Morphology does not tell us the entire story: biological behavior improves our ability to select patients with hepatocellular carcinoma waiting for liver transplantation

Brussels, Belgium

Morphology does not tell us the entire story: biological behavior improves our ability to select patients with hepatocellular carcinoma waiting for liver transplantation

Jan Lerut and Quirino Lai

Brussels, Belgium

The Milan criteria (solitary lesion ≤5 cm or twothree 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% fiveyear 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) locoregional treatment(s).[7]The two most important HCC markers are alpha-fetoprotein (AFP) and des-carboxyprothrombin (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-re-gional treatment(s)] in order to further refine inclusion criteria of HCC for LT. This is precisely what the Chengdu group reported in the issue ofHepatobiliary 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 at18F-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.

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.

1 Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-699.

2 Toso C, Kneteman NM, James Shapiro AM, Bigam DL. The estimated number of patients with hepatocellular carcinoma selected for liver transplantation using expanded selection criteria. Transpl Int 2009;22:869-875.

3 Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394-1403.

4 Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10: 35-43.

5 Lee SG, Hwang S, Moon DB, Ahn CS, Kim KH, Sung KB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl 2008;14:935-945.

6 Zheng SS, Xu X, Wu J, Chen J, Wang WL, Zhang M, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation 2008;85:1726-1732.

7 Todo S, Furukawa H, Tada M; Japanese Liver Transplantation Study Group. Extending indication: role of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 2007;13:S48-54.

8 Takada Y, Ito T, Ueda M, Sakamoto S, Haga H, Maetani Y, et al. Living donor liver transplantation for patients with HCC exceeding the Milan criteria: a proposal of expanded criteria. Dig Dis 2007;25:299-302.

9 Duvoux C, Roudot-Thoraval F, Decaens T, Pessione F, Badran H, Piardi T, et al. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:986-994.

10 Toso C, Meeberg G, Hernandez-Alejandro R, Dufour JF, Marotta P, Majno P, et al. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation. Hepatology 2015;62:158-165.

11 Harimoto N, Shirabe K, Nakagawara H, Toshima T, Yamashita Y, Ikegami T, et al. Prognostic factors affecting survival at recurrence of hepatocellular carcinoma after living-donor liver transplantation: with special reference to neutrophil/lymphocyte ratio. Transplantation 2013;96:1008-1012.

12 Lai Q, Castro Santa E, Rico Juri JM, Pinheiro RS, Lerut J. Neutrophil and platelet-to-lymphocyte ratio as new predictors of dropout and recurrence after liver transplantation for hepatocellular cancer. Transpl Int 2014;27:32-41.

13 Xiao GQ, Yang JY, Yan LN. Combined Hangzhou criteria with neutrophil-lymphocyte ratio is superior to other criteria in selecting liver transplantation candidates with HBV-related hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2015;14:588-595.

14 Yang SH, Suh KS, Lee HW, Cho EH, Cho JY, Cho YB, et al. The role of (18)F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. Liver Transpl 2006;12:1655-1660.

15 Le Treut YP, Grégoire E, Klempnauer J, Belghiti J, Jouve E, Lerut J, et al. Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study. Ann Surg 2013;257:807-815.

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

Received September 23, 2015

Accepted after revision October 7, 2015

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common disorder with poorly understood pathogenesis. Beyond environmental and genetic factors, cumulative data support the causative role of gut microbiota in disease development and progression.

DATA SOURCE: We performed a PubMed literature search with the following key words: "non-alcoholic fatty liver disease", "non-alcoholic steatohepatitis", "fatty liver", "gut microbiota" and "microbiome", to review the data implicating gut microbiota in NAFLD development and progression.

RESULTS: Recent metagenomic studies revealed differences in the phylum and genus levels between patients with fatty liver and healthy controls. While bacteroidetes and firmicutes remain the dominant phyla among NAFLD patients, their proportional abundance and genera detection vary among different studies. New techniques indicate a correlation between the methanogenic archaeon (methanobrevibacter smithii) and obesity, while the bacterium akkermanshia municiphila protects against metabolic syndrome. Among NAFLD patients, small intestinal bacterial overgrowth detected by breath tests might induce gut microbiota and host interactions, facilitating disease development.

CONCLUSIONS: There is evidence that gut microbiota participates in NAFLD development through, among others, obesity induction, endogenous ethanol production, inflammatory response triggering and alterations in choline metabolism. Further studies with emerging techniques are needed to further elucidate the microbiome and host crosstalk in NAFLD pathogenesis.(Hepatobiliary Pancreat Dis Int 2015;14:572-581)

non-alcoholic fatty liver disease;

non-alcoholic steatohepatitis;

gut microbiota;

16S rRNA sequencing;

archaea

Introduction

Non-alcoholic fatty liver disease (NAFLD), the

liver manifestation of metabolic syndrome, is

the main cause of liver enzymes abnormalities in Western countries.[1,2]NAFLD definition requires lack of ongoing or recent excessive alcohol consumption (＞20 g/d for men and ＞10 g/d for women, respectively) and exclusion of other causes of liver steatosis.[3]Histologic evidence of steatosis or in the absence of histology, γ-GT and/or aminotransferases elevations as well as compatible sonographic findings suffice for diagnosis. The spectrum of the disease encompasses liver steatosis, nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis and hepatocellular carcinoma.[4]Moreover, NAFLD patients are at greater risk to develop cardiovascular diseases[5]and their overall mortality is higher than that of a matched general population.[6]

Obesity, diabetes mellitus and hypertriglyceridemia are the main risk factors for the development and progression of NAFLD.[7]Given the mounting prevalence of overweighed and obese individuals (65% and 30%, respectively in the USA),[8]it is apparent that NAFLD and its consequences represent major public health issues. NAFLD prevalence ranges from 3% to 30%,[7,9]depending on the used diagnostic methods (biochemical markers, radiology, histology). NAFLD and NASH prevalence among an urban USA population is estimated to 20%[10]and 4%,[2]respectively. However, epidemiological data vary in special populations: Hispanics show higher prevalence than non-Hispanics, whereas non-Hispanics black individuals[11]as well as populations from Alaska[12]and American-Indians,[13]exhibit significantly lower prevalence (0.6%-2%) of NAFLD.

Author Affiliations:Hepatogastroenterology Unit, Second Department of Internal Medicine and Research Institute, Attikon University General Hospital, Medical School, Athens University, 124 62 Athens, Greece (Gkolfakis P, Dimitriadis G and Triantafyllou K)

Published online October 7, 2015.

Konstantinos Triantafyllou, MD, Hepatogastroenterology Unit, Second Department of Internal Medicine and Research Institute, Attikon University General Hospital, Medical School, Athens University, Rimini 1, 124 62 Athens, Greece (Tel: +302105832087; Email: ktriant@med.uoa.gr)

10.1016/S1499-3872(15)60026-1

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.

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