pregnancy) — modest elevation ≠ HCC confirmation. Ultrasound MORE sensitive than AFP. Des-γ-carboxy prothrombin also ↑, correlates with AFP.

Spread: reproduces primary structure. Intrahepatic=haematogenous, multiple mets. Extrahepatic=hepatic/portal veins→lungs+bones; lymphatic→porta hepatis/mediastinal/cervical nodes. Death: cachexia, variceal bleeding, hepatic failure/coma. Survival typically <2yrs.

Cholangiocarcinoma

From INTRAHEPATIC bile duct epithelium (peripheral type; hilar/extrahepatic = separate “bile duct carcinoma”). NONE of HCC’s etiologic factors apply. Distinct factors: thorotrast dye, anabolic steroids, clonorchiasis, fibrocystic disease. OLDER patients, resembles HCC clinically but prominent JAUNDICE.

Morphology: Gross=firm, hard, whitish. Micro: glandular, biliary-epithelium-like cells WITHOUT bile secretion, tubular/ductular/papillary patterns, fibrous stroma, little capillary formation. ±mucinous/signet-ring/adenosquamous patterns. Variant: combined HCC-cholangiocarcinoma.

Hepatoblastoma (embryoma)

Rare, primitive hepatic cells, presents BEFORE AGE 2, more common in BOYS. Progressive distension, anorexia, failure to thrive, fever, jaundice. High AFP. Rapidly fatal.

Morphology: Gross=circumscribed lobulated, 5-25cm, cystic/haemorrhagic/necrotic. Micro: EPITHELIAL component(embryonal=small dark hyperchromatic; fetal=larger, more cytoplasm; trabeculae/ribbons/rosettes) + MESENCHYMAL component(fibrous tissue, cartilage, osteoid, ±extramedullary haematopoiesis).

Secondary (metastatic) tumours

MORE COMMON than primary liver tumours. Blood-borne regardless of drainage route. Sources(↓frequency): stomach>breast>lung>colon>oesophagus>pancreas>melanoma>haematopoietic. Sarcomas rarely metastasise here. Hepatic dysfunction usually LATE in course.

Morphology: Gross=multiple spherical variable-size nodules, enlarged heavy liver(≥5kg), white well-demarcated/soft/haemorrhagic deposits, characteristic UMBILICATION (central necrosis). Micro: reproduces primary structure.

Clinical relevance

AFP specificity-vs-sensitivity trade-off (specific>500ng/ml but false-positive prone at lower levels) = most tested nuance — modest elevation doesn’t confirm HCC, ultrasound beats AFP for detection. HCC-macronodular/viral cirrhosis link (more than alcoholic/micronodular) = basis for differential surveillance intensity. Fibrolamellar = “exception proving the rule” — young, no cirrhosis, BETTER prognosis, opposite typical-HCC profile. Metastases >> primaries + dual portal/systemic blood supply = why hepatic met screening matters even for non-portal-draining primaries.

Hepatic Tumours

Overview

The liver hosts benign tumours, tumour-like lesions, and both primary and metastatic malignant tumours — metastatic tumours are far commoner than primary ones. Primary tumours may arise from hepatocytes, bile duct epithelium, or mesodermal structures.

Tumour-Like Lesions

Hepatic cysts — 3 types:

1. Congenital — uncommon, small (<1 cm), biliary-epithelium-lined; single or as polycystic liver disease (often with polycystic kidney); abundant connective tissue/ducts variant = congenital hepatic fibrosis.
2. Simple (non-parasitic) — solitary, more frequent in middle-aged women; large (up to 20 cm), subcapsular, serous-fluid-filled; palpable mass, ± jaundice. Wall: compact fibrous tissue lined by low columnar/cuboidal (occasionally squamous) epithelium.
3. Hydatid (Echinococcus) — covered elsewhere.

Focal nodular hyperplasia — etiology unknown, more common in oral contraceptive users. Gross: well-demarcated subcapsular nodule(s), ~5 cm, tan-yellow/bile-stained, with a central fibrous scar on cut section. Micro: collagenous septa radiating from the central scar, separating normal-hepatocyte nodules lacking portal triads/central veins; septa show prominent lymphocytic infiltrate.

Benign Hepatic Tumours

Uncommon; often incidental autopsy findings.

Hepatocellular (liver cell) adenoma — rare; reported in reproductive-age women on oral contraceptives/sex hormones or in pregnancy. Presents as an intrahepatic mass mimicking HCC; may rupture causing severe intraperitoneal haemorrhage. Gross: usually single (~10% multiple), partly/fully encapsulated, lighter-coloured or bile-stained, few cm to 30 cm; variable infarction/haemorrhage on cut section. Micro: sheets/cords of hepatocytes, normal-looking or mildly variable, no mitoses; more glycogen than surrounding liver, ± fatty change; lacks portal tracts and bile ducts (though bile-plugged canaliculi may be present); numerous (sometimes thrombosed) blood vessels — thrombosis causes infarction and can precipitate rupture/haemorrhage.

Bile duct adenoma (cholangioma) — rare, intra- or extrahepatic; small acini lined by biliary epithelium, or larger cystadenomas with biliary-epithelium-lined loculi.

Haemangioma — the commonest benign liver tumour; mostly asymptomatic, incidental; rarely ruptures into the peritoneal cavity. Gross: solitary/multiple, circumscribed, red-purple, commonly subcapsular, few mm to few cm; usually cavernous type with a spongy cut surface. Micro: large cavernous blood-filled spaces, single-endothelial-layer-lined, separated by connective tissue; may progressively fibrose and calcify.

Malignant Hepatic Tumours

Among primary malignant liver tumours: HCC ~85%, cholangiocarcinoma ~5–10%, occasional mixed pattern; remainder rare (hepatoblastoma, angiosarcoma, embryonal sarcoma — the latter two resembling their counterparts elsewhere in the body).

Hepatocellular Carcinoma (HCC, Hepatoma)

The commonest primary malignant liver tumour. Marked geographic variation tracking HBV/HCV prevalence: <1% of US/European autopsies vs 2–8% in sub-Saharan Africa/South-East Asia (especially China). Male:female = 4:1. Peak incidence 5th–6th decades, a decade or two earlier in high-HBV/HCV-prevalence regions. Supervenes on cirrhosis in 70–80% of cases.

Etiopathogenesis — multiple implicated factors, chiefly HBV/HCV and cirrhosis:

1. HBV — HBsAg-positive carriers in Taiwan have >200× the HCC risk of HBsAg-negative individuals, especially with early-life infection; 95% of African/Asian HCC cases have anti-HBc; direct evidence of HBV-DNA genome integration into tumour cell genomes.
2. HCV — major factor after >30 years of infection. Formerly-HBV-dominant regions (e.g. Japan) have shifted toward HCV as the leading cause; developing countries remain predominantly HBV-driven. Combined anti-HCV + anti-HBc positivity carries 3× the risk of either alone. HCV-related HCC more often follows established cirrhosis; HBV-related HCC is roughly half cirrhotic, half chronic-hepatitis-only. HBV and HCV may act synergistically.
3. Cirrhosis — all etiologic types associate with HCC, but macronodular post-necrotic cirrhosis most frequently. Mechanism: chronic regenerative activity, or general carcinogen vulnerability of damaged liver. Liver cell dysplasia (cellular enlargement, nuclear hyperchromatism, multinucleation) found in 60% of cirrhotic livers with HCC vs only 10% of non-cirrhotic livers.
4. Alcohol — ~4-fold increased HCC risk; likely acts as a co-carcinogen with HBV/HCV rather than a direct hepatic carcinogen.
5. Mycotoxins — aflatoxin B1 (from Aspergillus flavus contaminating poorly-stored wheat/groundnuts in hot humid regions) — carcinogenic, may co-act with HBV or suppress cellular immunity; drives higher HCC incidence in parts of Asia/Africa.
6. Chemical carcinogens — butter-yellow, safrole, nitrosamines (food additives); pyrrolizidine/tannic acid-containing bush plants; pesticide/insecticide pollutants.
7. Miscellaneous: haemochromatosis, α1-antitrypsin deficiency, prolonged immunosuppression (renal transplant), other hepatitis types, NASH, tobacco smoking, clonorchiasis/schistosomiasis, glycogen storage diseases.

Molecular pathogenesis: p53 inactivation by HBV; HBxAg (X-gene product) binding p53; K-RAS oncogene mutations; mutated hepatocyte growth factor receptors (c-MYC, c-MET); WNT and AKT pathway activation.

Morphology — gross growth patterns (decreasing frequency): expanding type (single, large, yellow-brown mass, often right lobe, central necrosis/haemorrhage, deceptively encapsulated — most frequent); multifocal type (multiple 3–5 cm masses scattered through the liver); infiltrating (spreading) type (rare, diffusely infiltrating).

Micro: tumour cells resemble hepatocytes, ranging well-differentiated to highly anaplastic; most show a trabecular growth pattern with tendency to invade blood vessels. Histologic patterns: trabecular/sinusoidal (most common — 2–8 cell-wide trabeculae separated by endothelium-lined vascular spaces); pseudoglandular/acinar (cells around central cystic spaces from trabecular breakdown); compact (large solid masses, inconspicuous sinusoids); scirrhous (abundant fibrous stroma). Cytology: hepatocyte-like cells with vesicular nuclei, prominent nucleoli; granular eosinophilic cytoplasm becoming more basophilic with increasing malignancy; pleomorphism, bizarre giant cells, spindle cells, clear-cytoplasm cells, bile within dilated canaliculi, intracytoplasmic Mallory’s hyalin. Immunohistochemistry: positive for AFP, EMA, keratin.

Fibrolamellar carcinoma — a clinicopathologic HCC variant in young patients of either sex; single, possibly encapsulated mass, occurring without underlying cirrhosis. Micro: eosinophilic polygonal cells (oncocytes) in cords/nests separated by fibrous stroma bands. Better prognosis than conventional HCC.

Clinical features: may go undetected initially (masked by underlying cirrhosis). Hepatomegaly with palpable mass, RUQ pain/tenderness, less often jaundice/fever/variceal haemorrhage. Ascites with RBCs and malignant cells in ~half. Rare paraneoplastic syndrome: hypercalcaemia, hypoglycaemia, gynaecomastia, acquired porphyria.

Labs: nonspecific anaemia, markedly raised alkaline phosphatase (as in cirrhosis), high serum alpha-fetoprotein (AFP) — specific but not sensitive: AFP >500 ng/ml in 70–80% of HCC, but also raised in yolk sac tumour, cirrhosis, chronic hepatitis, massive liver necrosis, and normal pregnancy. Ultrasound is more sensitive than AFP alone. Des-γ-carboxy prothrombin (abnormal prothrombin) also elevates and correlates with AFP.

Spread: reproduces the primary tumour’s structure. Intrahepatic — haematogenous, multiple liver metastases. Extrahepatic — via hepatic/portal veins to lungs and bones; lymphatically to porta hepatis, mediastinal, and cervical nodes. Death from cachexia, massive variceal bleeding, or hepatic failure/coma. Survival after diagnosis is typically <2 years.

Cholangiocarcinoma

Carcinoma from intrahepatic bile duct epithelium (peripheral cholangiocarcinoma) — hilar-duct and extrahepatic-duct carcinomas are termed bile duct carcinomas separately. None of the HCC etiologic factors apply here. Distinct etiologic factors: thorotrast (radio-opaque dye) exposure, anabolic steroids, clonorchiasis, fibrocystic disease. Affects older patients; clinical picture resembles HCC but with prominent jaundice.

Morphology: Gross — firm, hard, whitish tumour. Micro: glandular structure, tumour cells resembling biliary epithelium without bile secretion, patterns tubular/ductular/papillary; fibrous stroma with little/no capillary formation; occasional mucinous, signet-ring, or adenosquamous patterns. Uncommon variant: combined hepatocellular-cholangiocarcinoma.

Hepatoblastoma (Embryoma)

Rare malignant tumour from primitive hepatic parenchymal cells, presenting before age 2, more common in boys — progressive abdominal distension, anorexia, failure to thrive, fever, jaundice. High serum AFP. Rapidly fatal via haemorrhage, hepatic failure, or widespread metastases.

Morphology: Gross — circumscribed lobulated mass, 5–25 cm, with cystic degeneration/haemorrhage/necrosis. Micro — two components: epithelial (embryonal hepatocytes — small, dark hyperchromatic nuclei, scanty cytoplasm; and fetal hepatocytes — larger, more cytoplasm, granular/clear; organised in trabeculae/ribbons/rosettes) and mesenchymal (fibrous tissue, cartilage, variably mature osteoid; frequent extramedullary haematopoiesis).

Secondary (Metastatic) Hepatic Tumours

More common than primary liver tumours — mostly blood-borne, regardless of whether the primary drains via portal or systemic veins. Commonest sources (descending frequency): stomach, breast, lung, colon, oesophagus, pancreas, malignant melanoma, haematopoietic malignancies. Sarcomas rarely metastasise here. Occasionally metastases present without an obvious identified primary. Beyond general disseminated-malignancy features (anorexia, cachexia, anaemia), patients show hepatomegaly with a nodular free margin; hepatic dysfunction is typically late in the metastatic course.

Morphology: Gross — multiple, spherical, variable-size nodular masses; liver enlarged/heavy (≥5 kg); deposits white, well-demarcated, soft or haemorrhagic; surface shows characteristic umbilication from central nodule necrosis. Micro: generally reproduces primary tumour structure.

Clinical Relevance

• The AFP specificity-vs-sensitivity trade-off (highly specific at >500 ng/ml but false-positive-prone at lower levels from cirrhosis, chronic hepatitis, pregnancy, or yolk sac tumour) is the single most commonly tested nuance about this marker — a modestly elevated AFP does not confirm HCC, and ultrasound outperforms it for detection.
• HCC’s link to macronodular post-necrotic (viral) cirrhosis specifically, more than alcoholic (micronodular) cirrhosis, is the practical basis for differential HCC-surveillance intensity between these two cirrhosis populations.
• Fibrolamellar carcinoma is worth remembering as the “exception that proves the rule” for HCC — young patients, no cirrhosis, better prognosis — the opposite demographic and outcome profile of conventional HCC.
• Metastatic tumours vastly outnumbering primary liver tumours, combined with the liver’s dual portal+systemic blood supply, is the reasoning basis for why hepatic metastasis screening is relevant even for primaries that don’t obviously drain through the portal system.

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Hepatic Tumours

Overview

The liver hosts benign tumours, tumour-like lesions, and both primary and metastatic malignant tumours — metastatic tumours are far commoner than primary ones. Primary tumours may arise from hepatocytes, bile duct epithelium, or mesodermal structures.

Tumour-Like Lesions

Hepatic cysts — 3 types:

1. Congenital — uncommon, small (<1 cm), biliary-epithelium-lined; single or as polycystic liver disease (often with polycystic kidney); abundant connective tissue/ducts variant = congenital hepatic fibrosis.
2. Simple (non-parasitic) — solitary, more frequent in middle-aged women; large (up to 20 cm), subcapsular, serous-fluid-filled; palpable mass, ± jaundice. Wall: compact fibrous tissue lined by low columnar/cuboidal (occasionally squamous) epithelium.
3. Hydatid (Echinococcus) — covered elsewhere.

Focal nodular hyperplasia — etiology unknown, more common in oral contraceptive users. Gross: well-demarcated subcapsular nodule(s), ~5 cm, tan-yellow/bile-stained, with a central fibrous scar on cut section. Micro: collagenous septa radiating from the central scar, separating normal-hepatocyte nodules lacking portal triads/central veins; septa show prominent lymphocytic infiltrate.

Benign Hepatic Tumours

Uncommon; often incidental autopsy findings.

Hepatocellular (liver cell) adenoma — rare; reported in reproductive-age women on oral contraceptives/sex hormones or in pregnancy. Presents as an intrahepatic mass mimicking HCC; may rupture causing severe intraperitoneal haemorrhage. Gross: usually single (~10% multiple), partly/fully encapsulated, lighter-coloured or bile-stained, few cm to 30 cm; variable infarction/haemorrhage on cut section. Micro: sheets/cords of hepatocytes, normal-looking or mildly variable, no mitoses; more glycogen than surrounding liver, ± fatty change; lacks portal tracts and bile ducts (though bile-plugged canaliculi may be present); numerous (sometimes thrombosed) blood vessels — thrombosis causes infarction and can precipitate rupture/haemorrhage.

Bile duct adenoma (cholangioma) — rare, intra- or extrahepatic; small acini lined by biliary epithelium, or larger cystadenomas with biliary-epithelium-lined loculi.

Haemangioma — the commonest benign liver tumour; mostly asymptomatic, incidental; rarely ruptures into the peritoneal cavity. Gross: solitary/multiple, circumscribed, red-purple, commonly subcapsular, few mm to few cm; usually cavernous type with a spongy cut surface. Micro: large cavernous blood-filled spaces, single-endothelial-layer-lined, separated by connective tissue; may progressively fibrose and calcify.

Malignant Hepatic Tumours

Among primary malignant liver tumours: HCC ~85%, cholangiocarcinoma ~5–10%, occasional mixed pattern; remainder rare (hepatoblastoma, angiosarcoma, embryonal sarcoma — the latter two resembling their counterparts elsewhere in the body).

Hepatocellular Carcinoma (HCC, Hepatoma)

The commonest primary malignant liver tumour. Marked geographic variation tracking HBV/HCV prevalence: <1% of US/European autopsies vs 2–8% in sub-Saharan Africa/South-East Asia (especially China). Male:female = 4:1. Peak incidence 5th–6th decades, a decade or two earlier in high-HBV/HCV-prevalence regions. Supervenes on cirrhosis in 70–80% of cases.

Etiopathogenesis — multiple implicated factors, chiefly HBV/HCV and cirrhosis:

1. HBV — HBsAg-positive carriers in Taiwan have >200× the HCC risk of HBsAg-negative individuals, especially with early-life infection; 95% of African/Asian HCC cases have anti-HBc; direct evidence of HBV-DNA genome integration into tumour cell genomes.
2. HCV — major factor after >30 years of infection. Formerly-HBV-dominant regions (e.g. Japan) have shifted toward HCV as the leading cause; developing countries remain predominantly HBV-driven. Combined anti-HCV + anti-HBc positivity carries 3× the risk of either alone. HCV-related HCC more often follows established cirrhosis; HBV-related HCC is roughly half cirrhotic, half chronic-hepatitis-only. HBV and HCV may act synergistically.
3. Cirrhosis — all etiologic types associate with HCC, but macronodular post-necrotic cirrhosis most frequently. Mechanism: chronic regenerative activity, or general carcinogen vulnerability of damaged liver. Liver cell dysplasia (cellular enlargement, nuclear hyperchromatism, multinucleation) found in 60% of cirrhotic livers with HCC vs only 10% of non-cirrhotic livers.
4. Alcohol — ~4-fold increased HCC risk; likely acts as a co-carcinogen with HBV/HCV rather than a direct hepatic carcinogen.
5. Mycotoxins — aflatoxin B1 (from Aspergillus flavus contaminating poorly-stored wheat/groundnuts in hot humid regions) — carcinogenic, may co-act with HBV or suppress cellular immunity; drives higher HCC incidence in parts of Asia/Africa.
6. Chemical carcinogens — butter-yellow, safrole, nitrosamines (food additives); pyrrolizidine/tannic acid-containing bush plants; pesticide/insecticide pollutants.
7. Miscellaneous: haemochromatosis, α1-antitrypsin deficiency, prolonged immunosuppression (renal transplant), other hepatitis types, NASH, tobacco smoking, clonorchiasis/schistosomiasis, glycogen storage diseases.

Molecular pathogenesis: p53 inactivation by HBV; HBxAg (X-gene product) binding p53; K-RAS oncogene mutations; mutated hepatocyte growth factor receptors (c-MYC, c-MET); WNT and AKT pathway activation.

Morphology — gross growth patterns (decreasing frequency): expanding type (single, large, yellow-brown mass, often right lobe, central necrosis/haemorrhage, deceptively encapsulated — most frequent); multifocal type (multiple 3–5 cm masses scattered through the liver); infiltrating (spreading) type (rare, diffusely infiltrating).

Micro: tumour cells resemble hepatocytes, ranging well-differentiated to highly anaplastic; most show a trabecular growth pattern with tendency to invade blood vessels. Histologic patterns: trabecular/sinusoidal (most common — 2–8 cell-wide trabeculae separated by endothelium-lined vascular spaces); pseudoglandular/acinar (cells around central cystic spaces from trabecular breakdown); compact (large solid masses, inconspicuous sinusoids); scirrhous (abundant fibrous stroma). Cytology: hepatocyte-like cells with vesicular nuclei, prominent nucleoli; granular eosinophilic cytoplasm becoming more basophilic with increasing malignancy; pleomorphism, bizarre giant cells, spindle cells, clear-cytoplasm cells, bile within dilated canaliculi, intracytoplasmic Mallory’s hyalin. Immunohistochemistry: positive for AFP, EMA, keratin.

Fibrolamellar carcinoma — a clinicopathologic HCC variant in young patients of either sex; single, possibly encapsulated mass, occurring without underlying cirrhosis. Micro: eosinophilic polygonal cells (oncocytes) in cords/nests separated by fibrous stroma bands. Better prognosis than conventional HCC.

Clinical features: may go undetected initially (masked by underlying cirrhosis). Hepatomegaly with palpable mass, RUQ pain/tenderness, less often jaundice/fever/variceal haemorrhage. Ascites with RBCs and malignant cells in ~half. Rare paraneoplastic syndrome: hypercalcaemia, hypoglycaemia, gynaecomastia, acquired porphyria.

Labs: nonspecific anaemia, markedly raised alkaline phosphatase (as in cirrhosis), high serum alpha-fetoprotein (AFP) — specific but not sensitive: AFP >500 ng/ml in 70–80% of HCC, but also raised in yolk sac tumour, cirrhosis, chronic hepatitis, massive liver necrosis, and normal pregnancy. Ultrasound is more sensitive than AFP alone. Des-γ-carboxy prothrombin (abnormal prothrombin) also elevates and correlates with AFP.

Spread: reproduces the primary tumour’s structure. Intrahepatic — haematogenous, multiple liver metastases. Extrahepatic — via hepatic/portal veins to lungs and bones; lymphatically to porta hepatis, mediastinal, and cervical nodes. Death from cachexia, massive variceal bleeding, or hepatic failure/coma. Survival after diagnosis is typically <2 years.

Cholangiocarcinoma

Carcinoma from intrahepatic bile duct epithelium (peripheral cholangiocarcinoma) — hilar-duct and extrahepatic-duct carcinomas are termed bile duct carcinomas separately. None of the HCC etiologic factors apply here. Distinct etiologic factors: thorotrast (radio-opaque dye) exposure, anabolic steroids, clonorchiasis, fibrocystic disease. Affects older patients; clinical picture resembles HCC but with prominent jaundice.

Morphology: Gross — firm, hard, whitish tumour. Micro: glandular structure, tumour cells resembling biliary epithelium without bile secretion, patterns tubular/ductular/papillary; fibrous stroma with little/no capillary formation; occasional mucinous, signet-ring, or adenosquamous patterns. Uncommon variant: combined hepatocellular-cholangiocarcinoma.

Hepatoblastoma (Embryoma)

Rare malignant tumour from primitive hepatic parenchymal cells, presenting before age 2, more common in boys — progressive abdominal distension, anorexia, failure to thrive, fever, jaundice. High serum AFP. Rapidly fatal via haemorrhage, hepatic failure, or widespread metastases.

Morphology: Gross — circumscribed lobulated mass, 5–25 cm, with cystic degeneration/haemorrhage/necrosis. Micro — two components: epithelial (embryonal hepatocytes — small, dark hyperchromatic nuclei, scanty cytoplasm; and fetal hepatocytes — larger, more cytoplasm, granular/clear; organised in trabeculae/ribbons/rosettes) and mesenchymal (fibrous tissue, cartilage, variably mature osteoid; frequent extramedullary haematopoiesis).

Secondary (Metastatic) Hepatic Tumours

More common than primary liver tumours — mostly blood-borne, regardless of whether the primary drains via portal or systemic veins. Commonest sources (descending frequency): stomach, breast, lung, colon, oesophagus, pancreas, malignant melanoma, haematopoietic malignancies. Sarcomas rarely metastasise here. Occasionally metastases present without an obvious identified primary. Beyond general disseminated-malignancy features (anorexia, cachexia, anaemia), patients show hepatomegaly with a nodular free margin; hepatic dysfunction is typically late in the metastatic course.

Morphology: Gross — multiple, spherical, variable-size nodular masses; liver enlarged/heavy (≥5 kg); deposits white, well-demarcated, soft or haemorrhagic; surface shows characteristic umbilication from central nodule necrosis. Micro: generally reproduces primary tumour structure.

Clinical Relevance

• The AFP specificity-vs-sensitivity trade-off (highly specific at >500 ng/ml but false-positive-prone at lower levels from cirrhosis, chronic hepatitis, pregnancy, or yolk sac tumour) is the single most commonly tested nuance about this marker — a modestly elevated AFP does not confirm HCC, and ultrasound outperforms it for detection.
• HCC’s link to macronodular post-necrotic (viral) cirrhosis specifically, more than alcoholic (micronodular) cirrhosis, is the practical basis for differential HCC-surveillance intensity between these two cirrhosis populations.
• Fibrolamellar carcinoma is worth remembering as the “exception that proves the rule” for HCC — young patients, no cirrhosis, better prognosis — the opposite demographic and outcome profile of conventional HCC.
• Metastatic tumours vastly outnumbering primary liver tumours, combined with the liver’s dual portal+systemic blood supply, is the reasoning basis for why hepatic metastasis screening is relevant even for primaries that don’t obviously drain through the portal system.

Hepatic Tumours

• Classification tree of primary hepatic tumours (hepatocellular/biliary/mesodermal, each benign vs malignant)
• HCC’s three gross growth patterns (expanding/multifocal/infiltrating) side by side
• AFP interpretation flowchart showing its specific-but-not-sensitive trade-off and the conditions that cause false elevation

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Hepatic Tumours

• Classification tree of primary hepatic tumours (hepatocellular/biliary/mesodermal, each benign vs malignant)
• HCC’s three gross growth patterns (expanding/multifocal/infiltrating) side by side
• AFP interpretation flowchart showing its specific-but-not-sensitive trade-off and the conditions that cause false elevation

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