The patient undergoes a mammogram, which shows a 6.5mm sized mass with an irregular border and spiculated margins. A subsequent core needle biopsy of the mass shows infiltrating ductal carcinoma with HER2-positive, estrogen-negative, and progesterone-negative immunohistochemistry staining. Blood counts and liver function tests are normal. Laboratory studies show: Hemoglobin 12.5 g/dL Serum Na+ 140 mEq/L Cl- 103 mEq/L K+ 4.2 mEq/L HCO3- 26 mEq/L Ca2+ 8.9 mg/dL Urea Nitrogen 12 mg/dL Glucose 110 mg/dL Alkaline Phosphatase 25 U/L Alanine aminotransferase (ALT) 15 U/L Aspartate aminotransferase (AST) 13 U/L Which of the following is the most appropriate next step in management?

Breast-conserving therapy and sentinel lymph node biopsy

Bilateral mastectomy with lymph node dissection

A scientist is researching the long term effects of the hepatitis viruses on hepatic tissue. She finds that certain strains are oncogenic and increase the risk of hepatocellular carcinoma. However, they appear to do so via different mechanisms. Which of the following answer choices correctly pairs the hepatitis virus with the correct oncogenic process?

Hepatitis B virus - integration of viral DNA into host hepatocyte genome

Hepatitis A virus - chronic inflammation

Hepatitis C virus - chronic inflammation

Hepatitis E virus - integration of viral DNA into host hepatocyte genome

Hepatitis A virus - integration of viral DNA into host hepatocyte genome

A 56-year-old African American presents to the emergency department due to abdominal pain, fatigue, and weight loss over the past 3 months. He has a long-standing history of chronic hepatitis B virus infection complicated by cirrhosis. On examination, he has jaundice, leg edema, and a palpable mass in the right upper abdominal quadrant. Abdominal ultrasound shows a 3-cm liver mass with poorly defined margins and coarse, irregular internal echoes. Lab results are shown: Aspartate aminotransferase (AST) 90 U/L Alanine aminotransferase (ALT) 50 U/L Total bilirubin 2 mg/dL Albumin 3 g/dL Alkaline phosphatase 100 U/L Alpha-fetoprotein 600 ng/mL Which of the following is a feature of this patient's condition?

It arises from the bile duct epithelium

Daughter cysts are usually present on abdominal ultrasound

Liver biopsy is required for diagnosis in a majority of patients

Doppler blood flow shows venous pattern

A 27-year-old woman presents to the emergency department complaining of a left-sided headache and right-sided blurry vision. She states that 2 weeks ago she developed dark urine and abdominal pain. She thought it was a urinary tract infection so she took trimethoprim-sulfamethoxazole that she had left over. She planned on going to her primary care physician today but then she developed headache and blurry vision so she came to the emergency department. The patient states she is otherwise healthy. Her family history is significant for a brother with sickle cell trait. On physical examination, there is mild abdominal tenderness, and the liver edge is felt 4 cm below the right costal margin. Labs are drawn as below: Hemoglobin: 7.0 g/dL Platelets: 149,000/mm^3 Reticulocyte count: 5.4% Lactate dehydrogenase: 3128 U/L Total bilirubin: 2.1 mg/dL Indirect bilirubin: 1.4 mg/dL Aspartate aminotransferase: 78 U/L Alanine aminotransferase: 64 U/L A peripheral smear shows polychromasia. A Doppler ultrasound of the liver shows decreased flow in the right hepatic vein. Magnetic resonance imaging of the brain is pending. Which of the following tests, if performed, would most likely identify the patient’s diagnosis?

Glucose-6-phosphate-dehydrogenase levels

A 52-year-old man presents to his physician after his routine screening revealed that he has elevated liver enzymes. He complains of occasional headaches during the past year, but otherwise feels well. The patient reports that he was involved in a serious car accident in the 1980s. He does not smoke or drink alcohol. He has no history of illicit intravenous drug use. He does not currently take any medications and has no known allergies. His father had a history of alcoholism and died of liver cancer. The patient appears thin. His temperature is 37.8°C (100°F), pulse is 100/min, and blood pressure is 110/70 mm Hg. The physical examination reveals no abnormalities. The laboratory test results show the following: Complete blood count Hemoglobin 14 g/dL Leukocyte count 10,000/mm3 Platelet count 146,000/mm3 Comprehensive metabolic profile Glucose 150 mg/dL Albumin 3.2 g/dL Total bilirubin 1.5 mg/dL Alkaline phosphatase 75 IU/L AST 95 IU/L ALT 73 IU/L Other lab tests HIV negative Hepatitis B surface antigen negative Hepatitis C antibody positive HCV RNA positive HCV genotype 1 A liver biopsy is performed and shows mononuclear infiltrates localized to portal tracts that reveal periportal hepatocyte necrosis. Which of the following is the most appropriate next step in management?

Sofosbuvir and ledipasvir therapy

Interferon and ribavirin therapy

Tenofovir and entecavir therapy

Tenofovir and velpatasvir therapy

Hepatocellular carcinoma for USMLE Step 3: High-Yield Internal Medicine Lessons

Etiology & Risks - Seeds of Malignancy

Cirrhosis: The single most dominant risk factor. Over 80% of HCC cases arise from pre-existing cirrhosis, regardless of the underlying cause.
Chronic Viral Hepatitis:
- Hepatitis B (HBV): Directly oncogenic.
- Hepatitis C (HCV): Induces HCC primarily via cirrhosis.
Metabolic & Toxic insults:
- Non-alcoholic fatty liver disease (NAFLD/NASH).
- Alcohol-related liver disease.
- Aflatoxin B1 exposure (Aspergillus mold).
Genetic Disorders:
- Hereditary Hemochromatosis.
- Alpha-1 antitrypsin deficiency.

⭐ HBV can cause HCC without cirrhosis by integrating its DNA into host hepatocytes.

Pathways to Hepatocellular Carcinoma

Clinical Presentation - The Silent Progression

Often asymptomatic until advanced stages, growing silently within a cirrhotic liver.
Sudden decompensation in a previously stable cirrhotic patient is a classic red flag.
- New or worsening ascites, jaundice, or hepatic encephalopathy.
Nonspecific constitutional symptoms may appear late:
- RUQ pain or a palpable mass.
- Significant, unintentional weight loss.
- Early satiety.
Paraneoplastic Syndromes can be the first sign:
- Erythrocytosis (↑EPO)
- Hypercalcemia (↑PTHrP)
- Hypoglycemia
- Watery diarrhea, hypokalemia (↑VIP)

⭐ Suspect HCC in any patient with cirrhosis who suddenly decompensates.

Diagnosis & Staging - The Malignancy Map

Screening (At-Risk: Cirrhosis):
- Ultrasound +/- AFP every 6 months.
Diagnosis:
- Imaging: Multiphasic CT/MRI is key.
  - Arterial phase hyperenhancement.
  - Venous/delayed phase washout.
- Tumor Markers:
  - AFP >20 ng/mL is suggestive.
  - AFP >400 ng/mL is highly specific.
- LI-RADS: Standardizes reporting on imaging.

⭐ In a cirrhotic patient, classic imaging findings (arterial hyperenhancement, venous washout) are diagnostic for HCC, making a biopsy often unnecessary.

HCC on multiphasic CT: arterial hyperenhancement, washout

Staging: Barcelona Clinic Liver Cancer (BCLC) system guides treatment.

Management - The Treatment Gauntlet

Treatment is stratified by the Barcelona Clinic Liver Cancer (BCLC) staging system, guiding the therapeutic approach from curative to palliative intent.

Early Stage (Curative): Resection, liver transplant (within Milan criteria: 1 tumor <5 cm, or ≤3 tumors <3 cm), or ablation (RFA/MWA).
Intermediate Stage:

⭐ Trans-arterial chemoembolization (TACE) is the standard for multifocal HCC without vascular invasion or metastasis. It is palliative, not curative, but can bridge patients to transplant.
Advanced/Terminal Stage: Systemic therapy (e.g., Atezolizumab + Bevacizumab) for advanced disease; best supportive care for terminal illness.

High-Yield Points - ⚡ Biggest Takeaways

Chronic hepatitis B/C and cirrhosis are the primary risk factors.

Screen high-risk patients with ultrasound +/- AFP every 6 months.

Alpha-fetoprotein (AFP) is the key tumor marker, but can be normal.

Hallmark on imaging: arterial phase hyperenhancement and portal venous washout.

Early-stage disease may be cured with resection or transplantation.

Advanced HCC is treated with tyrosine kinase inhibitors like sorafenib.

Associated with paraneoplastic syndromes like erythrocytosis and hypercalcemia.

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