Authors & Institutions
Fabio Giannone, Gianluca Cassese, Antonio Cubisino, Emanuele Felli, Federica Cipriani, Bruno Branciforte, Rami Rhaiem, Alessandro Tropea, Edoardo Maria Muttillo, Andrea Scarinci, Bader Al Taweel, Raffaele Brustia, Ephrem Salame, Daniele Sommacale, Salvatore Gruttadauria, Tullio Piardi, Gian Luca Grazi, Guido Torzilli, Luca Aldrighetti, Mickael Lesurtel, Ho-Seong Han, Fabrizio Panaro, Patrick Pessaux

^a Hepato-Pancreato-Biliary, Oncologic and Robotic Unit, Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
^b Robotic and HPB Research Unit, Research and Innovation Department (DAIRI), Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
^c Department of Visceral and Digestive Surgery, University Hospital of Strasbourg, Strasbourg, France
^d Department of Clinical Medicine and Surgery, Division of Minimally Invasive and Robotic Hepato-Pancreato-Biliary Surgery, and Transplantation Service, Federico II University Hospital, Naples, Italy
^e Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
^f Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, APHP, University of Paris Cité, Clichy, France
^g Liver Transplant and Surgery Department, Trousseau Hospital, Tours, France
^h Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
ⁱ Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas University, Humanitas Clinical and Research Center – IRCCS, Rozzano, Milan, Italy
^j Department of Oncological Digestive Surgery, Hepatobiliary and Pancreatic Surgery Unit, University Reims Champagne-Ardenne, Reims, France
^k Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT, UPMC (University of Poittsburgh Medical Center), Palermo, Italy
^l Surgical and Medical Department of Translational Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy
^m Department of Surgery, Division of HBP Surgery and Transplantation, Saint-Eloi Hospital, University Hospital of Montpellier, Montpellier, France
ⁿ Department of Digestive and Hepato-pancreatic-biliary Surgery, AP-HP, Hôpital Henri-Mondor, Paris Est Créteil University, UPEC, Créteil, France and Team “Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers”, INSERM U955, Créteil, France
^o Department of Surgery and Medical and Surgical Specialties, University of Catania, Catania, Italy
^p Chirurgia Epatobiliopancreatica, AOU Careggi, Florence, Italy
^q Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques, U1110, Strasbourg, France 

Background
Curative options for large Hepatocellular carcinoma (LHCC) are limited because of the high risk of early and extrahepatic recurrence, which are associated with impaired outcomes. However, only a few studies report data on outcomes in resected LHCC. In this study, we therefore investigated timing and site of recurrence in these patients and assessed factors strictly associated with these patterns.

Method
This is a retrospective study conducted on a multicentric database provided by twelve hepato-biliary high-volume centers. Only surgical cases presenting an histo-pathologically confirmed HCC, with a tumor diameter > or = 5 cm at preoperative imaging, considered resectable at diagnosis and undergoing an anatomical hepatic resection with a curative intent between January 2014 and December 2021 were included. Extrahepatic recurrence was defined as the appearance of any distant site of metastasis, while recurrence within two years after surgical resection was classified as early recurrence.

Results
A total of 869 patients were included. Recurrence was observed in 487 (56%) resected cases. Patterns associated with impaired outcomes were early (p <0.001) and simultaneous intrahepatic and extrahepatic recurrence (p= 0.038). Variables independently associated with early recurrence were age (p= 0.037), major hepatectomy (p= 0.023), MVI (p= 0.011), satellites nodules (p= 0.005) and open approach (p= 0.025). Variables correlated with simultaneous intra and extrahepatic relapse were age (p <0.001), preoperative TACE (p <0.001), microvascular invasion (p <0.001) and satellite nodules (p= 0.026).

Conclusion
SR for LHCC is associated with a high risk of early recurrence, which are cases patients with a higher burden of disease. Apart from pathological variables, factors independently associated with worse patterns were open approach and use of preoperative TACE.