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Sensitive Serum Parameters for Hepatocellular Carcinoma Recurrence Monitoring After Liver Transplantation: A Case Report
Sensitive Serum Parameters for Hepatocellular Carcinoma Recurrence Monitoring After Liver Transplantation: A Case Report D. Duller, Jr, P. Stiegler, M. Schweiger, J. Kahn, D. Kniepeiss, E. Jakoby, K. Tscheliessnigg, and F. Iberer ABSTRACT Liver cell malignancy can be seen as one of the most common indications for hepatic transplantation, but the recurrence potential of the disease significantly limits its beneficial effects. Hepatic factors influencing the recurrence rate, such as nodule size and criteria wherein transplantations are expedited, are still investigated. Pretransplant intraarterial or percutaneous treatement seem to be predictive for recurrence-free patient survival. Early detection of malignancies via serum parameters as a prognostic factor seems promising. This article reports a special case, where despite an elevated, sensitive, serum marker profile, no HCC recurrence was detected over a 2-year follow-up.
H
EPATOCELLULAR CARCINOMA (HCC) is one of the five most common malignant tumors worldwide.1 Tumor resection or liver replacement within the Milan criteria2,3 is the only curative treatment. Although recurrence in the transplanted liver is not likely for small size HCC and the survival rate nearly approaches the normal,4 it still limits the benefit of the treatment itself. The 2-year graft survival ranges around 56%.5 Hepatic factors influencing the probability of HCC recurrence in the transplanted organ include size, number of lesions, and presence of microscopic vascular invasion. The early detection of HCC and the cutoff diameter for therapy are most important.6 Serum parameters combined with imaging techinques are used for detection at the earliest possible stage. ␣-Fetoprotein (AFP) is the most useful but not the most sensitive serologic marker to detect HCC recurrence after resection or transplantation. The serum tissue polypeptidespecific antigen (TPS) in addition to AFP and serum polypeptide antigen (TPA) have been shown to be predictive indicators for malignant hepatocellular proliferation.7 Apart from markers for disease recurrence, continuous radiologic observation and staging therapies are available to monitor the proliferation. Ablative treatment using chemical or thermal techniques provides locally effective tumor destruction.8,9 Combinations of transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection, and radiofrequecy ablation have been shown to be predictive for tumorfree graft survival. TACE is used as an adjunct to surgical resection and bridging therapy preceding liver transplantation. Some studies have reported a higher risk for HCC among patients with untreated tumors compared with patients
undergoing interventional bridging methods.10,11 Especially within limits of no vascular invasion or extrahepatic disease, TACE is useful to impede tumor progression.12 In clear contrast, Pérez Sborido et al13 showed that there was no significant benefit for tumor recurrence after liver transplantation for patients who previously underwent TACE.10 Data for the efficacy of adjuvant interventional radiologic treatments combined and measurement of serum markers were the objectives of this study. CASE REPORT
A 62-years-old woman suffering from hepatic cirrhosis, (Child B) based on hepatitis C viral (HCV) infection showed incessantly increased AFP levels. A biopsy performed in July 1997 showed hepatic infiltration and dysplastic cells, compatible with HCV. Pegylated interferon in combination with ribavirin was administered, but produced no response with constantly elevated liver enzymes and severe side effects. The therapy was discontinued in January 2002. The patient was a transplant candidate with MELD score of 11; aspartate aminotransferase (AST), 65 U/L; alanine aminotransferase (ALT), 35 U/L; ␥-glutamyl transferase (GGT), 24 U/L; CHE, 1501 U/L; ATIII, 44%; bilirubin 1, 67 mg/dL, and a hepatitis C PCR of 201,000 copies/mL. From the Department of Transplantation, Medical University Graz, Gratz, Styria, Austria. Address reprint requests to Doris Duller, Jr, Medical University Graz, Auenbruggerplatz 29, Graz, Styria A-8036, Austria. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.04.030
Transplantation Proceedings, 39, 3281–3283 (2007)
3281
3282
DULLER, STIEGLER, SCHWEIGER ET AL
Table 1. Pre- and Posttransplant TPA, TPS, and AFP Levels Time (mos)
Pretransplant 4 2 1 Posttransplant 4 6 10 16 18
TPA
TPS
AFP
179.3 62.6 38
497.5 228.1 358.8
13.8 17.8 1.8
117.1 135.2 122.4 121.1 178.4
404.9 831.3 778.3 691.7 920.5
0.8 1.6 1.9 1.8 2.2
The AFP level was 35 E/mL without evidence of expansion on computed tomography (CT). The patient was listed in August 2002 as status T4 (transplantable without complications). Due to elevated liver enzyme levels, a CT performed in September 2002 showed a subcapsular lesion in liver segments VII/VIII. In November 2002, a control CT showed increasing size of this lesion from 15 to 24 mm diameter, resulting in an initial TACE with a farmborubicin lipidol mixture. A control CT scan in December 2002 revealed no regression of the tumor. Furthermore, additional lipidol uptake was observed in a fresh lesion located in segment V. The AFP level remained steady. CT scans in March 2003 showed a reduction in diameter of the primary lesion to 15 mm but also a progression of the satellite expansion. Upon another TACE performed in July 2003, lipidol uptake was shown in segments VIII, VII, and VI. The following routine staging CT in October 2003 showed a nonvital area located in segment VIII without any sign of an active tumor lesion. AFP values were declined to 24 E/mL with a cascading bias to 13 E/mL in July 2004. The TPA and TPS levels were first taken 6 months before transplantation. Both showed a massive decrease, according to the chemoembolizations (Table 1). Further CT studies remained without signs of proliferation. After waiting 690 days, the patient was transplanted in August 2004 in our center using a piggyback technique with retrograde reperfusion.14 The histology of the explanted organ showed 100% necrotic expansion in the right liver lobe, dysplastic cells owing to chronic HCV infection, but no further evidence of malignancy. Initial immunosuppression including acrolimus, mycophenolate mofetil (MMF), and prednisolone was switched to MMF with sirolimus at 8 weeks after liver transplantation with sirolimus target trough levels between 10 and 12 ng/mL. Up to now, blood samples obtained every 3 months show AFP levels outside the interventional range and TPS and TPA levels constantly elevated (Table 1). CT scans are performed every 6 months without evidence of expanding lesions.
DISCUSSION
Within Eurotransplant, only 7.33% of liver transplant candidates are registered due to HCC15 as the primary disease. The number of grafts with neoplastic proliferation detected after transplantation in the explanted organ has only been estimated. Interventional bridging therapies can rarely be used as a curative treatment. The scarcity of cadaveric as well as living related donor organs has made bridging strategies the only chance to remain on the waiting list. Studies suggest that neither bridging nor staging within the Milan criteria has any impact on graft or patient survival.10,16 In this patient, continuous bridging through transarterial intervention led to complete tumor necrosis without return in the graft despite suggestive serum parameters. Even though the correlation between HCV-positive serology and the occurrence or rapid recurrence of HCC has been proven, as molecular events triggered by HCV might lead and maintain hepatic carcinogenesis,17 our patient had a 22-month follow-up without HCC recurrence. Elevated levels of serum indicators for HCC suggested a reccurrence of carcinoma, but no evidence of malignant cell proliferation was observed on radiological diagnosis. We think that in our case, with HCC of multifactorial genesis, TACE was the best interventional bridging technique, to bypass the long waiting time, caused by the rare blood group of the patient and her height and weight. Only one episode of interventional treatment as a bridging technique has been reported in the literature.13,18 According to Graziadei et al,12 the high frequency of TACE in our patient might have led to the complete necrosis but cannot be seen to be preventive for recurrence. The combination with serum parameters allows monitoring of the malignant potential and early staging and detection of suspected lesions. Serum TPS levels ⬎150 U/L have been reported to have a 50% recurrence rate at 12 months after resection or transplantation.19 The follow-up time now exceeds 10 months without evidence of recurrence. The benefit of TACE as an HCC recurrence-preventive treatment is underlined. The combination with monitoring serum parameters is a step toward a predictive transparent follow-up, providing foresight toward recurrence of malignancies. In clear contrast with the published results of elevated sensitive serum markers, that suggest recurrence, this was not correct in this case. The current discussion on recurrence rate after liver transplantation meeting the Milan criteria and the nearby acceptable results of some studies20 lead to the need for inclusion of additional parameters to distinguish liver transplant candidates suffering from HCC. Serum parameters will definitely have to be included as sensitive parameters, but as underlined by the mentioned case they are not sufficient to monitor recurrence.
POSTTRANSPLANT HCC RECURRENCE MONITORING
REFERENCES 1. INCTR: International Cancer Treatment and Network, at the Institute Pasteur, Rue Engeland 642, Bruessels. Available: www. inctr.org 2. 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 3. Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 33:1394, 2001 4. David S, Kotlyar BS, Mical S, et al: Recurrence of diseases after orthotopic liver transplantation. Am J Gastroenterol 101: 1370, 2006 5. Eurotransplant International Foundation: Statistical analysis via survival curves. Available: www.eurotransplant.nl 6. Grasso A, Stigliano R, Morisco F, et al: Liver transplantation and recurrent hepatocellular carcinoma: predictive value of nodule size in a retrospective and explant study. Transplantation 18:1532, 2006 7. Tu DG, Wang ST, Chang TT, et al: The value of serum tissue polypeptide specific antigen in the diagnosis of hepatocellular carcinoma. Cancer 85:1039, 1999 8. Lubienski A: Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 80(suppl 1):S113, 2005 9. Cormier JN, Thomas KT, Chari RS, et al: Managemt of hepatocellular surgery. J Gastrointest Surg 10:761, 2006 10. Sotiropoulos GC, Malago M, Molmenti EP, et al: Disease course after liver transplantation for hepatocellular carcinoma in patients with complete tumor necrosis in liver explants after performance of bridging treatments. Eur J Med Res 10:539, 2005
3283 11. Harnois DM, Steers J, Andrews JC, et al: Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transplant Surg 5:192, 1999 12. Graziadei IW, Sandmueller H, Waldenberger P, et al: Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transplant 9:557, 2003 13. Pérez Sborido B, Juan Carlos M, Moreno E, et al: Is transarterial chemoembolization necessary before liver transplantation for hepatocellular carcinoma? J Surg 190:383, 2005 14. Kniepeiss D, Iberer F, Grasser B, et al: A single-centre experience with retrograde reperfusion in liver transplantation. Transplant Int 16:730, 2003 15. Eurotransplant International Foundation Data Base: Available: www.eurotransplant.nl 16. Decaens T, Roudot-Thoraval F, Solange BH, et al: Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma. Liver Transplant 11:767, 2005 17. Khalifa A, Mady EA, Abadeer N, et al: Differential tumor markers and hepatitis markers profile in liver tumors. Anticancer Res 19:249, 1999 18. Livraghi T: Guidelines for treatement of liver cancer. Eur J Ultrasound 13:167, 2001 19. Yao WJ, Wang ST, Chow NH, et al: Serum tissue polypeptide specific antigen as a noninvasive prognostic indicator for early recurrence of hepatocellular carcinoma after curative resection. Cancer 19:112, 2002 20. Yao YF, Hirose R, La Berge JM, et al: A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transplant 11:1505, 2005
H
EPATOCELLULAR CARCINOMA (HCC) is one of the five most common malignant tumors worldwide.1 Tumor resection or liver replacement within the Milan criteria2,3 is the only curative treatment. Although recurrence in the transplanted liver is not likely for small size HCC and the survival rate nearly approaches the normal,4 it still limits the benefit of the treatment itself. The 2-year graft survival ranges around 56%.5 Hepatic factors influencing the probability of HCC recurrence in the transplanted organ include size, number of lesions, and presence of microscopic vascular invasion. The early detection of HCC and the cutoff diameter for therapy are most important.6 Serum parameters combined with imaging techinques are used for detection at the earliest possible stage. ␣-Fetoprotein (AFP) is the most useful but not the most sensitive serologic marker to detect HCC recurrence after resection or transplantation. The serum tissue polypeptidespecific antigen (TPS) in addition to AFP and serum polypeptide antigen (TPA) have been shown to be predictive indicators for malignant hepatocellular proliferation.7 Apart from markers for disease recurrence, continuous radiologic observation and staging therapies are available to monitor the proliferation. Ablative treatment using chemical or thermal techniques provides locally effective tumor destruction.8,9 Combinations of transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection, and radiofrequecy ablation have been shown to be predictive for tumorfree graft survival. TACE is used as an adjunct to surgical resection and bridging therapy preceding liver transplantation. Some studies have reported a higher risk for HCC among patients with untreated tumors compared with patients
undergoing interventional bridging methods.10,11 Especially within limits of no vascular invasion or extrahepatic disease, TACE is useful to impede tumor progression.12 In clear contrast, Pérez Sborido et al13 showed that there was no significant benefit for tumor recurrence after liver transplantation for patients who previously underwent TACE.10 Data for the efficacy of adjuvant interventional radiologic treatments combined and measurement of serum markers were the objectives of this study. CASE REPORT
A 62-years-old woman suffering from hepatic cirrhosis, (Child B) based on hepatitis C viral (HCV) infection showed incessantly increased AFP levels. A biopsy performed in July 1997 showed hepatic infiltration and dysplastic cells, compatible with HCV. Pegylated interferon in combination with ribavirin was administered, but produced no response with constantly elevated liver enzymes and severe side effects. The therapy was discontinued in January 2002. The patient was a transplant candidate with MELD score of 11; aspartate aminotransferase (AST), 65 U/L; alanine aminotransferase (ALT), 35 U/L; ␥-glutamyl transferase (GGT), 24 U/L; CHE, 1501 U/L; ATIII, 44%; bilirubin 1, 67 mg/dL, and a hepatitis C PCR of 201,000 copies/mL. From the Department of Transplantation, Medical University Graz, Gratz, Styria, Austria. Address reprint requests to Doris Duller, Jr, Medical University Graz, Auenbruggerplatz 29, Graz, Styria A-8036, Austria. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.04.030
Transplantation Proceedings, 39, 3281–3283 (2007)
3281
3282
DULLER, STIEGLER, SCHWEIGER ET AL
Table 1. Pre- and Posttransplant TPA, TPS, and AFP Levels Time (mos)
Pretransplant 4 2 1 Posttransplant 4 6 10 16 18
TPA
TPS
AFP
179.3 62.6 38
497.5 228.1 358.8
13.8 17.8 1.8
117.1 135.2 122.4 121.1 178.4
404.9 831.3 778.3 691.7 920.5
0.8 1.6 1.9 1.8 2.2
The AFP level was 35 E/mL without evidence of expansion on computed tomography (CT). The patient was listed in August 2002 as status T4 (transplantable without complications). Due to elevated liver enzyme levels, a CT performed in September 2002 showed a subcapsular lesion in liver segments VII/VIII. In November 2002, a control CT showed increasing size of this lesion from 15 to 24 mm diameter, resulting in an initial TACE with a farmborubicin lipidol mixture. A control CT scan in December 2002 revealed no regression of the tumor. Furthermore, additional lipidol uptake was observed in a fresh lesion located in segment V. The AFP level remained steady. CT scans in March 2003 showed a reduction in diameter of the primary lesion to 15 mm but also a progression of the satellite expansion. Upon another TACE performed in July 2003, lipidol uptake was shown in segments VIII, VII, and VI. The following routine staging CT in October 2003 showed a nonvital area located in segment VIII without any sign of an active tumor lesion. AFP values were declined to 24 E/mL with a cascading bias to 13 E/mL in July 2004. The TPA and TPS levels were first taken 6 months before transplantation. Both showed a massive decrease, according to the chemoembolizations (Table 1). Further CT studies remained without signs of proliferation. After waiting 690 days, the patient was transplanted in August 2004 in our center using a piggyback technique with retrograde reperfusion.14 The histology of the explanted organ showed 100% necrotic expansion in the right liver lobe, dysplastic cells owing to chronic HCV infection, but no further evidence of malignancy. Initial immunosuppression including acrolimus, mycophenolate mofetil (MMF), and prednisolone was switched to MMF with sirolimus at 8 weeks after liver transplantation with sirolimus target trough levels between 10 and 12 ng/mL. Up to now, blood samples obtained every 3 months show AFP levels outside the interventional range and TPS and TPA levels constantly elevated (Table 1). CT scans are performed every 6 months without evidence of expanding lesions.
DISCUSSION
Within Eurotransplant, only 7.33% of liver transplant candidates are registered due to HCC15 as the primary disease. The number of grafts with neoplastic proliferation detected after transplantation in the explanted organ has only been estimated. Interventional bridging therapies can rarely be used as a curative treatment. The scarcity of cadaveric as well as living related donor organs has made bridging strategies the only chance to remain on the waiting list. Studies suggest that neither bridging nor staging within the Milan criteria has any impact on graft or patient survival.10,16 In this patient, continuous bridging through transarterial intervention led to complete tumor necrosis without return in the graft despite suggestive serum parameters. Even though the correlation between HCV-positive serology and the occurrence or rapid recurrence of HCC has been proven, as molecular events triggered by HCV might lead and maintain hepatic carcinogenesis,17 our patient had a 22-month follow-up without HCC recurrence. Elevated levels of serum indicators for HCC suggested a reccurrence of carcinoma, but no evidence of malignant cell proliferation was observed on radiological diagnosis. We think that in our case, with HCC of multifactorial genesis, TACE was the best interventional bridging technique, to bypass the long waiting time, caused by the rare blood group of the patient and her height and weight. Only one episode of interventional treatment as a bridging technique has been reported in the literature.13,18 According to Graziadei et al,12 the high frequency of TACE in our patient might have led to the complete necrosis but cannot be seen to be preventive for recurrence. The combination with serum parameters allows monitoring of the malignant potential and early staging and detection of suspected lesions. Serum TPS levels ⬎150 U/L have been reported to have a 50% recurrence rate at 12 months after resection or transplantation.19 The follow-up time now exceeds 10 months without evidence of recurrence. The benefit of TACE as an HCC recurrence-preventive treatment is underlined. The combination with monitoring serum parameters is a step toward a predictive transparent follow-up, providing foresight toward recurrence of malignancies. In clear contrast with the published results of elevated sensitive serum markers, that suggest recurrence, this was not correct in this case. The current discussion on recurrence rate after liver transplantation meeting the Milan criteria and the nearby acceptable results of some studies20 lead to the need for inclusion of additional parameters to distinguish liver transplant candidates suffering from HCC. Serum parameters will definitely have to be included as sensitive parameters, but as underlined by the mentioned case they are not sufficient to monitor recurrence.
POSTTRANSPLANT HCC RECURRENCE MONITORING
REFERENCES 1. INCTR: International Cancer Treatment and Network, at the Institute Pasteur, Rue Engeland 642, Bruessels. Available: www. inctr.org 2. 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 3. Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 33:1394, 2001 4. David S, Kotlyar BS, Mical S, et al: Recurrence of diseases after orthotopic liver transplantation. Am J Gastroenterol 101: 1370, 2006 5. Eurotransplant International Foundation: Statistical analysis via survival curves. Available: www.eurotransplant.nl 6. Grasso A, Stigliano R, Morisco F, et al: Liver transplantation and recurrent hepatocellular carcinoma: predictive value of nodule size in a retrospective and explant study. Transplantation 18:1532, 2006 7. Tu DG, Wang ST, Chang TT, et al: The value of serum tissue polypeptide specific antigen in the diagnosis of hepatocellular carcinoma. Cancer 85:1039, 1999 8. Lubienski A: Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 80(suppl 1):S113, 2005 9. Cormier JN, Thomas KT, Chari RS, et al: Managemt of hepatocellular surgery. J Gastrointest Surg 10:761, 2006 10. Sotiropoulos GC, Malago M, Molmenti EP, et al: Disease course after liver transplantation for hepatocellular carcinoma in patients with complete tumor necrosis in liver explants after performance of bridging treatments. Eur J Med Res 10:539, 2005
3283 11. Harnois DM, Steers J, Andrews JC, et al: Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transplant Surg 5:192, 1999 12. Graziadei IW, Sandmueller H, Waldenberger P, et al: Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transplant 9:557, 2003 13. Pérez Sborido B, Juan Carlos M, Moreno E, et al: Is transarterial chemoembolization necessary before liver transplantation for hepatocellular carcinoma? J Surg 190:383, 2005 14. Kniepeiss D, Iberer F, Grasser B, et al: A single-centre experience with retrograde reperfusion in liver transplantation. Transplant Int 16:730, 2003 15. Eurotransplant International Foundation Data Base: Available: www.eurotransplant.nl 16. Decaens T, Roudot-Thoraval F, Solange BH, et al: Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma. Liver Transplant 11:767, 2005 17. Khalifa A, Mady EA, Abadeer N, et al: Differential tumor markers and hepatitis markers profile in liver tumors. Anticancer Res 19:249, 1999 18. Livraghi T: Guidelines for treatement of liver cancer. Eur J Ultrasound 13:167, 2001 19. Yao WJ, Wang ST, Chow NH, et al: Serum tissue polypeptide specific antigen as a noninvasive prognostic indicator for early recurrence of hepatocellular carcinoma after curative resection. Cancer 19:112, 2002 20. Yao YF, Hirose R, La Berge JM, et al: A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transplant 11:1505, 2005