HCC

**Epidemiology & Risk Factors** - Most common primary liver cancer in adults; male > female. - Cirrhosis of any cause is the main risk factor: chronic HBV (can cause HCC even without cirrhosis, via viral DNA integration), HCV, alcohol, MASLD/NASH (metabolic dysfunction-associated steatotic liver disease), hemochromatosis, alpha-1 antitrypsin deficiency, primary biliary cholangitis (less so), Wilson disease (rare). - Aflatoxin B1 (from Aspergillus flavus; contaminated grains/peanuts) causes a p53 mutation (codon 249 G→T transversion); this is a classic board association. - Other: androgenic anabolic steroids, tyrosinemia, glycogen storage disease.

**Pathophysiology** - Chronic inflammation, hepatocyte injury, regeneration, fibrosis, and then dysplastic nodules, leading to carcinoma. - Tumors spread by local invasion, portal vein invasion (tumor thrombus), and hepatic vein invasion. Can extend to the IVC and right atrium. Metastases go to lung and bone.

**Clinical Presentation** - Often asymptomatic and found on surveillance. May present with RUQ pain, weight loss, early satiety, hepatomegaly, or sudden decompensation of previously stable cirrhosis (new ascites, encephalopathy, variceal bleeding). - Paraneoplastic syndromes: erythrocytosis (EPO), hypoglycemia, hypercalcemia (PTHrP), watery diarrhea, and hypercholesterolemia. - Budd-Chiari syndrome can occur with hepatic vein invasion. - Rupture can cause hemoperitoneum.

**Diagnosis** - Serum AFP is elevated (>400-500 ng/mL is highly suggestive), but it is neither sensitive nor specific. - Multiphasic CT or MRI: arterial-phase hyperenhancement with portal/delayed-phase washout (LI-RADS 5). In cirrhotic patients this is diagnostic without biopsy. - Biopsy is reserved for atypical imaging because of the risk of tract seeding. - Histology: polygonal cells in trabecular/plate-like patterns, with bile production and Mallory bodies possible.

**Screening** - Ultrasound ± AFP every 6 months in patients with cirrhosis and in high-risk chronic HBV carriers (for example, Asian males >40, Asian females >50, African ancestry, or family history of HCC).

**Management** - Staging uses BCLC (considers tumor burden, liver function by Child-Pugh, and performance status). - Early disease: resection (if noncirrhotic or preserved function), ablation (RFA/microwave), or liver transplant (Milan criteria: single tumor ≤5 cm, or up to 3 tumors each ≤3 cm, no vascular invasion). - Intermediate disease: TACE (transarterial chemoembolization). - Advanced disease: systemic therapy. Current first-line options include atezolizumab + bevacizumab and durvalumab + tremelimumab. Sorafenib and lenvatinib are tyrosine kinase inhibitors used in some settings.

**Prevention** - HBV vaccination (the first vaccine to prevent a cancer), antiviral treatment of HBV/HCV, alcohol cessation, and control of metabolic risk factors.

**High-Yield Differentials** - Hepatic adenoma: associated with oral contraceptives and anabolic steroids, and can rupture or bleed. - Cholangiocarcinoma: associated with liver flukes (Clonorchis sinensis), primary sclerosing cholangitis, and Thorotrast. Typically has elevated CA 19-9. - Hepatic angiosarcoma: associated with vinyl chloride, arsenic, and Thorotrast. - Liver metastases (for example, from colon cancer) are more common than primary liver cancer overall.

**Note:** HCC can also stand for "hierarchical condition category," a risk-adjustment coding model used by CMS, or for "hypothalamic–pituitary" topics in other contexts. For USMLE, it almost always means hepatocellular carcinoma.