Hepatocellular carcinoma

Primary malignancy of hepatocytes (liver cells), usually arising in a cirrhotic liver. It is the most common primary liver cancer, characterized by highly vascular tumors that often grow and spread rapidly.

• Extremely high global impact and mortality – among the top causes of cancer death worldwide (5-year survival ~18%, second worst after pancreatic). Common end-stage complication of chronic liver diseases (HBV, HCV, alcohol, etc.), so recognizing early signs in at-risk patients (cirrhosis) can enable potentially curative treatment (resection or transplant). Frequently tested on exams due to its classic imaging and lab features and the importance of surveillance in liver disease.

• Often asymptomatic in early stages and detected via screening (e.g. routine ultrasound) in a patient with known cirrhosis. Larger or advanced HCC causes weight loss, RUQ pain, and signs of liver decompensation (new-onset ascites, jaundice, or variceal bleeding) in someone with chronic liver disease.
• Risk factors: Present in 80–90% of cirrhosis cases. Chronic hepatitis B and C are the most common causes worldwide (HBV can cause HCC even *without* cirrhosis). Other major etiologies: heavy alcohol use, non-alcoholic fatty liver disease (NASH/NAFLD), hereditary hemochromatosis (iron overload). In certain regions, aflatoxin B1 exposure (from Aspergillus mold on food) induces a p53 mutation and greatly increases HCC risk (especially with concurrent HBV).
• Patients may show a rising AFP (alpha-fetoprotein) level, which is a tumor marker for HCC (often elevated when tumors are larger; very high AFP is strongly suggestive, though HCC can occur with normal AFP). Physical exam can reveal hepatomegaly or a hepatic mass; a hepatic bruit may be heard due to tumor vascularity. Rare paraneoplastic features include polycythemia (from erythropoietin production) or hypoglycemia.

1. Surveillance: Any patient with cirrhosis (or high-risk HBV carrier) should undergo surveillance every 6 months (ultrasound ± AFP) to detect HCC at an early stage.
2. Imaging diagnosis: If a liver nodule is found, perform a contrast triple-phase CT or dynamic MRI of the liver. HCC classically shows arterial phase hyperenhancement and portal venous (or delayed) phase washout relative to the surrounding liver. This imaging pattern in a high-risk patient is considered diagnostic of HCC (no biopsy needed in typical cases, avoiding needle tract seeding).
3. If imaging findings are not classic or the patient is not known to have cirrhosis, obtain a liver biopsy for definitive diagnosis (histology). Biopsy is also indicated for nodules that are indeterminate by imaging (e.g. LI-RADS category 4 or "materializing" lesions) to distinguish HCC from benign lesions or other malignancies.
4. Always check AFP levels when evaluating a liver mass in a cirrhotic patient. An elevated AFP supports the diagnosis (and very high AFP often indicates more advanced disease), but a normal AFP does not rule out HCC. AFP can also be followed over time (rising AFP in a cirrhotic is worrisome for HCC).
5. Once HCC is diagnosed, stage the disease and assess liver function to guide therapy. Staging systems like BCLC incorporate tumor features (size, number, vascular invasion, metastases), Child-Pugh score (underlying liver function), and performance status. Early-stage, solitary tumors in patients with preserved liver function are candidates for curative therapy (resection or transplant), whereas multifocal or advanced tumors require palliative loco-regional or systemic treatment.

1. If early-stage and localized (BCLC 0 or A): pursue curative therapy. Options include surgical resection of the tumor (ideal for a solitary tumor in a patient with preserved liver function and no portal HTN) or liver transplantation if criteria are met (see Milan criteria). Liver transplant offers best long-term cure for small tumors within transplant criteria, as it also addresses the underlying cirrhosis.
2. For very small tumors (<3 cm) in patients who are not surgical candidates, local ablation can be curative. Radiofrequency ablation (RFA) is most commonly used (burns the tumor in situ); alternatively, percutaneous ethanol injection can be done. These are also used as bridge therapies while awaiting transplant.
3. If intermediate stage (multifocal disease confined to liver, no vascular invasion, good liver function): use loco-regional palliative therapy like TACE (transarterial chemoembolization). TACE involves injecting chemotherapy (or radioembolic beads) into the hepatic artery feeding the tumor and embolizing it, to shrink tumors and prolong survival. TACE is contraindicated in advanced liver failure (Child C) or main portal vein thrombosis due to risk of liver necrosis.
4. If advanced stage (tumor invades blood vessels or has distant metastases, or patient has poorer liver function): systemic therapy is indicated. Traditional first-line is sorafenib (an oral multikinase inhibitor). Newer therapies have improved outcomes: e.g. atezolizumab + bevacizumab (immune checkpoint inhibitor + anti-VEGF antibody) is now a standard first-line combination for unresectable HCC, showing superior survival to sorafenib. Other options include lenvatinib (another first-line TKI), and second-line agents like regorafenib, cabozantinib, or immunotherapies (nivolumab, etc.) in appropriate cases.
5. End-stage disease (diffuse tumor with liver failure, performance status 3–4) is managed with supportive care (symptom control, palliative care), as these patients are unlikely to benefit from aggressive treatments.

• HBV can → HCC without cirrhosis: Unlike most causes, chronic hepatitis B can induce HCC in the absence of cirrhosis (due to HBV DNA integration into hepatocyte genomes). So even non-cirrhotic HBV carriers need surveillance if viral load is high.
• Aflatoxin: Think moldy grains (Aspergillus) in parts of Africa/Asia → aflatoxin B1 causes a specific p53 mutation (G→T transversion) and synergizes with HBV to greatly increase HCC risk. This explains the high HCC incidence in some low-resource settings despite younger age.
• Imaging mnemonic: "Arterial in, portal out" – HCC lesions light up with contrast in arterial phase and then wash out (become hypodense) on portal/delayed phases. Benign hypervascular lesions (like focal nodular hyperplasia or adenoma) may enhance early but typically do not wash out, which helps tell them apart.
• HCC is one of the few cancers often diagnosed non-invasively – if a cirrhotic patient's imaging meets strict criteria, you skip biopsy and treat. (This avoids bleeding or seeding risks of biopsy.)
• Paraneoplastic clue: HCC can secrete erythropoietin, so unexplained polycythemia in a cirrhotic patient with a liver mass is a classic board hint.

• Any sudden decompensation in a cirrhotic (worsening ascites, abrupt weight loss, abdominal pain, jaundice or encephalopathy) should raise concern for HCC development. In a stable cirrhotic, these are red flags prompting imaging.
• Portal vein thrombosis on imaging in a patient with liver disease – this may indicate tumor invasion into the portal vein (tumor thrombus), which signals advanced HCC and a poor prognosis.
• Very high AFP levels (≥ 500 ng/mL, for example) in a cirrhotic patient strongly suggest HCC and often correlate with more aggressive disease. Also, any HCC >5 cm, or multifocal tumors, or the presence of vascular invasion/extrahepatic spread are poor prognostic signs.
• Bone pain in a patient with known HCC → suspect bone metastases (common metastatic site along with lung); new cough or chest lesions might indicate lung metastases. HCC spread often signifies limited survival.

1. Chronic liver disease (cirrhosis from any cause, or chronic HBV) → enroll in regular HCC surveillance (ultrasound ± AFP every 6 months).
2. If nodule detected on screening imaging → evaluate with high-quality contrast CT or MRI of liver. Look for the characteristic arterial enhancement and venous washout pattern. Check AFP as well.
3. If imaging is diagnostic of HCC (typical pattern in a high-risk patient) → confirm staging and begin management (no biopsy needed). If imaging is inconclusive or patient low-risk, get a biopsy of the lesion for diagnosis.
4. After diagnosis, perform full staging: imaging of chest/abdomen to check for multifocal disease or metastases; assess portal vein patency; determine Child-Pugh class and performance status. Use a staging system (e.g. BCLC) to guide therapy stratification.
5. Treatment decision tree: Early stage (resectable) → surgical resection (if one tumor and good liver reserve) or liver transplant (if within Milan criteria). Intermediate stage (multinodular, liver-limited) → loco-regional therapy (TACE, radioembolization). Advanced stage (vascular invasion or metastases) → systemic therapy (targeted TKIs or immunotherapy). End-stage (poor liver function, PS) → supportive care.

• Middle-aged patient with long-standing HCV cirrhosis (or alcoholic cirrhosis) who now has unintentional weight loss, an enlarging RUQ mass, and elevated AFP → HCC (suspect when a cirrhotic patient's condition suddenly worsens or a new mass is found). Imaging will show arterial enhancement and washout confirming the diagnosis.
• A patient from an HBV-endemic region (e.g. East Asia or sub-Saharan Africa), 35 years old with chronic hepatitis B (± mild cirrhosis), develops abdominal distension and weight loss. Exam finds hepatomegaly. This scenario suggests HCC due to untreated HBV (possibly compounded by aflatoxin exposure if diet factors). Such patients often present late with large tumors given limited surveillance.