Gastrointestinal · PANCE / PANRE

Hepatocellular Carcinoma (HCC)

Primary liver cancer in cirrhosis or chronic HBV; surveillance improves outcomes; many curative options.

Also known as: HCC, hepatocellular carcinoma, hepatoma, liver cancer

Overview

Primary malignancy of hepatocytes, accounting for >90% of primary liver cancers. Typically arises in cirrhotic livers but can occur in non-cirrhotic chronic HBV.

Epidemiology

~42,000 new cases and ~30,000 deaths annually in the US; rising incidence (HCV cohort, alcohol, MASLD). 5-year survival ~20% overall; >70% if detected at very early stage. Worldwide, leading cancer in some Asian/African countries due to endemic HBV.

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Risk factors

Cirrhosis of any etiology — most important risk factor
Chronic HBV — can cause HCC WITHOUT cirrhosis (integration of HBV DNA into host genome)
Chronic HCV (largely mitigated by DAA SVR but persists in cirrhotic patients)
MASH/MASLD with cirrhosis (rising etiology)
Alcohol-associated cirrhosis
Hemochromatosis with cirrhosis
Aflatoxin exposure (Aspergillus contamination of stored grains/nuts — sub-Saharan Africa, parts of Asia)
Alpha-1 antitrypsin deficiency, Wilson disease, autoimmune hepatitis (with cirrhosis)
Tobacco, diabetes, obesity (independent contributors)
Family history; Asian male >40, Asian female >50, African origin >20 (start surveillance earlier)

Pathophysiology

Chronic inflammation, oxidative stress, and regenerative hepatocyte turnover drive accumulation of genetic mutations (TERT promoter, TP53, CTNNB1, AXIN1). HBV DNA integration directly disrupts tumor suppressor genes and induces malignant transformation even in non-cirrhotic livers. HCC is highly vascular and characteristically derives blood supply from the hepatic artery (vs portal vein for normal liver).

Clinical presentation

Symptoms

Often ASYMPTOMATIC in early stage — detected on surveillance
RUQ pain or fullness
Weight loss, anorexia, fatigue
Worsening hepatic decompensation (new/worsening ascites, encephalopathy, jaundice) in a previously stable cirrhotic
Paraneoplastic syndromes: erythrocytosis (EPO), hypoglycemia (IGF-2), hypercalcemia (PTHrP), watery diarrhea
Acute hemoperitoneum from tumor rupture (rare but life-threatening)

Signs / physical exam

Hepatomegaly, palpable liver mass
Bruit over liver (highly vascular)
Stigmata of cirrhosis
Worsening ascites, encephalopathy, jaundice
Signs of metastatic disease (lung, bone, lymph nodes, adrenal)

Classic findings

New worsening of stable compensated cirrhosis — always evaluate for HCC.

Differential diagnosis

Cirrhotic regenerative nodule / dysplastic nodule — Lacks arterial enhancement with washout; LI-RADS classification
Intrahepatic cholangiocarcinoma — Peripheral, mass-forming or periductal; delayed/persistent enhancement vs HCC washout; biopsy
Hepatic hemangioma — Most common benign liver mass; peripheral nodular enhancement with centripetal fill-in on MRI
Focal nodular hyperplasia (FNH) — Central scar, hyperintense on hepatobiliary phase MRI with hepatocyte-specific contrast
Hepatocellular adenoma — Premenopausal women with OCP/anabolic steroid use; resect if >5 cm or beta-catenin mutated due to bleeding/malignancy risk
Metastasis (colon, breast, lung, melanoma) — Multiple lesions, no underlying cirrhosis, primary tumor history
Liver abscess — Fever, leukocytosis, fluid collection; risk factors (cholangitis, diverticulitis); aspiration culture

Diagnostic workup

Diagnostic criteria

LI-RADS (Liver Imaging Reporting and Data System) in cirrhotic patients: LR-5 (definite HCC) — arterial hyperenhancement + washout + capsule or threshold growth. Biopsy not required for LR-5 in cirrhosis. AASLD criteria similar.

Labs

Alpha-fetoprotein (AFP) — elevated in ~70% of HCC but not specific; ≥400 ng/mL with characteristic imaging supports diagnosis
PIVKA-II (DCP) — adjunct biomarker (not widely used in US)
LFTs, INR, albumin (Child-Pugh, MELD)
CBC (thrombocytopenia from hypersplenism; erythrocytosis from paraneoplastic EPO)
Hepatitis B and C serologies
Iron studies, ceruloplasmin, A1AT (etiologic workup if not established)

Imaging

Multiphasic CT or MRI with IV contrast — diagnostic; arterial phase hyperenhancement + portal venous or delayed phase washout (LR-5 by LI-RADS) is sufficient for diagnosis in cirrhotic patient WITHOUT biopsy
Liver biopsy — reserve for lesions with indeterminate imaging or in non-cirrhotic livers
Surveillance: abdominal ultrasound ± AFP every 6 months in cirrhotic patients and high-risk HBV carriers
Staging: CT chest/abdomen/pelvis; bone scan if symptoms; PET-CT not routinely used
Hepatobiliary contrast MRI (gadoxetate disodium) — useful for indeterminate small lesions

Diagnostic algorithm

BCLC Stage	Tumor Status	Liver Function / PS	Treatment
0 (Very early)	Single ≤2 cm	Child-Pugh A, PS 0	Resection or ablation
A (Early)	Single any size or ≤3 nodules ≤3 cm	Child-Pugh A-B, PS 0	Resection, transplant (if Milan), or ablation
B (Intermediate)	Multinodular	Child-Pugh A-B, PS 0	TACE or TARE; consider downstaging
C (Advanced)	Vascular invasion or extrahepatic spread	Child-Pugh A, PS 1-2	Systemic therapy (atezolizumab + bevacizumab)
D (Terminal)	Any	Child-Pugh C or PS ≥3	Best supportive care

Barcelona Clinic Liver Cancer (BCLC) staging and treatment algorithm for HCC.

Treatment

First-line

Stage- and liver-function-directed therapy (BCLC algorithm)
Multidisciplinary tumor board
Treat underlying liver disease (HBV antivirals, HCV DAAs, alcohol cessation, MASH management)

Very early / early (BCLC 0/A) — single tumor ≤2 cm or up to 3 tumors ≤3 cm; preserved liver function

Surgical resection (Child-Pugh A, no portal hypertension)
Liver transplantation — best for those within Milan criteria (single ≤5 cm OR up to 3 lesions each ≤3 cm)
Local ablation (radiofrequency or microwave ablation) — curative for small tumors when resection contraindicated

Intermediate (BCLC B) — multinodular, no vascular invasion or metastases

Transarterial chemoembolization (TACE) or transarterial radioembolization (TARE/Y-90)
Consider downstaging to transplant criteria

Advanced (BCLC C) — vascular invasion or extrahepatic spread, preserved liver function

First-line systemic: atezolizumab + bevacizumab (IMbrave150) — for Child-Pugh A only; EGD to exclude varices first
Alternative first-line: tremelimumab + durvalumab (HIMALAYA), lenvatinib, sorafenib (historical)
Second-line: cabozantinib, regorafenib, ramucirumab (if AFP ≥400), nivolumab + ipilimumab

Terminal (BCLC D) — poor performance status or end-stage liver function

Best supportive care, palliative care, hospice as appropriate

Complications

Tumor rupture with hemoperitoneum
Portal vein tumor thrombosis (poor prognostic factor)
Worsening hepatic decompensation
Paraneoplastic syndromes
Metastases — lung, bone, lymph nodes, adrenal
Liver failure as a competing risk for mortality
Treatment toxicity: post-TACE syndrome (fever, pain, transaminitis), Y-90 lung shunting, immune-related adverse events with checkpoint inhibitors, hemorrhage with bevacizumab

PANCE pearls

Surveillance with ultrasound ± AFP every 6 months is recommended in ALL cirrhotic patients (regardless of etiology or compensation) and high-risk HBV carriers — improves survival.
HBV is the only chronic hepatitis where HCC develops in non-cirrhotic livers — surveillance recommended in Asian male >40, Asian female >50, African origin >20, family history of HCC, all cirrhotic HBV.
Cure of HCV with DAAs reduces but does NOT eliminate HCC risk in cirrhotic patients — continue surveillance.
LR-5 imaging criteria (arterial hyperenhancement + washout) in a cirrhotic patient is diagnostic for HCC — BIOPSY NOT REQUIRED.
Milan criteria for liver transplant: single tumor ≤5 cm OR up to 3 tumors each ≤3 cm, no vascular invasion or extrahepatic spread.
Atezolizumab + bevacizumab (IMbrave150) is preferred first-line systemic therapy for advanced HCC over sorafenib — EGD to exclude varices first (bevacizumab bleeding risk).
Sorafenib was the first systemic agent (SHARP trial 2008) — now relegated to later lines.
Post-TACE: monitor for post-embolization syndrome (fever, RUQ pain, transaminitis) — supportive care.
Paraneoplastic erythrocytosis (EPO production) is a classic HCC association.
Fibrolamellar HCC — variant in young patients WITHOUT cirrhosis; better prognosis; surgical resection mainstay.

References

AASLD 2023 — Singal AG et al. AASLD Practice Guidance on Prevention, Diagnosis, and Treatment of Hepatocellular Carcinoma. Hepatology 2023;78:1922-1965
IMbrave150 — Finn RS et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. NEJM 2020;382:1894-1905
SHARP Trial — Llovet JM et al. Sorafenib in Advanced Hepatocellular Carcinoma. NEJM 2008;359:378-390
Milan Criteria — Mazzaferro V et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. NEJM 1996;334:693-699

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