Hepatocellular Carcinoma & Liver Tumours
Pathology · GIT & Liver · lean revision notes
Hepatocellular Carcinoma & Liver Tumours
Liver tumours are a recurring NEET PG theme spanning Pathology, Surgery and Medicine. This note builds a clean map of benign vs malignant, primary vs secondary lesions, with the marker, the radiology sign and the high-yield occupational and drug associations that examiners love.
Classification of liver tumours
The liver is a frequent site of both primary tumours (arising from hepatocytes, bile duct epithelium or mesenchyme) and metastatic deposits. Crucially, in most populations metastases are the commonest malignant tumour of the liver, while cavernous haemangioma is the commonest benign tumour and the commonest primary tumour of liver overall.
| Category | Benign | Malignant |
|---|---|---|
| Hepatocyte origin | Hepatic (hepatocellular) adenoma, focal nodular hyperplasia (FNH) | Hepatocellular carcinoma (HCC), hepatoblastoma (children) |
| Bile duct origin | Bile duct adenoma, von Meyenburg complex | Cholangiocarcinoma |
| Mesenchymal/vascular | Cavernous haemangioma, infantile haemangioendothelioma | Angiosarcoma, epithelioid haemangioendothelioma |
| Secondary | — | Metastases (commonest malignant lesion overall) |
High-yield: Commonest benign liver tumour = cavernous haemangioma. Commonest malignant liver tumour = metastasis. Commonest primary malignant liver tumour = hepatocellular carcinoma. Commonest liver malignancy in children = hepatoblastoma.
Hepatocellular Carcinoma (HCC)
Definition & epidemiology
HCC is a malignant tumour of hepatocytes, the third leading cause of cancer death worldwide and far more common in Asia and sub-Saharan Africa, reflecting endemic HBV. It arises most often (~80–90%) on a background of cirrhosis.
Etiology & risk factors
The dominant theme is chronic hepatocyte injury → regeneration → dysplastic nodule → HCC.
| Risk factor | Key exam point |
|---|---|
| Hepatitis B (HBV) | Commonest cause worldwide; integrates into host genome → can cause HCC even without cirrhosis |
| Hepatitis C (HCV) | Commonest cause in West/Japan; HCC only after cirrhosis develops |
| Alcoholic (Laennec) cirrhosis | Micronodular cirrhosis as substrate |
| Aflatoxin B1 (Aspergillus flavus on stored grains/peanuts) | Causes p53 codon 249 G→T transversion; synergistic with HBV |
| Non-alcoholic steatohepatitis (NASH) | Rising cause with the obesity/diabetes epidemic |
| Haemochromatosis | Highest relative risk among the metabolic causes |
| α1-antitrypsin deficiency, Wilson disease (rare), tyrosinaemia | Inherited substrates |
High-yield: Aflatoxin B1 → p53 mutation at codon 249. HBV → HCC without needing cirrhosis; HCV → HCC only via cirrhosis.
Pathophysiology
Repeated cycles of necrosis and regeneration in cirrhosis create proliferating clones that accumulate mutations (TERT promoter, CTNNB1/β-catenin, TP53). HBV DNA integration causes insertional mutagenesis and expresses the HBx protein, which is mitogenic and inhibits p53. The sequence runs:
Chronic injury → regenerative nodule → low-grade then high-grade dysplastic nodule → early HCC → progressed HCC.
Gross & microscopic pathology
- Gross patterns: unifocal (large solitary), multifocal (multiple nodules) and diffusely infiltrative. HCC has a striking propensity for vascular invasion, characteristically growing into the portal vein (and hepatic vein → can extend to IVC and right atrium).
- Micro: polygonal cells in trabecular/sinusoidal pattern resembling hepatocytes; bile production (bile in canaliculi/tumour) is diagnostic. Mallory–Denk hyaline and pale bodies may be seen. Fibrolamellar variant shows nests of large eosinophilic cells separated by dense lamellated collagen bands.
Fibrolamellar carcinoma — a favourite distractor
| Feature | Classic HCC | Fibrolamellar HCC |
|---|---|---|
| Age | Older, 50–70 yr | Young, 20–40 yr |
| Cirrhosis/HBV | Usually present | Absent |
| AFP | Often elevated | Usually normal |
| Sex | M > F | M = F |
| Prognosis | Poor | Better (resectable) |
| Genetics | TP53/CTNNB1 | DNAJB1–PRKACA fusion |
High-yield: A young patient, no cirrhosis, normal AFP, resectable tumour with fibrous bands → fibrolamellar carcinoma, with the DNAJB1–PRKACA fusion gene.
Clinical features
Often clinically silent until advanced. Suspect HCC when a stable cirrhotic suddenly decompensates — new ascites, worsening jaundice, weight loss, RUQ pain, an abdominal mass or an arterial bruit/friction rub over the liver. Bloody ascites in a cirrhotic strongly suggests HCC. Paraneoplastic syndromes include hypoglycaemia, erythrocytosis (EPO-like), hypercalcaemia (PTHrP) and hypercholesterolaemia.
Investigations & diagnosis
- Serum α-fetoprotein (AFP): the classic tumour marker. Levels >400 ng/mL (or >500 by some texts) in a cirrhotic with a liver mass are virtually diagnostic. AFP is not specific (raised in germ cell tumours, pregnancy, hepatitis) and may be normal in up to a third of small HCCs and in fibrolamellar variant. Newer markers: AFP-L3, des-γ-carboxy prothrombin (DCP/PIVKA-II), glypican-3.
- Triphasic (multiphase) CT / dynamic MRI is the imaging investigation of choice. The hallmark is arterial-phase hyperenhancement with venous/delayed-phase washout — this radiological signature (LI-RADS 5) can establish diagnosis without biopsy in a cirrhotic.
- Biopsy is reserved for indeterminate lesions; it carries a small risk of needle-tract seeding.
- Surveillance of cirrhotics: ultrasound ± AFP every 6 months.
High-yield: Investigation of choice for an HCC nodule in a cirrhotic = triphasic CT / dynamic contrast MRI showing arterial enhancement + delayed washout. Marker = AFP.
Staging & management
The Barcelona Clinic Liver Cancer (BCLC) system links stage to treatment and uniquely incorporates liver function (Child–Pugh) and performance status.
Treatment flow by BCLC stage:
- Very early/early (0–A): single small tumour, preserved function → resection, ablation (RFA) or liver transplantation (curative).
- Intermediate (B): multinodular, no vascular invasion → TACE (transarterial chemoembolisation).
- Advanced (C): vascular invasion/extrahepatic spread → systemic therapy — first line now atezolizumab + bevacizumab; alternatives sorafenib/lenvatinib (multikinase inhibitors).
- Terminal (D): end-stage liver, poor PS → best supportive care.
Milan criteria select cirrhotics for transplantation: single tumour ≤5 cm, OR up to 3 tumours each ≤3 cm, with no vascular invasion and no extrahepatic spread.
High-yield: Milan criteria (1 lesion ≤5 cm or ≤3 lesions each ≤3 cm) = eligibility for liver transplant. Sorafenib was the first approved systemic drug; current first-line is atezolizumab + bevacizumab.
Cholangiocarcinoma
Adenocarcinoma of biliary epithelium; the second commonest primary liver malignancy. Classified by site into intrahepatic, perihilar (Klatskin tumour, commonest type) and distal extrahepatic.
Risk factors (chronic biliary inflammation/stasis):
- Primary sclerosing cholangitis (PSC) — strongest Western association
- Liver flukes: Clonorchis sinensis, Opisthorchis viverrini (Southeast Asia)
- Thorotrast (historical contrast)
- Choledochal cysts, hepatolithiasis, Caroli disease
Pearls:
- Painless obstructive jaundice + a hilar stricture → think Klatskin tumour.
- Marker: CA 19-9 elevated (also raised in pancreatic cancer).
- Desmoplastic, markedly fibrous (scirrhous) tumours; often not AFP-positive.
High-yield: Klatskin tumour = perihilar cholangiocarcinoma at the confluence of right and left hepatic ducts. Liver fluke (Clonorchis/Opisthorchis) and PSC are the classic risk factors; marker is CA 19-9.
Hepatic Angiosarcoma
A rare but examiner-favourite malignant tumour of endothelial origin, notable almost entirely for its occupational/environmental carcinogen associations.
| Agent | Context |
|---|---|
| Vinyl chloride monomer | PVC plastics industry — the classic occupational link |
| Thorotrast | Old thorium-dioxide contrast agent (also linked to cholangiocarcinoma & HCC) |
| Arsenic (Fowler's solution, contaminated water) | Chronic exposure |
| Anabolic/androgenic steroids | Rare |
Pathology shows malignant spindled/epithelioid endothelial cells lining sinusoid-like channels; CD31, CD34, factor VIII–related antigen (vWF), ERG positive. Highly aggressive with early haematogenous spread and frequent haemorrhage; prognosis is dismal.
High-yield: Vinyl chloride → hepatic angiosarcoma (also acro-osteolysis and Raynaud-like changes). Thorotrast → angiosarcoma, cholangiocarcinoma and HCC. Endothelial markers: CD31/CD34/factor VIII.
Cavernous Haemangioma
The commonest benign liver tumour and commonest primary liver tumour overall, found incidentally in up to 5% of autopsies, more in women.
- Pathology: large blood-filled cavernous vascular spaces lined by flat endothelium, separated by fibrous septa.
- Clinical: almost always asymptomatic and discovered incidentally; large lesions may rarely rupture or cause pain.
- Imaging: characteristic peripheral nodular enhancement with progressive centripetal ("fill-in") enhancement on contrast CT/MRI; markedly hyperintense on T2.
- Pitfall: percutaneous biopsy is contraindicated — risk of catastrophic haemorrhage. Diagnosis is radiological.
- Management: observation; resect only if symptomatic, very large, or diagnostic uncertainty.
High-yield: Liver lesion with peripheral-to-central "fill-in" enhancement = cavernous haemangioma — do not biopsy.
Hepatic (Hepatocellular) Adenoma
Benign hepatocyte proliferation strongly tied to hormones.
- Associations: long-term oral contraceptive pills (OCPs) — the classic link; anabolic/androgenic steroids; pregnancy; glycogen storage disease (von Gierke type I, type III); MODY3 (HNF1A).
- Pathology: sheets/cords of benign hepatocytes without portal tracts, central veins or bile ducts — this architectural absence helps distinguish it from FNH and normal liver.
- Risks: the two key complications are rupture with intraperitoneal haemorrhage (especially during pregnancy or with large/subcapsular lesions) and malignant transformation to HCC (notably the β-catenin–activated molecular subtype).
- Management: stop OCPs (lesion may regress); resect adenomas >5 cm, those in men, or β-catenin subtype, and any that are symptomatic/bleeding.
High-yield: Young woman on OCPs with a liver mass that bleeds → hepatic adenoma. Subtypes: HNF1A-inactivated (steatotic, lowest cancer risk), inflammatory, and β-catenin–activated (highest HCC risk).
Focal Nodular Hyperplasia (FNH)
Not a true neoplasm but a hyperplastic response to a pre-existing arterial malformation; second commonest benign lesion.
- Hallmark: a central stellate scar with a radiating fibrous septa and a feeding artery; on MRI the scar is T2-hyperintense and enhances late.
- Pathology: all normal hepatocyte components present except organised portal tracts; bile ductular proliferation is present (unlike adenoma).
- No malignant potential, no significant bleeding risk → typically just observed. Not OCP-induced (though OCPs may enlarge it).
| Feature | Hepatic adenoma | FNH |
|---|---|---|
| OCP link | Strong (causal) | Weak (may enlarge only) |
| Central scar | Absent | Present (stellate) |
| Bile ducts | Absent | Present |
| Bleeding risk | High | Low |
| Malignant potential | Yes (β-catenin type) | None |
| Management | Stop OCP, resect if >5 cm | Observe |
Hepatoblastoma
- Commonest primary liver malignancy in children (usually <3 years).
- Associations: Beckwith–Wiedemann syndrome, familial adenomatous polyposis (FAP/APC), Wilms tumour.
- Markedly elevated AFP (useful for diagnosis and monitoring).
- Epithelial (fetal/embryonal) and mixed epithelial-mesenchymal subtypes; treated with chemotherapy + resection, good prognosis if resectable.
Liver metastases
- The commonest malignant tumour of the liver overall (far exceeding primaries).
- Common primaries: colorectal, lung, breast, pancreas, stomach, neuroendocrine, melanoma.
- Typically multiple nodules, may cause hepatomegaly with umbilicated ("cannon-ball") surface deposits and the classic "nutmeg" appearance is for congestion, not mets — don't confuse.
- Colorectal liver metastases may be cured by resection if limited.
Key differentials — putting it together
| Clinical clue | Most likely tumour |
|---|---|
| Cirrhotic, ↑AFP, arterial enhancement + washout | HCC |
| Young, no cirrhosis, normal AFP, fibrous bands | Fibrolamellar carcinoma |
| PVC factory worker / Thorotrast exposure | Angiosarcoma |
| PSC or liver fluke, hilar stricture, ↑CA 19-9 | Cholangiocarcinoma (Klatskin) |
| Incidental lesion, "fill-in" enhancement, no biopsy | Cavernous haemangioma |
| Woman on OCPs, lesion bleeds, no central scar | Hepatic adenoma |
| Central stellate scar, no malignant potential | FNH |
| Infant/toddler, very high AFP | Hepatoblastoma |
| Multiple nodules, known colon/breast cancer | Metastases |
Mnemonic for HCC risk factors — "VINYL is for angiosarcoma, but for HCC think HAVE A Cirrhosis": HBV, Aflatoxin, Viral C (HCV), Ethanol (alcohol), A1-antitrypsin/haemochromatosis, Cirrhosis (final common pathway).
Recently asked / exam angle
- Vinyl chloride → hepatic angiosarcoma is a perennial occupational-pathology one-liner; pair it with Thorotrast (which causes angiosarcoma + cholangiocarcinoma + HCC).
- Aflatoxin B1 → p53 codon 249 mutation — direct molecular-pathology MCQ.
- Marker matching: AFP → HCC/hepatoblastoma/yolk sac tumour; CA 19-9 → cholangiocarcinoma/pancreas.
- Fibrolamellar HCC profile (young, no cirrhosis, normal AFP, better prognosis, DNAJB1-PRKACA fusion).
- OCP → hepatic adenoma with risk of rupture; biopsy contraindication for cavernous haemangioma.
- HBV causes HCC without cirrhosis; HCV requires cirrhosis — a frequently tested distinction.
- Milan criteria for transplantation and BCLC staging-linked treatment.
- Image-based: peripheral nodular "fill-in" enhancement (haemangioma) vs arterial enhancement with washout (HCC) vs central scar (FNH).
Rapid revision
- Commonest benign liver tumour = cavernous haemangioma; commonest malignant = metastasis; commonest primary malignant = HCC.
- HBV → HCC even without cirrhosis; HCV → HCC only after cirrhosis.
- Aflatoxin B1 mutates p53 at codon 249 (G→T transversion).
- HCC tumour marker = AFP (>400 ng/mL diagnostic in a cirrhotic); other markers: DCP/PIVKA-II, AFP-L3, glypican-3.
- Investigation of choice for HCC = triphasic CT/dynamic MRI (arterial enhancement + delayed washout); biopsy usually avoidable.
- HCC characteristically invades the portal vein; bloody ascites in a cirrhotic suggests HCC.
- Fibrolamellar HCC = young, no cirrhosis, normal AFP, better prognosis, DNAJB1-PRKACA fusion.
- Vinyl chloride, Thorotrast, arsenic → hepatic angiosarcoma (CD31/CD34/factor VIII positive).
- Klatskin tumour = perihilar cholangiocarcinoma; risks = PSC + liver flukes; marker CA 19-9.
- OCPs → hepatic adenoma (risk of rupture and β-catenin-type malignant transformation); never biopsy a haemangioma.
- FNH = central stellate scar, contains bile ducts, no malignant potential, just observe.
- Hepatoblastoma = commonest paediatric liver cancer; very high AFP; linked to Beckwith–Wiedemann and FAP; Milan criteria govern transplant eligibility in HCC.