What is malignant hepatitis (primary liver cancer) and how should it be evaluated and managed?

Malignant Hepatitis (Hepatocellular Carcinoma)

Definition and Clinical Context

"Malignant hepatitis" is not standard medical terminology; the correct term is hepatocellular carcinoma (HCC), which is the most common primary malignancy of the liver in adults and the third leading cause of cancer-related death worldwide. 1

HCC is fundamentally different from viral hepatitis or inflammatory liver disease—it is a primary liver cancer that arises from hepatocytes. 1, 2 The term "malignant hepatitis" may cause confusion because it conflates inflammatory liver disease with cancer; HCC is associated with cirrhosis in 80% of cases, but 20% develops in non-cirrhotic livers. 1, 3

Epidemiology and Risk Factors

• HCC incidence is rising steadily in the United States and Europe, with rates of 2-5 per 100,000 per year, driven primarily by hepatitis C viral infection and other causes of hepatic cirrhosis. 1

• The major risk factors include chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, cirrhosis from any cause, nonalcoholic fatty liver disease (NAFLD), aflatoxin exposure, and tobacco smoking. 4, 3

• More than 70% of HCC patients present with advanced disease, making them ineligible for curative treatments like resection or transplantation. 1

Diagnostic Approach

Non-Invasive Diagnosis

In patients with cirrhosis, HBV infection, or previous HCC, a liver nodule can be diagnosed non-invasively as HCC when major imaging features are observed on contrast-enhanced CT, MRI, or contrast-enhanced ultrasound (CEUS). 1

• Use LI-RADS CT/MRI v2018 or LI-RADS CEUS v2017 criteria for standardized diagnosis. 1

• Major imaging features for CT/MRI include: tumor size, rim and non-rim arterial hyperenhancement, peripheral and non-peripheral washout in portal venous or delayed phases, enhancing capsule, and threshold growth. 1

• For CEUS: non-rim arterial hyperenhancement with late-onset (>60 seconds) washout of mild intensity. 1

Histopathological Confirmation

HCC diagnosis should be confirmed by tumor biopsy when non-invasive imaging criteria are not met or when the additional information will influence therapeutic decisions. 1

• Except in cirrhotic patients with alpha-fetoprotein (AFP) >500 mg/mL, histopathological examination of liver tissue obtained by open surgery, laparoscopy, or image-guided biopsy is the diagnostic standard. 1

• Fine-needle aspiration cytology is an option when core biopsy is not feasible. 1

Staging Evaluation

Standard Staging Work-Up

Assessment of locoregional extension requires clinical examination, liver ultrasonography, and hepatic CT scanning as standard investigations. 1

• MRI of the liver is an optional alternative imaging modality. 1

• Distant metastasis evaluation includes chest X-ray (CXR), spiral CT, and bone scan if clinically indicated. 1

• If liver transplant is planned and CXR is normal, obtain thoracic CT scan. 1

Hepatic Function Assessment

Evaluate hepatic function with liver enzyme levels, serum albumin, and coagulation screen as standard tests. 1

In cirrhotic patients, perform endoscopy to exclude esophagogastric varices. 1

Biomarkers

• AFP remains useful but has limitations; the GALAD score (combining AFP, AFP-L3, DCP, age, and gender) shows pooled sensitivity of 0.78 and specificity of 0.80 for detecting early-stage HCC in cirrhotic patients, but requires further validation before routine clinical use. 1

Classification Systems

Primary HCC is classified according to WHO classification as the standard approach. 1

• For surgical resection candidates, use TNM classification, where multiple tumors, large diameter, vascular invasion, and nodal involvement are adverse prognostic factors. 1

• The Child-Pugh classification is the standard for assessing underlying liver disease severity. 1

• For non-operable patients, the Okuda clinical classification system can be used, though it has recognized limitations. 1

• The Barcelona Clinic Liver Cancer (BCLC) Staging System remains the most widely used classification for HCC management guidelines. 4

Morphological Subtypes with Prognostic Significance

Eight distinct morphological subtypes beyond "not otherwise specified" (NOS-HCC) have significant prognostic implications: fibrolamellar, scirrhous, clear cell, steatohepatitic, macrotrabecular/massive, chromophobe, neutrophil-rich, and lymphocytic-rich. 5

• Macrotrabecular/massive HCC is associated with poor prognosis and aggressive behavior. 5

• Lymphocytic-rich HCC is associated with better prognosis. 5

• Fibrolamellar HCC typically occurs in younger patients without cirrhosis. 5

• Steatohepatitic HCC displays features of steatohepatitis and may present diagnostic challenges on imaging. 5

Treatment Modalities

Surgical Options

Resection is indicated for HCC in a cirrhotic liver when the tumor is single, non-metastatic, without portal invasion, and liver function permits the necessary excision. 1

For HCC in a healthy (non-cirrhotic) liver, partial hepatectomy is the only surgical option when there is no vascular involvement, no extrahepatic spread, and the tumor is unifocal. 1

• Elective incomplete excision should be avoided. 1

• Liver transplantation is considered for unifocal HCC <3 cm diameter in cirrhotic patients, though availability of donor organs and waiting times remain limiting factors. 1, 2

Locoregional Therapies

Percutaneous techniques (intratumoral injections of absolute alcohol or acetic acid) or radiofrequency ablation are alternatives when surgery is not possible. 1

• Tumor ablation by alcohol injection or radiofrequency ablation is associated with favorable outcomes and may be considered potentially curative treatment for small tumors. 2

Chemoembolization is not recommended as standard treatment for HCC, as it has no proven survival benefit over no therapy or systemic chemotherapy. 1

Systemic Therapy

Only one chemotherapeutic agent (sorafenib, a tyrosine kinase inhibitor) is approved for advanced HCC, benefiting only 30% of patients with a modest (~3 months) increase in overall survival and causing drug resistance within 6 months. 1, 6

Key Clinical Pitfalls

• Do not assume "malignant hepatitis" refers to severe viral hepatitis; clarify whether the patient has HCC (primary liver cancer) versus acute liver failure from viral or autoimmune hepatitis. 1

• Do not delay biopsy when imaging is equivocal; non-invasive criteria have not been pathologically validated in advanced-stage tumors. 1

• Do not overlook HCC in non-cirrhotic patients, particularly those with chronic HBV infection, advanced HCV-related fibrosis, or metabolic syndrome, as 20% of HCC arises without cirrhosis. 3

• Do not rely solely on AFP for diagnosis; up to 40% of early HCC cases have normal AFP levels. 1

• Early diagnosis remains the key goal because identifying HCC at an asymptomatic stage is associated with better treatment options and improved prognosis. 2