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Liver Transplantation as Cure of Hepatocellular Carcinoma: It is not a Matter of Time, it is a Matter of Tumor Biology
Christoph Jochum*, Ali Canbay**,
Corresponding author
ali.canbay@med.ovgu.de

Correspondence and reprint request:
* Department for Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
** Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0010" class="elsevierStylePara elsevierViewall">Hepatocellular carcinoma &#40;HCC&#41; is the third most common cause of cancer mortality world-wide&#46; Despite the success in the treatment of hepatitis C and the reduction of hepatitis B in Asia due to immunization programs the incidence of HCC will increase in Europe&#44; North and Southamerica and Asia&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">1&#44;2</span></a> This trend is due to the dramatic increase in Non-alcoholic fatty liver disease &#40;NAFLD&#47; NASH&#41;&#44; which is becoming more and more important in the development of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">3</span></a> Disease related mortality of HCC is still high&#44; since curative treatment options beside resection and liver transplantation &#40;LT&#41; are lacking&#46; In patients with advanced liver disease and cirrhosis LT is the only curative option&#46; Limitations of treating HCC with LT are the risk of tumor recurrence after LT and the relative organ shortage which causes a competition for organs between patients with HCC and non-malignant end stage liver diseases&#46;</p><p id="p0015" class="elsevierStylePara elsevierViewall">1996 Mazzaferro&#44; <span class="elsevierStyleItalic">et al&#46;</span> defined size criteria for HCC-patients suitable for LT &#40;Milan-criteria&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">4</span></a> which were extended by the UCSF group in 2001 &#40;San-Francisco-crite-ria&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">5</span></a> Both criteria were based on size and number of individual HCC-nodules in the liver&#46; Organ allocation was switched to the MELD system in the most countries in 2002 and 2003&#44; which raised the question how to deal with HCC patients waiting for a transplant with good liver function and consecutively low MELD&#46; Extrapoints &#40;exceptional MELD&#41; were introduced to deal with this issue&#46; First the points were allocated adjusted to an estimated three-months mortality causing a disadvantage for patients with non-malignant liver diseases&#46; The system was modified over time successive increasing the waiting time for patients with HCC in order to overcome a disadvantage for patients with non-malignant liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">6</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">It is not clear how the increase in waiting list will influence the recurrence free survival rate after LT for patients with HCC&#46; Palmer&#44; <span class="elsevierStyleItalic">et al&#46;</span> reported in this issue of <span class="elsevierStyleItalic">Annals of Hepatology</span> the impact of waiting time on recurrence free survival in a large single center retrospective analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">7</span></a> Interestingly&#44; they did not find any impact of waiting time on recurrence free survival&#46; Indeed&#44; 90&#37; of the patients initially enrolled for LT for HCC received a LT and only 5&#37; were excluded due to progress&#46; The dropout rate increased over waiting time to reach 6 &#37; at six months&#44; 15&#37; at one year 42&#37; at two years&#46; Regarding patients after LT the authors did not find any differences in recurrence free survival and&#47;or overall in patients waiting more or less than 180 days&#46; Moreover&#44; therapeutic local ablative interventions like RFA and TACE or both in order to downstage the tumor did not influence recurrence rate after LT&#46; The factors influencing the recurrence rate were explant vascular invasion&#44; tumor grade and AFP&#46; Ex-plant vascular invasion and AFP influenced also overall survival&#46;</p><p id="p0025" class="elsevierStylePara elsevierViewall">First conclusion of the work of Palmer&#44; <span class="elsevierStyleItalic">et al</span>&#46; is that successful LT for HCC is rather more dependent on tumor biology than on the waiting time on the transplant list&#46; This leads to the second conclusion that we might have to improve our pre-LT diagnostic work-up to identify patients at risk&#46;</p><p id="p0030" class="elsevierStylePara elsevierViewall">For the AFP the author found that an elevated AFP or quickly rising AFP above 400 ng&#47;mL was associated with recurrence&#46; AFP is already included in most diagnostic work-up of HCC on the waiting list and should be monitored carefully&#46; More difficult to evaluate is vascular invasion at the time of transplantation&#46; The authors did not analyze the impact of micro- or macrovascular invasion&#44; however it is clear that there must be a focus on pre-trans-plant diagnostic and surveillance&#46; Modern imaging tools like MRI and vascular ultrasound might be helpful&#46; Tumor grading was the third predictive factor in this study&#46; Grading as a prognostic tool leads us to the question of biopsy for HCC&#46; Most diagnostic guideline does not require biopsy for the diagnosis of HCC especially in cirrhotic patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">8&#44;9</span></a> The sensitivity and specificity of MRI&#44; contrast enhanced ultrasound and CT-Scan are high especially in larger nodules&#46; Smaller nodules are challenging for biopsies and there is a very low risk &#40;1-2&#37;&#41; for implantation metastases<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> which can be reduced by technical improvements&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">11</span></a> On the other hand histopathological examination and grading&#44; and genomics and&#47;or proteomics will be of importance in the future not only for identification of patients suitable for LT but also for identifying candidates for targeted therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">11</span></a> Liquid biopsies may be an alternative for the future&#44; however the technique for HCC is still in early stages of development&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">12</span></a></p><p id="p0035" class="elsevierStylePara elsevierViewall">In conclusion the important paper of Palmer&#44; <span class="elsevierStyleItalic">et al&#46;</span> underscores the tumor biology in course of HCC recurrence after LT&#46; It is therefore important to focus the future research on biomarkers for HCC&#44; which may establish more individualized criteria for patients with HCC who are considered for LT&#46;</p></span>"
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ISSN: 16652681
Original language: English
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