Hepatocellular Carcinoma in Unrelated Viral Cirrhosis: Long-Term Results After Liver Transplantation

Hepatocellular Carcinoma in Unrelated Viral Cirrhosis: Long-Term Results After Liver Transplantation A. Lauterio, S. Di Sandro, A. Slim, A. Giacomoni, I. Mangoni, P. Mihaylov, V. Pirotta, P. Aseni, and L. De Carlis ABSTRACT Introduction. Chronic viral hepatitis is considered to be the most significant risk factor for development of hepatocellular carcinoma (HCC). Nevertheless, about 5%–15% of HCC occur in noncirrhotic or virus-unrelated cirrhotic patients. The natural history of HCC in terms of incidence, clinical features, and tumor progression differs according to the underlying cancerogenic factors and differences in hepatocarcinogenetic pathways. Little is know about the relationship between HCC outcomes after liver transplantation (OLT) and the primary liver disease. We retrospectively analyzed the outcomes of patients transplanted due to HCC in settings of either virus—related or virus-unrelated cirrhosis. Patients and Methods. From January 2000 to December 2007, 179 patients underwent OLT due to HCC: 157 (87.8%) affected by virus-related (group A) and 22 (12.2%) virus-unrelated cirrhosis (group B). We analyzed patient characteristics including demographics, tumor features, downstaging treatments, and recurrences. Results. At a mean follow-up of 41.2 months, the 3- and 5-year overall long-term survivals between group A versus group B were 81% versus 75% and 85% versus 78.4% respectively (P ⫽ NS). The 3- and 5-year disease-free survivals between group A versus group B were 90.8% versus 89.6% and 85.6% versus 85.6%, respectively (P ⫽ NS). After OLT, HCC recurrences occurred in 14 group A (14/157, 8.9%) and 4 patients (4/22, 18.1%) group B subjects. Discussion. Our data demonstrated that after OLT, HCC outcomes were not different between patients with virus-related or -unrelated cirrhosis. The direct oncogenetic role played by hepatitis B and C appear to not be associated with a greater risk to develop HCC recurrence. EPATOCELLULAR carcinoma (HCC) is the third most common cause of cancer-related death and the fifth most prevalent cancer in the world.1 HCC is the commonest primary malignancy of the liver. It usually occurs in the setting of chronic liver disease.2– 4 Due to the chronic necroinflammation and hepatocellular regeneration, chronic viral hepatitis is considered to be the most significant risk factor for developing HCC. Nevertheless, about 5%–15% of HCC occurrs in noncirrhotic or virusfree patients.4,5 The natural history in terms of incidence, clinical features, and tumor progression is different according to the underlying cancerogenic factors. Hepatitis B virus (HBV) and hepatitis C virus (HCV) play different roles in the hepatocarcinogenetic pathways. HBV infection can causes HCC in the absence of cirrhosis as a result of its

H

direct carcinogenetic effects.6,7 HCV shows a lower oncogenic action; it is currently believed that the main mechanism leading to HCC is a necro-inflammatory process promoted by the infection. However, data from recent studies have suggested that HCV also shows direct hepatocarcinogenic effect.6,8,9 From the Department of General Surgery and Transplantation (A.L., S.D.S., A.S., A.G., I.M., P.M., V.P., P.A. L.D.C.), Niguarda Hospital, Milan, Italy; and the Department of Surgical Sciences (S.D.S., P.M.), University of Pavia, Italy. Address reprint requests to Andrea Lauterio, MD, General Surgery and Transplantation, Niguarda Hospital, Piazza Ospedale Maggiore, 3, 20162, Milano, Italy. E-mail: andrea.lauterio@ ospedaleniguarda.it

0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.03.127

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The role of alcohol abuse as a direct hepatocarcinogen in the absence of cirrhosis seems of minor importance; the mechanisms by which alcohol contributes to HCC risk are not well known.10,11 The relative roles of other underlying liver diseases, such as nonalcoholic steatohepatitis, cryptogenic cirrhosis, and metabolic diseases including hemochromatosis, in hepatocarcinogenesis are unclear.10,12 Among patients who undergo liver resections for HBV-related HCC, tumor and viral factors play different roles in the long-term outcome.13 In the field of liver transplantation, other authors have reported different outcomes liver transplantation for HCC, when comparing the impact of HCV versus other etiologies of cirrhosis.14 Therefore, considering these differences in hepatocarcinogenetic pathways, we can expect different long-term results among patients affected by viral hepatitis or virus free, who were transplanted as a consequence of HCC. In this study, we have retrospectely analyzed the outcomes of a patient cohort who received liver transplantations owing to HCC either in the setting of virus-related or virus-unrelated cirrhosis. PATIENTS AND METHODS Among 1040 liver transplantations (OLT) performed at our Institute since 1986, we retrospectively analyzed 179 patients who underwent OLT from January 2000 to December 2007 due to HCC and liver cirrhosis. From January 2000 to December 2007, 179 patients underwent liver OLT due to HCC. One hundred fiftyseven (87.8%) were affected by virus-related cirrhosis (88 HCV, 50 HBV, 19 HCV-HBV; group-A); 22 (12.2%) had virus-unrelated cirrhosis (13 alcoholic, 1 hemochromatosis, 2 primary biliary cirrhosis, 6 cryptogenetic cirrhosis). Patients were selected for OLT according to the Milan Criteria (MC).15 Patients not meeting MC at the diagnosis of HCC, were considered eligible for OLT only after effective downstaging (DS) and tumor downsizing with radiological evidence. Extrahepatic tumor or macrovascular invasion was considered to be an absolute contraindication for OLT. The patient priorization over the waiting list for decreased donor OLT was based on the United Network for Organ Sharing (UNOS) criteria.16

Patients affected by HCC nodules ⱕ3 cm of diameter with no contraindications for DS procedures, owing to intrahepatic localization or patient performance status, underwent local ablation of HCC nodules. Ablative techniques consisted of radiofrequency ablation, transarterial chemoembolization, and percutaneous ethanol injection. Patients affected by liver cirrhosis, not more severe than Child Pugh B9 score or HCC nodules ⱖ3 cm, underwent liver resection. Liver resection was also offered as a DS treatment for patients with HCC ⱕ3 cm diameter but not otherwise eligible for ablative treatments. Patients underwent ⬎1 DS procedure in cases of non effectiveness as evaluated by a computed tomography 1 month after the DS procedure. The immunosuppressive regimen was maintained only with calcineurin inhibitors for the first month after transplantation in the absence of related complications. According to our protocol, HBV prophylaxis was based on a combination of low-dose hepatitis B immunoglobulin and lamivudine therapy. Patients who developed biopsy-proven HCV recurrence after OLT were treated with interferon and ribavirin, as reported in the previous published study.17 Statistical analysis was performed using the SPSS program 13.0 for Windows (SPSS, Chicago, Ill). Survival was analyzed using Kaplan-Meier estimates with comparison using the log rank chisquare and Student’s t rest. Statistical significance was reached at P ⬍ .05.

RESULTS

Patient demographic and baseline clinical characteristics are shown in Table 1. Patients’ clinical conditions at the transplantation were similar between the 2 groups; indeed, the mean MELD score was not significantly different between group A and group B, although the result was lower among patients not affected with virus-related cirrhosis (14.4 vs 11.2). The most common underlying liver disease in group A was the HCV-related cirrhosis and alcoholic cirrhosis in group B. The interval from patient listing to transplantation was similar in the 2 groups (312 vs 396 days). Group B showed a slightly longer mean waiting time before transplantation (P ⫽ NS). At the time of HCC diagnosis, we evaluated tumor nodule numbers, mean diameters of the largest nodule,

Table 1. Baseline Patient Demographic and Clinical Characteristics Variables

Gender (M/F) Mean age (y) (range) Mean MELD (range) Waiting list time (d) (median) Cadaveric/living donor Retransplantation Underlying liver disease Emocromatosis Alcohol Cryptogenic PBC HBV HCV HBV/HCV

Group A (n ⫽ 157) (Virus-related cirrhosis)

Group B (n ⫽ 22) (Virus-unrelated cirrhosis)

P

125 (79.6%)/32 (20.4%) 55 (36–68) 14.4 (8–34) 312 (46–738) 133 (84.7%)/24 (15.3%) 11/157 (7%)

8 (36.4%)/14 (63.6%) 54.5 (30–66) 11.2 (6–32) 396 (126–846) 16 (72.3%)/6 (27.7%) 2/22 (9%)

NS NS NS NS NS NS

— — — — 50/157 (31.8) 88/157 (56%) 19/157 (12.2%)

1/22 (4.5%) 13/22 (59.2%) 6/22 (27.3%) 2/22 (9%) — — —

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unilobar or bilobar localization, and median serum alfafetoprotein. Moreover, patients were classified by MC. Over the 2 groups, the patient cohorts showed homogeneous results, without a difference in terms of tumor stages. In contrast, there was worse histologic patterns in the explanted liver among patients with virus-related cirrhosis (group A), in addition to adverse tumor characteristics; percentage of G3 tumors, number of nodules, mean dimension of the largest nodule, unilobar localization, vascular invasion, and number of patients within MC. Indeed, the percentage of tumors showing vascular invasion in group A was significantly higher (16.6% vs 4.5%; P ⫽ .05). Furthermore, G3 tumors were significantly more common in group A than group B (respectively, 27.4% vs 9.1%; P ⫽ .03; Table 2). HCC DS was performed in 107/157 (68.1%) group A subjects, and 15/22 (68.2%) of those in group B. In 67/107 (62.6%), cases we should have performed ⬎1 DS treatments due to HCC recurrence after the DS procedure. In contrast, only 5/15 patients (33.3%) in group B underwent ⬎1 DS treatment due to a good response after the first treatment and a low incidence of HCC recurrence after DS. The median times between HCC diagnosis and the first DS treatment, and between the last DS treatment and transplantation were similar in the 2 groups. With a mean follow-up of 41.2 months, the 3- and 5-year overall long-term survivals of groups A versus B were 81% versus 75% and 85% versus 78.4% respectively (P ⫽ NS). The 3- and 5-year disease-free survivals between the group A versus B were 90.8% versus 89.6% and 85.6% versus 85.6%, respectively. After OLT, HCC recurrence occurred in 14 group A patients (14/157; 8.9%) with HBV- and Table 2. Patient and Tumor Features at Time of HCC Diagnosis and OLT Variables

Patients within MC Number of nodules (ⱕ2) Diameter of largest nodule (mean), cm Unilobar localization Serum alfa-fetoprotein (ng/mL) Pts underwent DS treatments Number of DS treatments (1 vs ⬎1) Median interval time, diagnosis to DS (mo) Median interval time, DS to LTx (mo) Grading G3 Number of nodules (ⱕ2) Diameter of largest nodule (mean), cm Unilobar localization Vascular invasion Patients within MC

Group A (n ⫽ 157) (Virus related)

Group B (n ⫽ 22) (Virus unrelated)

P

135/157 (85.9%) 80.157 (51.1%) 2.3 (0.5–8.0)

19/22 (86.3%) 15/22 (68.1%) 2.2 (1–3.5)

NS NS NS

124/157 (79%) 84 (5.4–240)

15/22 (68.2%) 92 (1.4–847)

NS NS

107/157 (68.1%)

15/22 (68.2%)

NS

67/107 (62.6%)

5/15 (33.3%)

.05

3.2

4.0

NS

9.1

9.2

NS

43/157 (27.4%) 86/157 (54.7%) 2.6 (1–7)

2/22 (9.1%) 14/22 (63.6%) 2 (0.4–6)

.03 NS NS

97/157 (61.8%) 26/157 (16.6%) 110/157 (70.6%)

13/22 (60%) 1/22 (4.5%) 15/22 (68.2%)

NS .05 NS

HCV-related cirrhosis the underlying disease in 6 and 8 patients respectively. In group B, HCC recurrence occurred in 4 patients (4/22; 18.1%). The causes of death correlated with tumor recurrence in 8 group A patients and 3 group B subjects. Log-rank tests showed not significant differences in the overall and recurrence-free survival rates between the 2 groups. DISCUSSION

This retrospective study sought to evaluate the long-term outcomes of patients who underwent OLT due to HCC in the setting of virus-related versus virus-unrelated cirrhosis. Currently, 1 previous study compared HCC clinical presentations and outcomes after OLT in these settings.14 The development of HCC is associated with various independent risk factors that cause differences in tumor aggressiveness and natural history.14 An HCC diagnosis is sometimes delayed among patients not affected by liver disease due to the lack of specific symptoms or, more probably, of appropriate clinical and instrumental follow-ups, as, instead, tend to occur among patients with liver disease.4,5,18 However, the therapeutic approach for HCC is the same between patients with or without liver disease; whereas, their outcome in term of long term survival and recurrence free survival is different. The leading cause of these differences is related to the liver disease itself, which plays a role in HCC pathogenesis and also in posttreatment recurrence. As previously reported in the literature, noncirrhotic HCC patients show more advanced tumor features at the time of diagnosis; they are generally detected at a symptomatic stage.4,6 Despite that finding, the outcomes of these patients after liver resection seem to be better than those of subjects with underlying cirrhosis probably because of the preserved function of the liver generally offers the chance to perform very large resections.4,6,18,19 As opposed to liver resection, the long-term outcomes after OLT among patients with HCC in noncirrhotic livers are poor due to the advanced tumor stage, which leads to an high recurrence rate.20 Moreover, apart from the coexisting liver cirrhosis, patients affected with viral hepatitis seem to show a major risk to develop HCC and tumor recurrences after treatment, due not only to cirrhosis, but also to a specific oncogenetic role of HBV and HCV. Some authors have demonstrated a direct relationship between virus activity and HCC, demonstrating that controlling virus replication may obtain a better recurrence-free survival after liver resection.13,21 They have reported that tumor factors were associated with early HCC recurrence, whereas high viral loads and hepatic inflammatory activity were associated with late recurrence. Moreover, other authors have suggested that antiviral therapy for chronic hepatitis B with advanced liver disease reduces HCC as well as interferon therapy after resection reduces late recurrences in HCVrelated HCC patients.22 In this view, patients who undergo OLT due to HCC may have different outcomes based on the virus or no virus

HCC AND UNRELATED VIRAL CIRRHOSIS

relation to their liver disease. In our experience, despite the different baseline cancerogenesis in the 2 groups of cirrhotic patients, the tumor features did not show significant differences, apart for rate of patients with G3 tumor grading and rate of patients with vascular invasion. No patient developed HBV recurrence thanks to the HBV prophylaxis protocol, and only 1 patient died due to HCV recurrence, without signs of HCC recurrence at the time of death. Our data demonstrated that long-term patient and recurrence-free survival rates were similar for virus-related versus virus-unrelated liver disease. Thus, HBV or HCV infections were not associated with poor patient outcomes, in terms of HCC recurrence, compared with patients with virus unrelated cirrhosis. We acknowledge the small sample size of patients in the virus-unrelated cirrhosis group as a major limitation of our study. We may explain our data to be a consequence of appropriate virus replication control after liver transplantation. Indeed, after OLT progression to cirrhosis in an accelerated process probably attributable to virus activity in the background of immunosuppression.14,22-24 This accelerated progression of histopathologic changes associated with viral activity under immunosuppression was also related to accelerated HCC tumor outcomes in terms of recurrence. This mechanism could explain the results reported by Bozorgzadeh et al14—that HCV was an independent significant predictor of HCC recurrence after OLT. In conclusion, OLT represents the best treatment for patients affected by HCC, even among those with HCC not associated with a viral cirrhosis, although the tumor pathogenesis is different. After OLT, HCC outcomes were not different between patients with virus-related versus -unrelated liver cirrhosis. The direct oncogenetic role played by HBV and HCV seems to not be associated with a higher risk to develop HCC recurrence after OLT. REFERENCES 1. World Health Organization: Mortality database. Available from: www.who.int/whosis/en 2. Chuang SC, La Vecchia C, Boffetta P: Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett 286:9, 2009 3. Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 362:1907, 2003 4. Lubrano J, Huete E, Tsilividis B, et al: Long-term outcome of liver resection for hepatocellular carcinoma in noncirrhotic nonfibrotic liver with no viral hepatitis or alcohol abuse. World J Surg 32:104, 2008 5. Stroffolini T, Sagnelli E, Mariano A, et al: Characteristics of hepatocellular carcinoma in Italy. J Epatol 29:944, 1998

1215 6. Chang CH, Chau GY, Lui WY, et al: Long term results of hepatic resection for hepatocellular carcinoma originating from the noncirrhotic liver. Arch Surg 139:320, 2004 7. Farazi PA, DePinho RA: Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674, 2006 8. Yuen MF, Tanaka Y, Shinkai N, et al: Risk for hepatocellular carcinoma with respect to hepatitis b virus genotype B/C, specific mutations of enhancer II/core promoter/precor regions and HBV DNA levels. Gut 57:98, 2008 9. Ray RB, Meyer K, Ray R: Hepatitis c virus core protein promotes immortalization of primary human hepatocytes. Virology 271:197, 2000 10. Fao JG, Farrel GC: Prevention of hepatocellular carcinoma in nonviral-related liver disease. J Gastroenterol Hepatol 24:712, 2009 11. Morgan TR, Mandayam S, Jamal M: Alcohol and hepatocellular carcinoma. Gastroenterology 127:87, 2004 12. Kowdley KV: Iron, hemochromatosis, an hepatocellular carcinoma. Gastroenterology 127:79, 2004 13. Wu JC, Huang YH, Chau GY, et al: Risk factors for early and late recurrence in hepatitis B- related hepatocellular carcinoma. J Hepatol 51:890, 2009 14. Bozorgzadeh A, Orloff M, Tsoulfas G, et al: Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis c versus other etiology of corrhosis. Liver Transplantation 13:807, 2007 15. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693, 1996 16. United Network for Organ Sharing: Policy 3.6: Available at: http://www.unos.org/policiesandbyaws/policies.asp?resources⫽true 17. Belli L, Burroughs AK, Alberti AB, et al: Liver transplantation for HCV cirrhosis: improved survival in recent years and increased severity of recurrent disease in female recipients: results of a long term retrospective study. Liver Transpl 13:733, 2007 18. Xu L, Huang L, Li BK, et al: Clinicopathologic features and long-term outcomes of chinese patientswith hepatocellular carcinoma in non-cirrhotic liver. Dig Surg 25:376, 2008 19. Shimada M, Rikimaru T, Sugimaky K, et al: The importance of hepatic resection for hepatocellular carcinoma originating from nonfibrotic liver. J Am Coll Surg 191:531, 2000 20. Houben KW, McCall JL: Livr transplantation for hepatocellular carcinoma in patients without underlyingliver disease: a sistematic review. Liver Transplant Surg 5:91, 1999 21. Inamura H, Matsuyama Y, Tanaka E, et al: Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma aftre hepatectomy. J Hepatol 38:200, 2003 22. Mazzaferro V, Romito R, Schiavo M, et al: Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver rection in HCv cirrhosis. Hepatology 44:1543, 2006 23. Berenguer M: Host and donor risk factors before and after liver transplantation that impact HCv recurrence (review). Liver Transpl 9:S44, 2003 24. Rodriguez-Luna H, vargas HE: Natural history of hepatitis C and outcomes following liver transplantation. Minerva Gastroenterol Dietol 50:51, 2004