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Hepatocellular carcinoma in F0 livers: Clinical and prognostic insights
Mizuki Endo, Koichi Honda, Tomoko Tokumaru, Tomoko Saito, Takuro Uchida, Masao Iwao, Mie Arakawa, Masataka Seike, Masaaki Kodama, Takashi Masuda, Yuichi Endo, Masafumi Inomata, Kazunari Murakami, Kazuhiro Mizukami
Mizuki Endo, Koichi Honda, Tomoko Tokumaru, Tomoko Saito, Masao Iwao, Mie Arakawa, Masataka Seike, Masaaki Kodama, Kazunari Murakami, Kazuhiro Mizukami, Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu 879-5593, Japan
Takuro Uchida, Division of Travel Medicine and Health, Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University, Yufu 879-5593, Japan
Takashi Masuda, Yuichi Endo, Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Yufu 879-5593, Japan
Masafumi Inomata, Department of Gastroenterological and Pediatric Surgery, Oita University, Yufu 879-5593, Japan
Author contributions: Endo M conceptualized and designed the study, performed data analysis, interpreted the results, and drafted the manuscript; Honda K, Tokumaru T, Saito T, Uchida T, Iwao M, Arakawa M, Seike M, and Kodama M contributed to data acquisition, clinical interpretation, and critical revision of the manuscript; Murakami K contributed to study supervision and interpretation of surgical findings; Masuda T, Endo Y, and Inomata M contributed to surgical management of patients and provided critical revision of the manuscript; Mizukami K supervised the study, contributed to interpretation of the data, and critically revised the manuscript; all authors read and approved the final manuscript.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of Oita University, Japan.
Informed consent statement: All participants provided informed consent.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Data sharing statement: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Corresponding author: Mizuki Endo, Assistant Professor, Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Yufu 879-5593, Japan.
emizuki@oita-u.ac.jp
Received: October 21, 2025
Revised: December 29, 2025
Accepted: February 4, 2026
Published online: April 15, 2026
Processing time: 169 Days and 20.6 Hours
BACKGROUND
Hepatocellular carcinoma (HCC) is typically associated with advanced liver fibrosis or cirrhosis. However, the clinical characteristics, prognosis, and recurrence risk factors of F0 HCC remain uncertain, and data directly comparing F0 with cirrhotic (F4) HCC are limited.
AIM
To clarify the clinical characteristics, prognosis, and risk factors for recurrence of F0 vs F4 HCC.
METHODS
We retrospectively analyzed 315 patients [F0 HCC (n = 42); F4 HCC (n = 105)] who underwent curative hepatic resection for HCC at the Oita University (January 2010-December 2021). Fibrosis stage was determined histologically using Hematoxylin–Eosin and Azan staining according to the New Inuyama Classification. Clinical characteristics, laboratory data, and tumor features were compared. Survival analyses were performed using Kaplan-Meier curves and log-rank tests. Cox proportional hazards regression was applied to identify recurrence risk factors in F0 HCC. The mean observation period was 1463 ± 1110 days.
RESULTS
Patients with F0 HCC were significantly older; more often male; and more frequently had negative for both hepatitis B and C etiology compared with F4 cases (P < 0.05). Platelet counts and prothrombin activity were higher in the F0 group (P < 0.001). Tumor size was significantly larger in F0 HCC, whereas tumor number did not differ between groups. Overall survival (OS) and recurrence-free survival were comparable between F0 and F4 HCC. Cases of F0 and F4 HCC had no significant difference in OS. Among patients with F0 HCC, those without recurrence had significantly better OS than those with recurrence (P = 0.001). However, patients with F4 HCC exhibited similar OS, irrespective of recurrence. Multivariate analysis identified tumor number as the only independent predictor (P < 0.05).
CONCLUSION
F0 HCC presents with distinct clinical features, including older age, male predominance, negative for both hepatitis B and C background, and larger tumor size. Despite preserved liver function, recurrence significantly compromised survival, underscoring recurrence as a key determinant of outcome. Tumor number was an independent predictor of recurrence, highlighting the importance of early detection and aggressive treatment. Given that patients without cirrhosis are not under standard HCC surveillance, interdisciplinary collaboration is essential to improve early diagnosis and outcomes in this population.
Core Tip: Hepatocellular carcinoma (HCC) arising in nonfibrotic (F0) livers is uncommon and its clinical behavior remains unclear. This study directly compared F0 and cirrhotic (F4) HCC, revealing that F0 HCC typically occurs in older men with negative for both hepatitis B and C etiology and larger tumors. Despite preserved liver function, recurrence significantly worsened prognosis. Tumor number was the sole independent risk factor for recurrence in F0 HCC. These findings emphasize the need for early detection strategies, even in non-cirrhotic populations.
