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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Surg. Sep 27, 2021; 13(9): 967-978
Published online Sep 27, 2021. doi: 10.4240/wjgs.v13.i9.967
Finding the seed of recurrence: Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment
Francesca Carissimi, Matteo Nazzareno Barbaglia, Livia Salmi, Cristina Ciulli, Linda Roccamatisi, Giuseppe Cordaro, Venkata Ramana Mallela, Rosalba Minisini, Biagio Eugenio Leone, Matteo Donadon, Guido Torzilli, Mario Pirisi, Fabrizio Romano, Simone Famularo
Francesca Carissimi, Cristina Ciulli, Linda Roccamatisi, Giuseppe Cordaro, Biagio Eugenio Leone, Fabrizio Romano, Simone Famularo, School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
Matteo Nazzareno Barbaglia, Livia Salmi, Venkata Ramana Mallela, Rosalba Minisini, Mario Pirisi, Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
Biagio Eugenio Leone, Unit of Pathology, San Gerardo Hospital, Monza 20900, Italy
Matteo Donadon, Guido Torzilli, Simone Famularo, Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
Fabrizio Romano, Department of Medicine and Surgery, University of Milan-Bicocca, Monza 20900, Italy
Author contributions: Carissimi F, Famularo S, Barbaglia MN, and Salmi L wrote the manuscript; Carissimi F, Famularo S, Barbaglia MN, Salmi L, Roccamatisi L, Cordaro G, Ciulli C, and Mallela VR collected and analyzed data; Carissimi F, Famularo S, Barbaglia MN, Salmi L, Roccamatisi L, Cordaro G, Ciulli C, Mallela VR, and Minisini R reviewed the literature; Salmi L, and Barbaglia MN realized figures; Famularo S, Carissimi F, Minisini R, Leone BE, Donadon M, Torzilli G, Pirisi M, and Romano F designed the study.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Fabrizio Romano, MD, Professor, Surgeon, Surgical Oncologist, Department of Medicine and Surgery, University of Milan-Bicocca,
via pergolesi 33, Monza 20900, Italy.
fabrizio.romano@unimib.it
Received: March 21, 2021
Peer-review started: March 21, 2021
First decision: April 29, 2021
Revised: May 25, 2021
Accepted: August 10, 2021
Article in press: August 10, 2021
Published online: September 27, 2021
Processing time: 180 Days and 15.6 Hours
The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as “seeds” in peripheral blood, then reach the target organ as dormant cells which could be subsequently “awakened” and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.
Core Tip: In recent years many studies have shown that surgery is the first choice treatment for hepatocellular carcinoma (HCC) patients; although undergoing surgery at early stage many patients develop relapse during follow-up. Currently, there are no tools sensitive enough to identify recurrence risk factors. Recent studies have identified liquid biopsy as a valid method for diagnosis, prognosis and treatment allocation in HCC patients thanks to its effectiveness in identification of circulating tumor cells (CTCs), advocated to be responsible for relapse. In this manuscript we describe the main markers expressed by CTCs and how their presence in blood sample may be implied in the progression mechanism, and how they can modify the surgical strategy.
