What is the incidence of hepatocellular carcinoma in patients with metabolic‑dysfunction‑associated steatohepatitis (MASH) who have fibrosis (stage F2‑F3) but no cirrhosis?

Incidence of HCC in MASH Patients with Non-Cirrhotic Fibrosis (F2-F3)

The incidence of HCC in MASH patients with fibrosis stages F2-F3 but no cirrhosis is extremely low, ranging from 0.08 to 0.63 per 1,000 person-years overall, with the highest risk (2.3-2.8 per 1,000 person-years) concentrated in those with F3 (bridging fibrosis) and elevated FIB-4 scores >2.67. 1

Overall Incidence in Non-Cirrhotic MASH

The 2024 EASL-EASD-EASO guidelines establish that HCC incidence in MASH patients without cirrhosis is very low, ranging from 0.08 to 0.63 per 1,000 person-years across multiple cohort studies. 1 A recent 10-year follow-up study found only 2.7% cumulative HCC incidence in non-cirrhotic MASLD patients. 1

In a Swedish histologically-confirmed MASLD cohort, the HCC rate for fibrosis stages F1-F3 combined (without cirrhosis) was 2.3 per 1,000 person-years, compared to 6.2 per 1,000 person-years in cirrhosis. 1 This represents approximately one-third the risk of cirrhotic patients.

Risk Stratification by Fibrosis Stage

F2 Fibrosis (Moderate Fibrosis)

The incidence of HCC in MASLD patients with F2 fibrosis (stage 0-2) is extremely low, and determinants of risk have not been well quantified. 1 The guidelines explicitly state that HCC incidence in earlier stages of fibrosis (stage 0-2) is too low to justify routine screening. 1

F3 Fibrosis (Bridging Fibrosis)

Patients with F3 fibrosis have an intermediate risk of developing HCC that is lower than cirrhosis but not negligible. 1

Specific incidence rates for F3 fibrosis include:

• 2.8 per 1,000 person-years when FIB-4 >2.67 1
• 0.39 per 1,000 person-years when FIB-4 >2.67 in Veterans Affairs cohort (compared to 0.04 per 1,000 person-years with persistently low FIB-4) 1
• Risk exceeds 1% per year when FIB-4 >3.25 1

Non-Invasive Test Thresholds for Risk Assessment

The guidelines emphasize using non-invasive tests to identify highest-risk non-cirrhotic patients:

FIB-4 Score Stratification:

• FIB-4 >3.25: HCC risk >1% per year (approaching surveillance threshold) 1
• FIB-4 >2.67: Annual HCC incidence 2.8 per 1,000 person-years 1
• FIB-4 <1.30: Annual HCC incidence 0.7 per 1,000 person-years 1

Liver Stiffness Measurement (LSM):

• Baseline LSM >10 kPa with increasing change over time in patients with histologic F3-F4 fibrosis: Hazard ratio 1.72 for HCC development 1

Clinical Context: Surveillance Implications

Current guidelines do not recommend routine HCC surveillance in MASH patients without cirrhosis, even with F2-F3 fibrosis, because the incidence remains below the cost-effectiveness threshold of 1.0-1.5% per year. 1 However, the guidelines acknowledge that F3 patients represent an intermediate-risk group where surveillance decisions are harder and less favorable from a cost-effectiveness standpoint. 1

The 2024 EASL guidelines state there is insufficient evidence to warrant HCC surveillance in individuals with MASLD without cirrhosis, and systematic reviews concluded the risk estimate is too low to justify routine screening without evidence of advanced fibrosis. 1

Additional Risk Modifiers in Non-Cirrhotic MASH

Beyond fibrosis stage, several factors increase HCC risk in non-cirrhotic MASH patients:

• Type 2 diabetes and obesity: Associated with increased HCC risk in large cohort studies, though the absolute increase in HCC risk attributable to metabolic factors in non-cirrhotic MASLD is very small 1
• Older age: Consistently associated with higher HCC incidence 1
• Male sex: Increases likelihood of HCC development 2
• Concurrent alcohol intake and smoking: Accelerate HCC risk 1

Important Clinical Caveats

HCC in non-cirrhotic MASH presents differently than in cirrhotic patients:

• More frequently presents as larger nodules (>5 cm in 77.8% vs. 10.6% in cirrhotic patients) 3
• Higher rate of HCC recurrence (86% vs. 14% in cirrhotic patients) 3
• Less likely to undergo curative treatments due to lack of surveillance 1
• Only one in six non-cirrhotic MASH-HCC patients underwent curative treatment in one case series 1

The proportion of MASH-related HCC occurring without cirrhosis is substantial: Studies show cirrhosis is absent in 38-49% of individuals with MASLD-related HCC in Japanese cohorts, and 14.2% in a large US Veterans Affairs study. 1, 2, 4 This indicates that while the incidence per patient is low, a meaningful proportion of MASH-HCC cases arise in non-cirrhotic livers.