Author Affiliations: Starzl Unit of Abdominal Transplantation, Université catholique Louvain (UCL), Brussels, Belgium (Lerut J and Lai Q)

Corresponding Author: Jan Lerut, MD, Starzl Unit of Abdominal Transplantation, Université catholique Louvain (UCL), B-1200 Brussels, Belgium (Tel: +32-2-76453060; Fax: +32-2-7649039; Email: jan.lerut@uclouvain.be)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60028-5

Published online October 21, 2015.

 

Contributors: LJ and LQ wrote the draft. LJ is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

The Milan criteria (solitary lesion ≤5 cm or two-three lesions ≤3 cm), published in 1996 in relation to the selection of patients harboring hepatocellular carcinoma (HCC) in a diseased liver are still dominating the allocation of liver allografts in all international organ allocation organisms, this despite the fact that excellent results have been reported after liver transplantation (LT) done for patients presenting HCC outside these criteria.^[1]

 

Indeed, several groups showed during the last two decades that very good to almost similar results can be obtained when (substantially) widening the Milan criteria inclusion criteria. The review of the HCC transplant literature revealed that strict adherence in fact to Milan criteria denies access to a possible curative LT in up to one third of potential recipients.^[2] The San Francisco group was the first to show that one can extend safely the Milan criteria by adding about 1.5 cm to tumor diameter or burden.^[3] Mazzaferro et al^[4] confirmed later on in a retrospective, transcontinental study including 1556 recipients that many Milan criteria beyond patients performed as good as Milan criteria within patients well after LT: As an example a patient harboring one single tumor of 6 cm (1+6=7) or four tumors, the largest diameter of them being three cm (4+3=7) can have an excellent outcome after LT. These observations allowed the authors to come forward with the "up to seven criteria" concept patients within these criteria reached a 71% five-year overall survival.^[4] Many, especially, Asian centers (in China, Japan and Korea) further elaborated on this concept mainly in the context of living donor LT.^{[5, 6]} The inclusion criteria for LT in HCC patients were widened by combining the sound oncologic principles of biologic and morphologic tumor behavior. The behavior of whatever tumor can be monitored using dynamic changes in tumor markers and/or morphology based on state of the art imaging before and after (neo-adjuvant) loco-regional treatment(s).^[7] The two most important HCC markers are alpha-fetoprotein (AFP) and des-carboxy-prothrombin (DCP, also called protein induced by vitamin K absence--PIVKA). Such combination allowed e.g. the Kyoto group to successfully transplant patients presenting up to 10 lesions and the Japanese LT study group to refine selection criteria for LT based on the combination of tumor morphology (Milan criteria) and AP score (AFP and PIVKA levels) on outcome after LT for HCC.^[8] Two Western retrospectives reviews indeed confirmed that static and/or dynamic levels tumor markers indeed impact on outcome.^{[9, 10]} Total tumor volume, AFP absolute and dynamic values (set at different cut-off levels of 100, 400, 1000 ng/mL) have all been shown to markedly influence outcome after LT.

 

Studies in different fields of gastrointestinal oncology also demonstrated the value of neutrophil-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio as simple markers of inflammation in the tumor microenvironment and therefore of tumor aggressiveness. Similar findings have been observed in several HCC studies.^[11,12] It seems therefore logic to combine the evolution of inflammatory and tumor markers and of tumor morphology [number and diameter of tumor(s) under loco-regional treatment(s)] in order to further refine inclusion criteria of HCC for LT. This is precisely what the Chengdu group reported in the issue of Hepatobiliary Pancreat Dis Int.^[13] The combination of the biologic marker NLR (with a cut-off value of 4) and the morphologic (beyond the Milan criteria) Hangzhou criteria [total tumor diameter ≤8 cm or >8 cm (histopathological grade I or II) along with a preoperative AFP ≤400 ng/mL] allowed to more precisely differentiate the outcome of HCC recipients after LT. Recently, the Seoul National University Hospital added another piece to the puzzle by looking at the combination of tumor biology, morphology and tracer uptake at ¹⁸F-FDG PET scanning, the uptake being a prognostic factor for tumor recurrence.^[14]

 

Without any doubt, several Asian centers show the Western world how to progress (safely) in this field of transplant oncology. Without any doubt these centers took profit from the fact that their clinical cancer research took place under the umbrella of living donor LT allowing not only to eliminate the factor "time" but also to concentrate better on tumor biology and morphology. As many, nowadays available, medical treatments will be able to cure many liver diseases such as HBV and HCV infections, the role of liver transplant oncology will become more and more relevant. The successes of LT obtained in the treatment of primary liver tumors even led to a renewed interest of the transplant community for the role of LT in the treatment of selected patients presenting with liver (neuroendocrine and colorectal) secondary tumors.^{[15, 16]} Undoubtedly, the concept of minimized immunosuppression will also be a key player in the widening of indications for LT in primary as well as secondary tumors. Several Chinese transplant groups showed how to progress in the field of LT and HCC. Without any doubt, many patients, especially in the Western world, will take profit from the pioneering work done by both the Hangzhou and Chengdu LT teams.

 

 

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16 Foss A, Lerut JP. Liver transplantation for metastatic liver malignancies. Curr Opin Organ Transplant 2014;19:235-244. PMID: 24807212