ARTICLE

Long-term Results of Incidental Hepatocellular Carcinoma After Liver Transplant
Sema Aktas,1 Hamdi Karakayali,1 Gokhan Moray,1 Nihan Haberal,2 Banu Bilezikci,2 Mehmet Haberal1

Objectives: The incidence of detecting hepatocellular carcinoma in a removed recipient liver after a liver transplant is not rare. Here, we sought to evaluate incidental hepatocellular carcinoma at our center.

Materials and Methods: Among 296 patients who had undergone a liver transplant between September 2001 and November 2010, we retrospectively analyzed the outcomes of 6 patients with incidental hepatocellular carcinoma. The proportion of incidental hepatocellular carcinoma was 2%. The rate of incidental hepatocellular carcinoma among all hepatocellular carcinoma patients is 11.5%. There were 3 children and 3 adults (mean age, 28.3 ± 26 years; age range, 1-57 years). Two of the 6 patients were 1 year old. Alpha-fetoprotein levels were mildly elevated in 3 patients.

Results: The results of preoperative imaging studies in all patients were normal, except for those that demonstrated regenerative or dysplastic nodules. One of the grafts was from a deceased donor, the remaining 5 were from living-related donors. We encountered no complications after the transplants. Pathology findings showed a mean tumor size of
0.8 ± 0.3 cm (range, 0.5-1.2 cm) and multiplicity in 1 patient. One patient with multiple tumors had microvascular invasion. According to the Tumor Node Metastasis staging system, 5 patients had Stage I, and the remaining patient had Stage II carcinoma. There were no recurrences of hepatocellular carcinoma, and no deaths occurred during a mean follow-up of 63 ± 16.5 months (range, 33-79 months).

Conclusions: The incidence of hepatocellular carcinoma in patients with cirrhosis who have undergone a liver transplant at our hospital is similar to those reported in other studies. Incidentally found hepatocellular carcinomas showed less-invasive pathologic features and better prognoses than did preoperatively found hepatocellular carcinomas.

Key words: Hepatocellular carcinoma, Liver trans­plantation, Alpha-fetoprotein

Introduction

Orthotopic liver transplant is the best treatment for end-stage liver disease and hepatocellular carcinoma (HCC) if no contraindications exist.1 Because of high recurrence rates for advanced HCC in initial series of liver transplants, most transplant units use highly restrictive protocols to decrease recurrence rates and improve their results. Imaging examinations are used pretransplant for HCC diagnosis. However, these examinations do not diagnose lesions smaller than 2 cm.2 The literature describes an average of 20% of incidental HCC (iHCC) observed in explanted livers with similar results after liver transplant owing to nonneoplastic hepatic disease.3, 4 Several reports show better results and have low recurrence rates for iHCC compared with preoperatively diagnosed HCC.5, 6 However, other authors report poor long-term outcomes with iHCC.7-9 This study sought to evaluate the clinical and pathologic features of liver transplants with iHCC at our center.

Patients and Methods

From September 2001 to November 2010, 296 liver transplants were performed for 289 patients at Baskent University’s Department of General Surgery and Transplantation in Ankara, Turkey. Of these 289 patients, 46 patients underwent a liver transplant for HCC, and another 6 were identified as having iHCC on their pathology reports. There were 3 children and 3 adults (mean age, 28.3 ± 26 years; age range, 1-57 years). Two of these patients were 1 year old. All patients were male. The causes for undergoing a liver transplant were progressive familial intrahepatic cholestasis in 2 patients, hepatitis B viral infection in 2, Wilson disease in 1, and cryptogenic cirrhosis in 1. All grafts were obtained from living-related liver donors except 1, which was obtained from a deceased donor.

An incidental hepatocellular carcinoma is defined as a hepatocellular carcinoma that was not diagnosed before liver transplant with pretransplant imaging studies and was found only by the pathological review of the explanted liver. Pretransplant imaging studies included serum alpha-fetoprotein level, a 3-phase helical abdominal computed tomography, and an abdominal ultrasonography. A pathology examination was done for all explanted livers. Serial sections were taken at 5-mm cross-sections. All of the suspected nodules in macroscopy were isolated for microscopic examination.

All patients initially received a calcineurin inhibitor-based immunosuppressive regimen after the liver transplant. In 1 patient who developed an increase of creatine, we changed from tacrolimus to sirolimus. Tacrolimus blood levels were maintained between 10 and 15 ng/mL during the first month and then between 5 and 10 ng/mL thereafter. Methylprednisolone (10 mg/kg) was administered intraoperatively. It was continued, postoperatively, from 10 mg/kg, tapered to 0.1 mg/kg at the end of the first month, and then stopped at the end of the third month. No postoperative chemotherapy was administered to any patient. Tumor recurrence was evaluated every 3 months by measuring serial alpha-fetoprotein levels and performing abdominal ultrasonography. Additionally, abdominal or chest computed tomography scans were evaluated every 6 months.

Results

The proportion of iHCC among all HCC was 11.5% (6 of 52 patients). Preoperative imaging studies revealed regenerative nodules in all 6 patients. The average calculated Model End-Stage Liver Disease score for adult patients was 24 (range, 16-36), the average calculated Pediatric End-Stage Liver Disease score for pediatric patients was 29 (range, 26-32). According to the Child-Pugh Classification system, 2 patients were in class B, and 4 were class C. Preoperative alpha-fetoprotein levels were normal in 3 patients and mildly elevated in the remaining 3. The mean alpha-fetoprotein level was 3.98 IU/mL (range, 1.9-8.3 IU/mL).

Pathology findings were as follows: The mean size was 0.8 ± 0.3 cm (range, 0.5-1.2 cm). Multiplicity was detected in 1 patient whose native liver consisted of 3 tumors. The diameters of these 3 tumors were 0.7, 0.5, and 0.6 cm. In the remaining 5 patients, each native liver had a single tumor. The diameters of these tumors were 0.5, 0.6, 1.1, 1.2, and 1.1 cm. In 1 patient, the tumor showed poor differentiation. In the remaining 5 patients, the tumors were intermediate in 3, and well-differentiated in 2. The Edmonson grades were grade 1 in two patients, grade 2 in three patients, and grade 3 in the remaining patient. According to the Tumor Node Metastasis staging system, 5 patients had Stage I carcinoma, and the remaining patient had Stage II. In terms of vascular invasion, 5 patients showed no signs of vascular involvement; the remaining patient showed microscopic invasion of the portal vein branches. The patient who had microvascular invasion had a poorly differentiated, grade 3 tumor. Patients and tumor characteristics are summarized in the Table. The mean follow-up was 63 ± 16.5 months (range, 33-79 mo). No recurrences and no deaths occurred during follow-up.

Discussion

Presence of iHCC in explanted liver specimens varies between 4.2% and 40%.5, 7-9 Mion and associates10 reported a prevalence of 17.5% of iHCC 80 liver explants. On the other hand, Loinaz and associates reported an incidence of 2.8% of iHCC.6 In our study, the incidence of iHCC in liver explants was 2%, and the incidence of iHCC among all hepatocellular carcinoma patients was 11.5%, which was comparable to the other studies.

There is persistent controversy regarding the effect of incidental cancers on patient survival and disease-free survival. Sotiropoulos and associates4 reviewed 31 studies with a total of 705 patients with iHCC and found that survival was better for iHCC than other HCC in studies representing only 24 patients (3%). In 343 patients (49%), survival was no better in an iHCC than in other HCC; in the remaining 338 patients (47%), no comparison was made. Klintmalm,8 in an initial analysis of his International Tumor Registry, found no survival advantage in 169 patients with iHCC versus 253 patients with other HCC. A subsequent analysis of the database11 found an advantage in survival and recurrence-free survival in 324 patients with iHCC versus 466 patients with other HCC. Both studies were remarkable for a high percentage of the reported HCC being incidental. There were no recurrences and mortality of iHCC in our patients. According to our results, similar to previous reports,5, 6, 12 iHCC a had less-invasive pathologic features and a better prognosis than did preoperatively diagnosed HCC.

The preoperative diagnosis of these small lesions is difficult because of some similarities with regeneration nodules in cirrhotic livers in imaging results. Despite its frequent use, imaging methods may underestimate the number of HCC in cirrhotic livers, as shown by previous studies that compared ultrasonography, computerized tomography, and magnetic resonance with morphologic studies of the explanted livers, mainly in early stage tumors, which are defined as lesions up to 2.0 cm.13, 14, 15 Ultrasonography is not sensitive enough to detect HCC in patients with advanced cirrhosis, and as such, is not an appropriate modality for this purpose. In addition, enhanced computed tomography scans have a true sensitivity of 68% to 71% in detecting malignancy,5, 6 and are particularly insensitive to HCC that are smaller than 2 cm in a cirrhotic liver. We believe that the reason we could not detect HCC preoperatively in these 6 patients, was because the largest tumor diameter in our study was only 1.2 cm.

Loinaz and associates reported their series that included 12 iHCC patients and 4 patients with mildly elevated preoperative alpha-fetoprotein levels.6 Raphe and associates reported 27 iHCC patients who had normal alpha-fetoprotein levels.16 In our study, the preoperative alpha-fetoprotein levels were normal in 3 patients, and mildly elevated in the other 3. The mean alpha-fetoprotein level was 3.98 IU/mL. The cases of iHCC showed less multiplicity and bilobar distribution and were more likely to be well-differentiated compared with nonincidental tumors.5, 7 Cho and associates, in an analysis of iHCC, observed 77% to be well-differentiated tumors, 74.1% were free of vascular invasion, and the mean tumor size was 2 cm.7 In relation to the Edmondson and Steiner classification, Choi and associates highlighted the presence of well-differentiated tumors: 60% degree 1, and 40% degree 2.5 In the study by Raphe and associates, 96% of tumors were well-differentiated.16 Our study included 1 poor, 3 moderate, and 2 well-differentiated tumors. A multifocal tumor was diagnosed in only 1 patient.

In conclusion, it is important to study explanted liver specimens carefully for the possibility of detecting iHCC. Although there were no cases of recurrence after liver transplant with iHCC at our center, it is important that such cases are followed-up closely postoperatively owing to the possibility of recurrence.

References:

  1. Karakayali H, Sevmis S, Moray G, et al. Liver transplantation in patients with hepatocellular carcinoma: one center's experience. Transplant Proc. 2008;40(1):213-218.
  2. Adham M, Oussoultzoglou E, Ducerf C, et al. Results of orthotopic liver transplantation for liver cirrhosis in the presence of incidental and/or undetected hepatocellular carcinoma and tumor characteristics. Transpl Int. 1998;11(suppl 1):197-200.
  3. Castillo E, Pelletier S, Kumer S, Abouljoud M, Divine G, Moonka D. Incidental hepatocellular carcinoma after liver transplantation: population characteristics and outcomes. Transplant Proc. 2009;41(1):219-221.
  4. Sotiropoulos GC, Malago M, Molmenti EP, et al. Liver transplantation and incidentally found hepatocellular carcinoma in liver explants: need for a new definition. Transplantation. 2006;81(4):531-535.
  5. Choi SH, Lee HH, Lee DS, et al. Clinicopathological features of incidental hepatocellular carcinoma in liver transplantation. Transplant Proc. 2004;36(8):2293-2294.
  6. Loinaz C, Abradelo M, Gómez R, et al. Liver transplantation and incidental primary liver tumors. Transplant Proc. 1998;30(7):3301-3302.
  7. Cho CS, Knechtle SJ, Heisey DM, et al. Analysis of tumor characteristics and survival in liver transplant recipients with incidentally diagnosed hepatocellular carcinoma. J Gastrointest Surg. 2001;5(6):594-601; discussion 601-602.
  8. Klintmalm GB. Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg. 1998;228(4):479-490.
  9. Charco R, Hidalgo E, Lázaro JL, et al. Outcome of cirrhotic patients with incidental hepatocellular carcinoma undergoing liver transplantation. Transplant Proc. 2002;34(1):299-300.
  10. Mion F, Grozel L, Boillot O, Paliard P, Berger F. Adult cirrhotic liver explants: precancerous lesions and undetected small hepatocellular carcinomas. Gastroenterology. 1996;111(6):1587-1592.
  11. Molmenti EP, Klintmalm GB. Liver transplantation in association with hepatocellular carcinoma: an update of the International Tumor Registry. Liver Transpl. 2002;8(9):736-748.
  12. Toufeeq Khan TF, Reddy KS, Johnston TD, Ranjan D. Orthotopic liver transplantation in hepatocellular carcinoma: comparison of results in incidental and known hepatocellular carcinoma. Int Surg. 2006;91(4):185-187.
  13. Libbrecht L, Bielen D, Verslype C, et al. Focal lesions in cirrhotic explanted livers: pathological evaluation and accuracy of pretransplantation imaging examinations. Liver Transplant. 2002;8(9):749-761.
  14. Krinsky GA, Lee VS, Theise ND, et al. Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: prospective diagnosis with MR imaging and explantation correlation. Radiology. 2001;219(2):445-454.
  15. Farinati F, Sergio A, Baldan A, et al. Early and very early Hepatocellular carcinoma. When and how much do staging and choice of treatment really matter? BMC Cancer. 2009;9:33.
  16. Raphe R, Felý´cio HCC, Rocha MF, et al. Histopathologic characteristics of incidental hepatocellular carcinoma after liver transplantation. Transplant Proc. 2010;42(2):505-506.
 

Volume : 9
Issue : 3
Pages : 187-190

PDF VIEW

 

From the Departments of 1General Surgery and 2Pathology, Baţkent University Faculty of Medicine, Ankara, Turkey
Address reprint requests to: Mehmet Haberal, MD, FACS (Hon), FICS (Hon), Baskent University, 1. Cad. No: 77 Kat:4 Bahcelievler, 06490, Ankara, Turkey
Phone: + 90 312 212 7393
Fax: +90 312 215 0835
E-mail: rektorluk@baskent-ank.edu.tr

 

Table. Patients and hepatocellular carcinoma characteristics.

 

Copyright © Baskent University 2003. Printed in Turkey. All Rights Reserved.