US

Late Recurrence of Hepatocellular Carcinoma after LiverTransplantation: Is an Active Surveillance for Recurrence Needed?J.F. Castroagudín, E. Molina-Pérez, R. Ferreiro-Iglesias, I. Abdulkader, E. Otero-Antón, S. Tomé,and E. Varo-Pérez

ABSTRACT

Introduction. Liver transplantation (OLT) is considered the most efficient therapeuticoption for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) interms of overall survival and recurrence rates, when restrictive selection criteria areapplied. Nevertheless, tumor recurrence may occur in 3.5% to 21% of recipients. It usuallyoccurs within 2 years following OLT, having a major negative impact on prognosis. Theefficacy of active posttransplantation surveillance for recurrence has not been demon-strated, due to the poor prognosis of recipients with recurrences.Aim. To analyze the clinical, pathological, and prognostic consequences of late recur-rence (�5 years after OLT).Method. We analyzed the clinical records of 165 HCC patients including 142 males ofoverall mean age of 58 � 6.9 years who underwent OLT between July 1994 and August 2011.Results. Overall survival was 84%, 76%, 66.8%, and 57% at 1, 3, 5, and 10 years,respectively. Tumor recurrence, which was observed in 18 (10.9%) recipients, was a majorpredictive factor for survival: its rates were 72.2%, 53.3%, 26.7%, and 10% at 1, 3, 5, and 10years, respectively. HCC recurrence was detected in 77.8% of patients within the first 3 yearsafter OLT. Three recipients (100% males, aged 54–60 years) showed late recurrences after 7,9, and 10 years. In only one case were Milan criteria surpassed after the examination ofexplanted liver; no vascular invasion was detected in any case. Recurrence sites wereperitoneal, intrahepatic, and subcutaneous abdominal wall tissue. In all cases, immunosup-pression was switched from a calcineurin-inhibitor to a mammalian target of rapamycin inhibitor.We surgically resected the extrahepatic recurrences. The remaining recipient was treated withtransarterial chemoembolization with doxorubicin-eluting beads and sorafenib. Prognosis afterdiagnosis of recurrence was poor with median a survival of 278 days (range, 114–704).Conclusions. Global survival, recurrence rate, and pattern of recurrence were similar topreviously reported data. Nevertheless, in three patients recurrence was diagnosed �5years after OLT. Although recurrence was limited and surgically removed in two cases,disease-free survival was poor. Thus, prolonged active surveillance for HCC recurrence

beyond 5 years after OLT may be not useful to provide a survival benefit for these patients.

(Am

LIVER TRANSPLANTATION (OLT) is considered tobe the most efficient therapeutic option for patients

with liver cirrhosis and early stage hepatocellular carcinoma

From the Liver Transplantation Unit (J.F.C., E.M.-P., R.F.-I.,E.O.-A., S.T., E.V.-P.) and Pathology Department (I.A.),

niversity Hospital of Santiago, Santiago de Compostela,

pain.

© 2012 by Elsevier Inc. All rights reserved.360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 44, 1565–1567 (2012)

HCC) in terms of overall survival and recurrence rate.pplication of restrictive selection criteria based on tumororphology, namely size and number of nodules, is advised

Address reprint requests to Javier F. Castroagudín, Unidad deTrasplantes Abdominales, Hospital Clínico Universitario de San-tiago C/Choupana, s/n 15706 Santiago de Compostela, Spain.

E-mail: javier.fernandez.castroagudin@sergas.es

0041-1345/–see front matterhttp://dx.doi.org/10.1016/j.transproceed.2012.05.007

1565

hs

3

wytr1p

1566 CASTROAGUDÍN, MOLINA-PÉREZ, FERREIRO-IGLESIAS ET AL

to obtain optimal results after OLT.1 Nevertheless, tumorrecurrence occurs in 3.5% to 21% of recipients, despitecareful pretransplant staging and patient selection. It usu-ally occurs within 2 years with a median time to recurrenceof 8 to 14 months. This interval is shorter when tumors arelarge and poorly differentiated. Recurrence is usually extra-hepatic mainly in lung and bones, in multiple sites, withbiological behavior similar to advanced HCC in nontrans-planted patients.2–4 Posttransplant HCC recurrence clearly

as a major negative impact on prognosis, with medianurvival of 9 months thereafter.5 The aim of this work was

to analyze the clinical, pathological, and prognostic conse-quences of late HCC recurrences at �5 years after OLT.

PATIENTS AND METHODS

Between July 1994 and August 2011, 165 HCC patients including142 males of overall mean age of 58 � 6.9 years underwent OLT.Median pretransplant alpha-fetoprotein (AFP) was 4.2 ng/mL(range 1–2593). Etiology of underlying liver disease was alcoholic(n � 91, 55.1%), hepatitis C virus (HCV) infection (n � 51,0.9%), hepatitis B virus (HBV) infection (n � 10, 6.1%), concom-

itant HBV and HCV infection (n � 2, 1.2%), autoimmune/cholestatic (n � 3, 1.8%), hemochromatosis (n � 2, 1.2%),cryptogenic (n � 2, 1.2%), and other causes (n � 2). HCC was theindication for OLT in 86.1% of cases. In 4.2%, HCC was detectedduring the waiting list period, and in 9.7% after examination of theexplanted liver.

Clinical records of recipients were evaluated for global survival,recurrence, interval between liver transplantation and recurrence,AFP values at recurrence, treatment including immunosuppressionchanges, and postrecurrence survival. Survival analysis was per-formed using the Kaplan-Meier method. The log-rank test wasapplied to compare group survival curves. Statistical analysis wasperformed using the statistical package SPSS version 12 (SPSS Inc,Chicago, Ill, USA).

Fig 1. Time profile of post-transplantation recurrence ofhepatocellular carcinoma. In thisseries, �80% of recurrences

ere diagnosed in the first 5ears after transplantation. Al-hough infrequent, late recur-ences were detected at 7, 9, and0 years after liver trans-

lantation.

RESULTS

Global survivals were 84%, 76%, 66.8%, and 57% at 1, 3, 5,and 10 years, respectively. After a median follow-up of 52months, tumor recurrence was observed in 18 recipients(10.9%). Median interval time between transplantation andrecurrence diagnosis was 613 days (range, 118–3648). Tu-mor recurrence sites were: liver graft (38.9%), lung(33.3%), bone (27.8%), adrenal gland (27.8%), ganglion(27.8%), peritoneal (11.1%), subcutaneous (11.1%), mus-cular (5.5%), and mediastinal (5.5%). Recurrence wasdetected in multiple sites in 61.1% of cases. Median AFPvalue at the time of recurrence was 23.4 ng/mL (range,0.9–2455). HCC recurrence was a major predictive factorfor posttransplant survival with survival rates of 72.2%,53.3%, 26.7%, and 10% in recipients with recurrence versus85.5%, 78.9%, 71.9%, and 61.7% for those who did notexperience this event, at 1, 3, 5, and 10 years respectively.

Tumor recurrence was detected in the first 3 years afterOLT in 77.8% of patients (Fig 1). Three recipients showedlate HCC recurrences at 7, 9, and 10 years. All of theserecipients were males with range age 54 to 60 years. In twoof them, HCV infection was the etiologic agent for theunderlying liver disease. Tumor grade was well differenti-ated in all cases. In only one case were Milan criteria weresurpassed upon examination of the explanted liver: onenodule was 8 cm in diameter. No vascular invasion wasdetected in any case. AFP values were within the rangelimits at the diagnosis of recurrence. Recurrence sites wereperitoneal, intrahepatic, and subcutaneous abdominal walltissue. In all cases, immunosuppression was switched fromcalcineurin-inhibitors to mammalian target of rapamycininhibitors. The extrahepatic recurrences were surgicallyresected, but one patient developed additional peritoneal

parncma

stb

sXs

LATE RECURRENCE OF HCC 1567

recurrences after surgery, and succumbed due to respira-tory failure 2 years after the diagnosis of a recurrence. Theother surgically treated patient died due to a severe post-operative respiratory infection. The remaining recipientwas treated with two cycles of transarterial chemoemboli-zation with doxorubicin-eluting beads and sorafenib, butthe tumor progressed with death at 8 months after thedetection of the recurrence. The clinical and pathologicalfeatures of recipients with late HCC recurrence are sum-marized in Table 1.

DISCUSSION

OLT is an effective option to treat HCC with good long-term survivals and low neoplastic recurrence rates.6 Multi-

le studies have identified morphological, epidemiological,nd biochemical factors that influence both survival andecurrence of HCC after transplantation, such as size andumber of nodules, neoplastic portal thrombosis, microvas-ular invasion, differentiation grade, satellite nodules, tu-or capsule, bilobular distribution, gender, HCV infection,

nd elevated AFP levels.7,8 Thus, selection of patients forwhom liver transplantation offers the optimal chance of

Table 1. Clinical and Pathological Features of Late Recurrenceof Hepatocellular Carcinoma After Liver Transplantation

Variables Case 1 Case 2 Case 3

Age/gender 60/male 60/male 54/maleEtiology of liver disease HCV HCV AlcoholicMilan criteria met in

explanted liverYes Yes No

Vascular invasion No No NoTumor differentation

gradeWell Well Well

Previous treatments No Resection �

PEINo

Time from OLT torecurrence (d)

3648 2838 3522

AFP at recurrence(ng/mL)

2.7 5.1 5.4

Site of recurrence Peritoneum Liver graft Abdominalwall

Treatment ofrecurrence

Resection TACE �

sorafenibResection

mTOR Sirolimus Everolimus EverolimusSurviva 1 after

recurrence (d)704 278 114

OLT, orthotopic liver transplantation; AFP, alpha-fetoprotein; mTOR, mam-

malian target of rapamycin; HCV, hepatitis C virus, PEI, percutaneous ethanolinjection; TACE, transarterial chemoembolisation.

urvival with a low recurrence rate is essential. Neverthelessumor recurrence is unavoidable constituting a major draw-ack for the survival of these transplant recipients.Posttransplantation recurrence surveillance has not been

tandardized. It includes abdominal ultrasonography, chest-ray, chest and abdominal computed tomography, bone

cintigraphy, and AFP measurements.9 Nevertheless, effi-cacy of active surveillance for recurrence has not beensatisfactorily demonstrated, due to the poor prognosis ofrecipients in whom a recurrence occurs; only resectable,limited recurrences show prolonged median survival timesto 24 months.2 Additionally, active surveillance protocolswould be most beneficial in the first 5 years after livertransplantation when �80% of recurrences are detected.

In our series, the global survival as well as the recurrencerate and pattern were similar to previously reported data.Nevertheless, in three patients a recurrence was diagnosedafter 5 years. No distinctive features were observed betweencases of late versus early recurrences. Although recurrencewas limited and surgically removed in two cases, disease-free survival was poor. Thus, prolongation of active surveil-lance for HCC recurrence beyond 5 years after OLT may benot useful to provide a survival benefit for these patients.

REFERENCES

1. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantationfor treatment of small hepatocellular carcinomas in patients withcirrhosis. N Engl J Med 334:693, 1996

2. Roayaie S, Schwartz JD, Sung MW, et al: Recurrence ofhepatocellular carcinoma after liver transplant: patterns and prog-nosis. Liver Transpl 10:534, 2004

3. Schlitt HJ, Neipp M, Weimann A, et al: Recurrence patternsof hepatocellular carcinoma after liver transplantation. J ClinOncol 17:324, 1999

4. Regalia E, Fassati LR, Valente U, et al: Pattern and manage-ment of recurrent hepatocellular carcinoma after liver transplan-tation. J Hepatobiliary Pancreat Surg 5:29, 1998

5. Castroagudín JF, Molina E, Bustamante M, et al: Orthotopicliver transplantation for hepatocellular carcinoma: a thirteen-yearsingle-center experience. Transplant Proc 40:2975, 2008

6. Bruix J, Sherman M: Practice Guidelines Committee, Amer-ican Association for the Study of Liver Diseases. Management ofhepatocellular carcinoma. Hepatology 42:1208, 2005

7. Figueras J, Ibañez L, Ramos E, et al: Selection criteria forliver transplantation in early-stage hepatocellular carcinoma withcirrhosis: results of a multicenter study. Liver Transpl 7:877, 2001

8. Tamura S, Kato T, Berho M, et al: Impact of histologicalgrade of hepatocellular carcinoma on the outcome of liver trans-plantation. Arch Surg 136:25, 2001

9. Schwartz M, Roayaie S, Llovet JM: How should patients with

hepatocellular carcinoma recurrence after liver transplantation betreated? J Hepatol 43:584, 2005