Systematic Reviews
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2019; 25(35): 5356-5375
Published online Sep 21, 2019. doi: 10.3748/wjg.v25.i35.5356
De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature
Tommaso Maria Manzia, Roberta Angelico, Carlo Gazia, Ilaria Lenci, Martina Milana, Oludamilola T Ademoyero, Domiziana Pedini, Luca Toti, Marco Spada, Giuseppe Tisone, Leonardo Baiocchi
Tommaso Maria Manzia, Carlo Gazia, Luca Toti, Giuseppe Tisone, HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
Roberta Angelico, Domiziana Pedini, Marco Spada, Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
Carlo Gazia, Oludamilola T Ademoyero, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, United States
Ilaria Lenci, Martina Milana, Leonardo Baiocchi, Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
Author contributions: Manzia TM and Angelico R contributed equally to the work, paper conception and design and critical revision; Gazia C, Lenci I, Milana M, Ademoyero OT, Pedini D and Toti L contributed to acquisition of data, analysis and interpretation, drafting of manuscript and critical revision; Spada M, Tisone G and Baiocchi L contributed to study conception and critical revision.
Conflict-of-interest statement: The authors declare they have no conflicts of interest to disclose.
PRISMA 2009 Checklist statement: Authors read the PRISMA 2009 Checklist and the manuscript was prepared and revised according to the PRISMA 2009.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: Tommaso Maria Manzia, MD, PhD, Assistant Professor, HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Viale Oxford, 81, Rome 00133, Italy. tomanzia@libero.it
Telephone: +39-6-20902498
Received: May 2, 2019
Peer-review started: May 4, 2019
First decision: May 30, 2019
Revised: August 8, 2019
Accepted: August 24, 2019
Article in press: August 24, 2019
Published online: September 21, 2019
Processing time: 143 Days and 10.3 Hours
ARTICLE HIGHLIGHTS
Research background

Immunosuppression (IS) has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to IS is associated with critical systemic morbidities. De novo malignancies (DNMs) following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between IS and DNMs in liver transplant patients.

Research motivation

DNMs represent a major threat in OLT children and adults. Multiple experiences were described to analyze the connection between IS and DNMs in liver transplant patients. Different pathways seem to be involved in the incidence of DNMs, but molecular mechanisms are still unknown. Giving an answer to this concern might lead to a solution for the complications related to the long-term use of IS.

Research objectives

To study the role of IS on the incidence of DNMs in liver transplant recipients.

Research methods

A systematic literature examination of DNMs and IS weaning in adult and pediatric OLT recipients was described in the present review. Data from worldwide clinical trials was collected from highly qualified institutions performing OLTs. Patient follow-up, IS discontinuation and incidence of DNMs were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted IS regimens and the type of diagnosed solid and blood malignancy.

Research results

Emerging evidence suggests that the liver is an immunologically privileged organ able to support IS discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily IS regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected DNMs in pediatric and adult OLT patients, respectively. To date, IS withdrawal has been achieved in 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of IS weaning protocols on DNMs is difficult to ascertain because data have not been specified in most of the clinical experiences.

Research conclusions

The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from IS weaning. There is still no strong clinical evidence on the usefulness of IS withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of DNMs and may also help in treating liver transplanted patients suffering from cancer.

Research perspectives

Most of the current studies on IS withdrawal describe patients with a stable clinical pathway with normal liver function test levels and no history of rejection post-OLT. In the future, an international registry including all IS weaning experiences in OLT patients would offer a promising database to explore the connections between DNMs and the final outcomes after IS withdrawal in such patients. Seriate graft biopsies should always be considered in future studies to take into account the risk of graft fibrosis. Fibrosis is independent from IS maintenance or withdrawal, and further investigations are strongly suggested to fully understand the etiopathogenetic pathways involved. The minimization of IS dosages may decrease all IS complications and induce remarkable savings in IS drugs. Moreover, the recipient’s quality of life after the reduction of daily medications could significantly boost their compliance and graft outcomes in the long-term. IS withdrawal is still arduous to realize. However, it is possible, and it is supported by the described cases of clinical operational tolerance in OLT individuals. In-depth investigations are needed to study the possibilities of achieving a complete IS-free state and clinical operational tolerance in OLT patients affected by DNMs because few studies explore this possibility. Regenerative medicine and clinical operational tolerance biomarkers are new promising frontiers that could provide novel insights about tolerance mechanisms in order to replace liver biopsies as the currently recognized gold standard method for rejection diagnosis.