Hepatocellular carcinoma in patients without cirrhosis

Table 1 Non-cirrhotic hepatocellular carcinoma characteristics vs cirrhotic counterparts

Ref.	Population	Prevalence (%)	General characteristics	Tumor characteristics	Outcome
Gawrieh et al[11]	605 HCC non-cirrhotic; 4539 HCC cirrhotic	11.7	Older age, lower prevalence of T2DM and obesity	Large tumor size, higher prevalence of advanced tumor stage, being outside the Milan criteria, and vascular invasion	Better OS at 1 and 3 years, but no difference at 5 years
Pinyopornpanish et al[12]	290 HCC non-cirrhotic; 1947 HCC cirrhotic	13	Older age, higher prevalence of HTN, hyperlipidemia	Large tumor size, higher prevalence being outside the Milan criteria. Lower prevalence of vascular invasion	Better OS
Sigurdsson et al[16]	49 HCC non-cirrhotic; 152 HCC cirrhotic	N/A	No difference in age between the groups	Large tumor size, lower prevalence of portal vein thrombosis	No difference in OS between the groups
Engstran et al[17]	1431 HCC non-cirrhotic; 2828 HCC cirrhotic	34	Older age	Large tumor size, higher prevalence of advanced disease	Worse OS, irrespective of the treatment
Van Meer et al[19]	238 HCC non-cirrhotic; 983 HCC cirrhotic	19	No difference in age between the groups	Larger tumor size, higher prevalence of advanced stages	N/A
Karaoğullarından et al[21]	82 HCC non-cirrhotic; 138 HCC cirrhotic	37.3	No difference in age between the groups	No difference in tumor size and morphology. Lower prevalence of vascular and portal vein invasion	Better OS at 1, 3, and 5 years
Araz et al[22]	42 HCC non-cirrhotic; 146 HCC cirrhotic	22.3	No difference in age between the groups	Large tumor size	Better OS, PFS, and DFS
Yen et al[28]	259 HCC non-cirrhotic; 1796 HCC cirrhotic	25.7	Younger age	Large tumor size	Better OS at 5 years
Altshuler et al[65]	Unresectable HCC: 264 non-cirrhotic; 1230 cirrhotic	17.7	Older age, higher prevalence of HTN and CAD	Large tumor size, higher prevalence of distant metastasis	No difference in OS or PFS between groups
Chen et al[66]	26 HCC-non-cirrhotic; 85 HCC cirrhotic	23.4	No difference in age between the groups	Large tumor size, higher prevalence of vascular invasion, and being outside the Milan criteria.	No difference in OS, RFS, and bleeding-free survival between the groups
Schütte et al[68]	93 HCC non-cirrhotic; 571 HCC cirrhotic	14	Older age, higher prevalence of T2DM and HTN	More advanced tumor stage	No difference in OS between the groups
Donica et al[69]	4545 HCC non-cirrhotic; 18592 HCC cirrhotic	19.6	Older age	Large tumor size, higher prevalence of localized disease	Better OS
Vitellius et al[71]	124 MASLD-HCC non-cirrhotic; 230 MASLD-HCC cirrhotic	35	Older age, lower prevalence of T2DM	Large tumor size, lower prevalence of portal vein thrombosis	Better OS
Pommergaard et al[72]	HCC underwent LT: 792 non-cirrhotic; 21995 cirrhotic	3.5	Younger age	Large tumor size	Worse OS

CAD: Coronary artery disease; DFS: Disease-free survival; HCC: Hepatocellular carcinoma; HTN: Hypertension; LT: Liver transplantation; MASLD: Metabolic dysfunction-associated steatotic liver disease; N/A: Not available; OS: Overall survival; PFS: Progression-free survival; RFS: Recurrence-free survival; T2DM: Type 2 diabetes.

Table 2 Recommendations for hepatocellular carcinoma screening and surveillance by medical societies

Medical societies	Cirrhotic individuals		Non-cirrhotic individuals		Both populations
	At-risk population	Additional notes	At-risk population	Additional notes	Surveillance tests	Frequency
EASL[8]	Individuals with Child-Pugh A and B, or Child-Pugh C if awaiting LT	N/A	Chronic HBV infection with PAGE-B score ≥ 10	No current recommendation for individuals with chronic liver disease and advanced fibrosis without cirrhosis	Ultrasound ± AFP	Every 6 months
AASLD[9]	Individuals with Child-Pugh A or B with any etiology, and Child-Pugh C if awaiting LT	CT or MRI is suggested if limited liver visualization with ultrasound	Chronic HBV infection: From endemic countries (women > 50 years old and men > 40 years old); From Africa at an earlier age; Family history of HCC; PAGE-B Score ≥ 10	Same as the cirrhotic population	Ultrasound ± AFP	Every 6 months
AGA[10]	All individuals with cirrhosis	CT or MRI is suggested if limited liver visualization with ultrasound	N/A	Screening should be considered in advanced liver fibrosis	Ultrasound ± AFP	Every 6 months
NCCN[86]	Individuals with Child-Pugh A or B with any etiology, and Child-Pugh C if awaiting LT	CT or MRI is suggested if limited liver visualization with ultrasound	Chronic HBV infection: Asian women > 50 years old and men > 40 years old); Family history of HCC; African/North American Blacks	Same as the cirrhotic population	Ultrasound ± AFP	Every 6 months
ESMO[85]	All individuals with cirrhosis	N/A	Chronic HBV infection with moderate to high HCC risk score at the onset of nucleoside analogue therapy	N/A	Ultrasound ± AFP	Every 6 months
BSG[84]	All individuals with cirrhosis	N/A	Chronic HBV infection: From endemic countries (women > 50 years old and men > 40 years old); Family history of HCC; African Black people	No current recommendation for individuals with non-cirrhotic MASLD	Ultrasound + AFP	Every 6 months
APASL[82]	All individuals with cirrhosis	N/A	Chronic HBV infection: From endemic countries (women > 50 years old and men > 40 years old); Family history of HCC; African individuals > 20 years old	No current recommendation for chronic HCV individuals with bridging fibrosis	Ultrasound ± AFP	Every 6 months
JSH[83]	All individuals with cirrhosis	Individuals with cirrhosis type B and C should undergo dynamic CT/MRI every 6-12 months, which is optional	Individuals with chronic HBV and HCV	N/A	Ultrasound + tumor marker	Every 6 months for chronic hepatitis B/C and non-viral cirrhosis; Every 3-4 months for cirrhosis types B and C

AASLD: American Association for the Study of Liver Disease; AFP: Alpha fetoprotein; AGA: American Gastroenterological Association; APASL: Asia-Pacific Association for the Study of the Liver; BSG: British Society of Gastroenterology; CT: Computed tomography; EASL: European Association for the Study of the Liver; ESMO: European Society of Medical Oncology; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; JSH: Japanese Society of Hepatology; LT: Liver transplantation; MRI: Magnetic resonance imaging; N/A: Not available; NAFLD: Non-alcoholic fatty liver disease; NCCN: National Cancer Comprehensive Network; PAGE-B: Platelet-age-gender-hepatitis B virus.

Table 3 Summary of the scores and stage systems in individuals with non-cirrhotic hepatocellular carcinoma

	Controversies	Limitations	Research hotspots
Scores and stage systems
BCLC	New update in 2022, introducing more flexibility and personalized treatment decisions with no strictly stage-based approach could be advantageous for individuals without cirrhosis	Primarily focus on individuals with underlying chronic liver disease, especially with cirrhosis. Not validated in non-cirrhotic individuals	Studies validated the BCLC stage systems in non-cirrhotic individuals with HCC, which evaluate treatment options, long-term outcomes, and explicitly stratified categories for those individuals are needed
Child-Pugh	The use of ascites and encephalopathy may be underestimated due to the common presentation of preserved liver functions observed in individuals without cirrhosis	Designed to evaluate the severity and prognosis in individuals with cirrhosis. Not validated in non-cirrhotic individuals	Studies that validate the Child-Pugh score in individuals with HCC without cirrhosis are needed; Creating a new score potentially without ascites and encephalopathy is needed to compare if the individuals are being underestimated
TNM	It is a valuable staging system for anatomical tumor burden, but is not sufficient alone for accurate HCC treatment guidance or outcomes	Focus on anatomical staging; Best for post-operative prognosis	Studies redefining TNM, evaluating treatment responses, and long-term outcomes are needed
HKLC	Proposed more aggressive treatments with more curative therapy but with potential risk of over-treatment	Developed based on a population predominantly with hepatitis B; Not well validated with other etiologies	Studies validating the stage system in diverse populations with different background etiologies are needed; Studies evaluating treatment options and long-term outcomes are needed
LI-RADS	Only individuals with hepatitis B or cirrhosis benefit from this, but individuals outside these criteria may be leading to a missed diagnosis. No consensus on biopsy, follow-up time, or surveillance in intermediate categories	Designed for individuals with cirrhosis or with HCC-associated hepatitis B; Not well validated with other etiologies	Studies validating the diagnosis in populations with different background etiologies are needed; Studies integrating LI-RADS with biomarkers to improve early HCC detection are needed

BCLC: Barcelona Clinic Liver Cancer; HCC: Hepatocellular carcinoma; HKLC: Hong Kong liver cancer; LI-RADS: Liver imaging reporting and data system TNM: Tumor-node-metastasis.

Table 4 Clinical comparison of individuals with and without cirrhosis with hepatocellular carcinoma in systemic therapy

	Cirrhotic	Non-cirrhotic
Liver function	Impaired (Child-Pugh A, B, C)	Preserved
Therapeutic flexibility	Limited	Higher freedom for the TKI and IO combination
Toxicity risk	High (decompensation, bleeding, and encephalopathy)	Low (better tolerance)
Clinical trial inclusion	Most Child-Pugh A (B or C are typically excluded)	No well-classified
TKI use	Reduced dose in Child-Pugh B, and avoided in Child-Pugh C	Full dose (according to guidelines)
IO	Can be used in Child-Pugh A, but has uncertain use in Child-Pugh B or C	Well tolerated (first-line treatment)
Treatment goals	Controlling the tumor while maintaining liver function	Aggressive tumor control; Potential cure
Liver transplant eligibility	Yes, it is within the criteria (e.g., Milan criteria)	Usually not applicable
Prognosis	Hepatic functional reserve is more critical than tumor stage	Determined by tumor size and stage

IO: Immunotherapy; TKI: Tyrosine kinase inhibitor.

Table 5 Summary of available clinical trials on systemic therapy in individuals with hepatocellular carcinoma

Clinical trials	Treatment	Child-Pugh score	Cirrhosis status reported?	Key notes
SHARP[113]	Sorafenib vs placebo	Only A	Not mentioned, but approximately 95% with cirrhosis	First trial to show OS benefit with systemic therapy in advanced HCC
REFLECT[115]	Lenvatinib vs sorafenib	Only A	Reported, but not explained	Individuals with more than 50% liver involvement or main portal vein invasion were excluded
IMBRAVE150[116]	Atezolizumab + bevacizumab vs sorafenib	Only A	Not mentioned, but primarily cirrhotic	Untreated high-risk variceal individuals were excluded
HIMALAYA[117]	Durvalumab +/- tremelimumab vs sorafenib	Only A	Not specified	Primarily MASLD or viral causes, without subclassifying for cirrhosis
CARES-310[118]	Camrelizumab + rivoceranib vs sorafenib	Only A (A5 & A6)	Most had cirrhosis	Excluded patients at high risk for GI bleeding, including varices

CARES-310: Camrelizumab plus rivoceranib as first-line therapy for unresectable hepatocellular carcinoma; GI: Gastrointestinal; HCC: Hepatocellular carcinoma; MASLD: Metabolic dysfunction-associated steatotic liver disease; OS: Overall survival; SHARP: Sorafenib hepatocellular carcinoma assessment randomized protocol.