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1
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Ma KW, Cheung TT. When to consider liver transplantation in hepatocellular carcinoma patients? Hepat Oncol 2017; 4:15-24. [PMID: 30191050 PMCID: PMC6095144 DOI: 10.2217/hep-2016-0010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 04/06/2017] [Indexed: 12/12/2022] Open
Abstract
Orthotopic liver transplantation (LT) has been regarded as the best cure among the three curative treatment modalities. However, when to consider LT in hepatocellular carcinoma (HCC) patients remains a complicated clinical question. In this article, we will look into the recent updates in the context of LT for HCC, including the timing of orthotopic LT (primary or salvage LT), patient selection criteria, newer prognostic markers and scoring systems, down-staging and bridging therapy, salvage LT and treatment option of post-LT HCC recurrence. Evolution of immunosuppressive therapy and future development of the LT for HCC will also be discussed.
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Affiliation(s)
- Ka Wing Ma
- Department of Surgery, Queen Mary Hospital, the University of Hong Kong, Hong Kong
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, the University of Hong Kong, Hong Kong
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2
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Boussouar S, Itti E, Lin SJ, Decaens T, Evangelista E, Chiaradia M, Chalaye J, Baranes L, Calderaro J, Laurent A, Pigneur F, Duvoux C, Azoulay D, Costentin C, Rahmouni A, Luciani A. Functional imaging of hepatocellular carcinoma using diffusion-weighted MRI and (18)F-FDG PET/CT in patients on waiting-list for liver transplantation. Cancer Imaging 2016; 16:4. [PMID: 26883745 PMCID: PMC4756529 DOI: 10.1186/s40644-016-0062-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 02/02/2016] [Indexed: 02/08/2023] Open
Abstract
Background To compare the apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) with the standardized uptake values (SUV) measured by18F-FDG-PET/CT in naïve hepatocellular carcinoma (HCC) nodules, and to determine whether these markers are associated with tumours at high-risk of aggressiveness. Methods From 2007 to 2010, all patients with HCC on the waiting list for liver transplantation and who underwent both FDG-PET/CT and 1.5-T DWI-MRI (b values: 0, 200, 400, and 800 s/mm2) were included in this institutional review board-approved retrospective study. Tumour size, tumour ADC, tumour-to-liver ADC ratio (ADCT/L), maximal tumour SUV and tumour-to-liver SUV ratio (SUVT/L) were measured and compared to serum alpha-fetoprotein (AFP) levels, tumour size and differentiation grade on explanted specimens. Results A total of 37 HCC nodules in 28 patients were available for correlation between MRI and PET/CT, 7 of which (in 7 patients) showed a SUVT/L > 1.15. We did not find any correlation between tumour ADC or ADCT/L and tumour SUV or SUVT/L. To note, SUVT/L was positively correlated with AFP levels (R = 0.95, P ≤ 0.0001), while ADCT/L was not (P = 0.73). Twenty-four patients (with 32 nodules) underwent liver transplantation. In this subgroup, an increased SUVT/L ratio was associated with larger tumours (average size, 32 ± 14 mm; range, 18–60 mm; P < 0.0001) and with poor differentiation on pathology (grades 3 and 4; P = 0.04), while ADCT/L was neither associated with tumour size or differentiation grade. Conclusions ADC and SUV measures in HCC nodules are not correlated. SUVT/L ratio correlates with AFP levels, tumour size and poor differentiation, and should probably be integrated as a co-variable in a predictive outcome model of patients on the waiting-list for liver transplantation.
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Affiliation(s)
- Samia Boussouar
- AP-HP, Hôpitaux Universitaires Henri Mondor, Imagerie Médicale, Créteil, F-94010, France.
| | - Emmanuel Itti
- Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Médecine Nucléaire, Créteil, F-94010, France. .,INSERM Unité U 955, GRC Amyloid Research Institute, Créteil, F-94010, France. .,Service de Médecine Nucléaire, CHU Henri Mondor, 51 Avenue du Marechal de Lattre de Tassigny, 94010, Créteil, Cedex, France.
| | - Shih-Jui Lin
- Biomedical Informatics, Stanford University, Stanford, CA, 94305, USA.
| | - Thomas Decaens
- Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Hépatologie, Créteil, F-94010, France.
| | - Eva Evangelista
- AP-HP, Hôpitaux Universitaires Henri Mondor, Médecine Nucléaire, Créteil, F-94010, France.
| | - Melanie Chiaradia
- AP-HP, Hôpitaux Universitaires Henri Mondor, Imagerie Médicale, Créteil, F-94010, France. .,Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France.
| | - Julia Chalaye
- AP-HP, Hôpitaux Universitaires Henri Mondor, Médecine Nucléaire, Créteil, F-94010, France.
| | - Laurence Baranes
- AP-HP, Hôpitaux Universitaires Henri Mondor, Imagerie Médicale, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Médecine Nucléaire, Créteil, F-94010, France.
| | - Julien Calderaro
- Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Pathologie, Créteil, F-94010, France. .,INSERM Unité U 955, Equipe 18, Créteil, F-94010, France.
| | - Alexis Laurent
- Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,INSERM Unité U 955, Equipe 18, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Chirurgie hépatique, Créteil, F-94010, France.
| | - Frederic Pigneur
- AP-HP, Hôpitaux Universitaires Henri Mondor, Imagerie Médicale, Créteil, F-94010, France.
| | - Christophe Duvoux
- Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Hépatologie, Créteil, F-94010, France.
| | - Daniel Azoulay
- Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Chirurgie hépatique, Créteil, F-94010, France.
| | - Charlotte Costentin
- Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,AP-HP, Hôpitaux Universitaires Henri Mondor, Hépatologie, Créteil, F-94010, France.
| | - Alain Rahmouni
- AP-HP, Hôpitaux Universitaires Henri Mondor, Imagerie Médicale, Créteil, F-94010, France. .,Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France.
| | - Alain Luciani
- AP-HP, Hôpitaux Universitaires Henri Mondor, Imagerie Médicale, Créteil, F-94010, France. .,Université Paris Est Créteil, Faculte de Médecine, Créteil, F-94010, France. .,INSERM Unité U 955, Equipe 18, Créteil, F-94010, France.
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Mazzola A, Costantino A, Petta S, Bartolotta TV, Raineri M, Sacco R, Brancatelli G, Cammà C, Cabibbo G. Recurrence of hepatocellular carcinoma after liver transplantation: an update. Future Oncol 2015; 11:2923-36. [PMID: 26414336 DOI: 10.2217/fon.15.239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation is the only curative alternative for selected patients with hepatocellular carcinoma (HCC) who are not eligible for resection and/or with decompensated cirrhosis. According to Milan criteria the 5-year survival rate is 70-85%, with a recurrence-free survival of 75%. However, HCC recurrence rate after liver transplantation remains a significant problem in the clinical practice. The prognosis in patients with HCC recurrence is poor. The treatment of choice for HCC recurrence is surgery, but it seems that a systemic treatment based on combination of an mTOR inhibitor with sorafenib can be used. Data on safety and efficacy are limited, clinical monitoring is necessary. The aim of this review is to underline the main concerns, pitfalls and warnings for these patients.
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Affiliation(s)
- Alessandra Mazzola
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy.,Unité Médicale de Transplantation Hépatique AP-HP, Hôpital Pitié-Salpêtrière, UPMC Paris, Paris, France
| | - Andrea Costantino
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Salvatore Petta
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | | | - Maurizio Raineri
- Section of Anesthesiology, Analgesia, Intensive Care & Emergency, Department of Biopathology, Medical & Forensic Biotechnologies (DIBIMEF), Policlinico 'P Giaccone', University of Palermo, Palermo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Cisanello Hospital, Pisa, Italy
| | | | - Calogero Cammà
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
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Itri JN, Heller MT, Tublin ME. Hepatic transplantation: postoperative complications. ACTA ACUST UNITED AC 2014; 38:1300-33. [PMID: 23644931 DOI: 10.1007/s00261-013-0002-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Advances in surgical techniques and immunosuppression have made orthotopic liver transplantation a first-line treatment for many patients with end-stage liver disease. The early detection and treatment of postoperative complications has contributed significantly to improved graft and patient survival with imaging playing a critical role in detection. Complications that can lead to graft failure or patient mortality include vascular abnormalities, biliary abnormalities, allograft rejection, and recurrent or post-transplant malignancy. Vascular abnormalities include stenosis and thrombosis of the hepatic artery, portal vein, and inferior vena cava, as well as hepatic artery pseudoaneurysm, arteriovenous fistula, and celiac stenosis. Biliary abnormalities include strictures, bile leak, obstruction, recurrent disease, and infection. While imaging is not used to diagnose allograft rejection, it plays an important role in identifying complications that can mimic rejection. Ultrasound is routinely performed as the initial imaging modality for the detection and follow-up of both early and delayed complications. Cholangiography and magnetic resonance cholangiopancreatography are used to characterize biliary complications and computed tomography is used to confirm abnormal findings on ultrasound or for the evaluation of postoperative collections. The purpose of this article is to describe and illustrate the imaging appearances and management of complications associated with liver transplantation.
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Affiliation(s)
- Jason N Itri
- University of Pittsburgh Medical Center, 200 Lothrop Street Presby South Tower, Suite 4896, Pittsburgh, PA, USA,
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Welker MW, Bechstein WO, Zeuzem S, Trojan J. Recurrent hepatocellular carcinoma after liver transplantation - an emerging clinical challenge. Transpl Int 2012; 26:109-18. [PMID: 22994652 DOI: 10.1111/j.1432-2277.2012.01562.x] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective literature review addresses follow-up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced-stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.
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Affiliation(s)
- Martin-Walter Welker
- Medizinische Klinik 1, Klinikum der Johann-Wolfgang Goethe-Universität, Frankfurt am Main, Germany
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Radiologic complete response with sirolimus and sorafenib in a hepatocellular carcinoma patient who relapsed after orthotopic liver transplantation. J Gastrointest Cancer 2011; 42:50-3. [PMID: 20714941 DOI: 10.1007/s12029-010-9196-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND No standard therapies have been established for the treatment of recurrent hepatocellular carcinoma (HCC) after liver transplantation. DISCUSSION Sirolimus is a mTOR inhibitor which has been used as an immunosuppressive medication in patients who are at high risk of tumor reoccurrence after liver transplantation. Sorafenib is a multikinase inhibitor approved for the treatment of advanced HCC. However the role of sorafenib in patients with HCC reoccurrence after liver transplantation is unclear. RESULTS Combination of sirolimus and sorafenib appears to have synergistic effect when treating HCC in preclinical settings. We report a case of a post-liver transplant patient treated with sorafenib and sirolimus for hepatic HCC recurrence who exhibited complete radiologic response after 5A months of therapy.
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Alvite Canosa M, Pita Fernández S, Quintela Fandiño J, Aguirrezabalaga J, Otero A, Suárez F, Corbal G, Fernández C, Gutiérrez MG. [Surgical treatment of liver cancer: experience of the A Coruña UHC (Spain)]. Cir Esp 2011; 89:223-9. [PMID: 21353668 DOI: 10.1016/j.ciresp.2010.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Revised: 10/21/2010] [Accepted: 12/02/2010] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Liver cancer (LC) is one of the most frequent tumours, in which the potentially curative treatment is surgery: partial surgical resection or liver transplant. OBJECTIVES To determine the morbidity and mortality, survival, and their associated factors in patients with LC, according to the type of surgical treatment: partial surgical resection or liver transplant. MATERIAL AND METHODS A retrospective, observational follow-up study of LC patients diagnosed and treated from June 1994 to December 2007. A descriptive analysis of the variables was performed, as well as a Kaplan- Meier survival analysis and Cox regression. RESULTS The incidence of tumour recurrence in the 150 transplant patients was 13.3%, with a survival at 1, 3, and 5 years of 89.3%, 73.1% and 61.4%, respectively. The multivariate analysis showed that only the histological grade/differentiation was an independent risk factor. In the 33 patients with partial surgical resection, the incidence of tumour was 51.5%, with a survival at 1, 3, and 5 years of 90.9%, 60.2%, and 38.6%, respectively. A significantly higher mortality was observed in patients with higher tumour and TNM staging. CONCLUSIONS The survival throughout follow-up was higher in liver transplant, and tumour recurrence was more frequent in patients with partial surgical resection. The survival results in transplanted patients are consistent with the Spanish and European Liver Transplant Register and with the United Network for Organ Sharing register.
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Affiliation(s)
- Marlén Alvite Canosa
- Unidad de Cirugía Hepatobiliopancreática y Trasplante Hepático, Complejo Hospitalario Universitario de A Coruña, A Coruña, España.
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8
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Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg 2011; 253:166-72. [PMID: 21294289 DOI: 10.1097/sla.0b013e31820508f1] [Citation(s) in RCA: 227] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Liberal acceptance criteria are used when offering liver transplantation (LTx) for treatment of hepatocellular carcinoma (HCC) at our center. This provides a unique opportunity to assess outcomes in a large North American series of patients with advanced tumors. OBJECTIVE We hypothesized that acceptable survival rates can be achieved with LTx for any size or number of HCC provided that (a) imaging studies ruled out vascular invasion; (b) the HCC was confined to the liver; and (c) the HCC was not poorly differentiated on biopsy. METHODS Survival, based on pretransplant imaging staging, was compared between 189 Milan Criteria (M) and 105 beyond Milan Criteria (M+) HCC patients who received an LTx between 1996 and 2008. RESULTS Imaging understaged 30% of the M group and over staged 23% of the M+ group. There was no difference in the 5-year overall survival in the M (72%) and M+ (70%) groups or 5-year disease-free survival in the M (70%) and M+ (66%) groups. The introduction of a protocol for a biopsy to exclude patients with poorly differentiated tumors and use of aggressive bridging therapy improved overall survival in the M+ group (P = 0.034). Serum alpha-fetoprotein more than 400 at LTx was associated with poorer disease-free survival (hazard ratio: 2.3; P = 0.031). CONCLUSIONS Cross-sectional imaging did not reliably stage patients with HCC for LTx. A protocol using a biopsy to exclude poorly differentiated tumors and aggressive bridging therapy achieved excellent survival rates with LTx for otherwise incurable advanced HCC, irrespective of tumor size and number.
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9
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Alvite-Canosa M, Pita-Fernández S, Quintela-Fandiño J, Aguirrezabalaga J, Corbal G, Fernández C, Suárez F, Otero A, Gómez-Gutiérrez M. Prognostic and developmental factors in patients receiving liver transplant due to hepatocellular carcinoma: one center's experience in the north of Spain. Transplant Proc 2010; 42:4578-81. [PMID: 21168741 DOI: 10.1016/j.transproceed.2010.09.161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2010] [Accepted: 09/30/2010] [Indexed: 01/11/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most frequent types of tumor. The aim of this study was to determine the survival of patients who had received liver transplants as a result of the disease. METHODS This observational follow-up study included 150 patients who received liver transplantations from June 1994 to December 2007. The study considered epidemiological and staging variables, tumor descriptions, and follow-up variables. We employed Kaplan-Meier methodology together with a Cox multivariate regression analysis. RESULTS The incidence of tumor relapse was 13.3%, with survival rates at 1, 3, and 5 years of 89.3%, 73.1%, and 61.4%, respectively. Variables that showed an independent effect to predict mortality were the degree of histological differentiation and of macrovascular invasion. Patients with poorly differentiated HCC had a 4.03 fold (95% confidence interval [CI]: 1.61-10.06) greater possibility of dying. Macrovascular involvement increased the risk of death (relative risk = 2.23), an effect that was at the limit of significance (95% CI 0.99-5.04). CONCLUSIONS The survival rate was consistent with the literature. Poor tumor differentiation and macrovascular involvement were independent predictors of mortality.
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Affiliation(s)
- M Alvite-Canosa
- Liver Transplant Unit, Complejo Hospitalario Universitario A Coruña, Xubias, A Coruña, Spain.
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Isse K, Grama K, Abbott IM, Lesniak A, Lunz JG, Lee WMF, Specht S, Corbitt N, Mizuguchi Y, Roysam B, Demetris AJ. Adding value to liver (and allograft) biopsy evaluation using a combination of multiplex quantum dot immunostaining, high-resolution whole-slide digital imaging, and automated image analysis. Clin Liver Dis 2010; 14:669-85. [PMID: 21055689 DOI: 10.1016/j.cld.2010.07.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Various technologies including nucleic acid, protein, and metabolic array analyses of blood, liver tissue, and bile are emerging as powerful tools in the study of hepatic pathophysiology. The entire lexicon of liver disease, however, has been written using classical hematoxylin-eosin staining and light microscopic examination. The authors' goal is to develop new tools to enhance histopathologic examination of liver tissue that would enrich the information gained from liver biopsy analysis, enable quantitative analysis, and bridge the gap between various "-omics" tools and interpretation of routine liver biopsy results. This article describes the progress achieved during the past 2 years in developing multiplex quantum dot (nanoparticle) staining and combining it with high-resolution whole-slide imaging using a slide scanner equipped with filters to capture 9 distinct fluorescent signals for multiple antigens. The authors first focused on precise characterization of leukocyte subsets, but soon realized that the data generated were beyond the practical limits that could be properly evaluated, analyzed, and interpreted visually by a pathologist. Therefore, the authors collaborated with the open source FARSIGHT image analysis project (http://www.farsight-toolkit.org). FARSIGHT's goal is to develop and disseminate the next-generation toolkit of automated image analysis methods to enable quantification of molecular biomarkers on a cell-by-cell basis from multiparameter images. The resulting data can be used for histocytometric studies of the complex and dynamic tissue microenvironments that are of biomedical interest. The authors envisage that these tools will eventually be incorporated into the routine practice of surgical pathology and precipitate a revolution in the specialty.
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Affiliation(s)
- Kumiko Isse
- Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, E741 Montefiore, 200 Lothrop Street, Pittsburgh, PA 15231, USA
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Kornberg A, Freesmeyer M, Bärthel E, Jandt K, Katenkamp K, Steenbeck J, Sappler A, Habrecht O, Gottschild D, Settmacher U. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am J Transplant 2009; 9:592-600. [PMID: 19191771 DOI: 10.1111/j.1600-6143.2008.02516.x] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Vascular invasion of hepatocellular carcinoma (HCC) is a major risk factor for poor outcome after liver transplantation (LT). The aim of this retrospective analysis was to assess the value of preoperative positron emission tomography (PET) using (18)F-fluorodeoxyglucose ((18)F-FDG) in liver transplant candidates with HCC for predicting microvascular tumor invasion (MVI) and posttransplant tumor recurrence. Forty-two patients underwent LT for HCC after PET evaluation. Sixteen patients had an increased (18)F-FDG tumor uptake on preoperative PET scans (PET +), while 26 recipients revealed negative PET findings (PET-) pre-LT. PET- recipients demonstrated a significantly better 3-year recurrence-free survival (93%) than PET + patients (35%, p < 0.001). HCC recurrence rate was 50% in the PET + group, and 3.8% in the PET-population (p < 0.001). PET + status was identified as independent predictor of MVI [hazard ratio: 13.4]. Patients with advanced PET negative tumors and patients with HCC meeting the Milan criteria had a comparable 3-year-recurrence-free survival (80% vs. 94%, p = 0.6). Increased (18)F-FDG uptake on PET is predictive for MVI and tumor recurrence after LT for HCC. Its application may identify eligible liver transplant candidates with tumors beyond the Milan criteria.
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Affiliation(s)
- A Kornberg
- Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University, Jena, Germany.
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Current approach to down-staging of hepatocellular carcinoma prior to liver transplantation. Curr Opin Organ Transplant 2008; 13:234-40. [PMID: 18685309 DOI: 10.1097/mot.0b013e3282fc2633] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW Orthotopic liver transplantation is currently the best curative treatment for hepatocellular carcinoma within conventional Milan criteria. Recent data have suggested that modest expansion of tumor size limits could still preserve acceptable long-term recurrence-free survival. Down-staging of hepatocellular carcinoma initially exceeding conventional criteria for transplantation provides a unique perspective on tumor biology in that those with more favorable tumor biology are more likely to be successfully down-staged and do well after transplantation. This article reviews the principles and published data on down-staging of hepatocellular carcinoma prior to orthotopic liver transplantation. RECENT FINDINGS Several groups have examined the use of loco-regional therapy such as chemoembolization and radiofrequency ablation for tumor down-staging before Orthotopic liver transplantation. According to the latest results from the University of California, San Francisco involving 61 patients with hepatocellular carcinoma exceeding Milan criteria but meeting specific criteria for tumor size and number, 70% were successfully down-staged to within Milan criteria by an intention-to-treat analysis, with no posttransplant recurrence and a 4-year posttransplant survival of 92%. SUMMARY Strictly defined upper limits of tumor size and number for patient inclusion, as well as criteria for response to loco-regional therapy, are essential in achieving excellent posttransplant outcome following tumor down-staging.
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Schwartz M, Dvorchik I, Roayaie S, Fiel MI, Finkelstein S, Marsh JW, Martignetti JA, Llovet JM. Liver transplantation for hepatocellular carcinoma: extension of indications based on molecular markers. J Hepatol 2008; 49:581-8. [PMID: 18602719 PMCID: PMC2646906 DOI: 10.1016/j.jhep.2008.03.032] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2007] [Revised: 03/22/2008] [Accepted: 03/25/2008] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIMS Liver transplantation usually cures hepatocellular carcinoma when the Milan selection criteria are applied, whereas there is substantial risk of posttransplant recurrence with tumors beyond these criteria. This study uses molecular data to identify a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have favorable outcomes. METHODS Allelic imbalance of 18 microsatellites was analyzed in 70 consecutive patients (35 within Milan, 35 beyond Milan criteria) transplanted for hepatocellular carcinoma of whom 24 had recurrence and 46 survived at least 5 years recurrence-free. Fractional allelic imbalance (the fraction of significant microsatellites that demonstrated allelic imbalance) and relevant clinical/pathological variables were tested for correlation with time to recurrence. RESULTS Allelic imbalance in 9/18 microsatellites correlated with recurrence. Fractional allelic imbalance > 0.27 and macrovascular invasion were independent predictors of recurrence in patients with tumors beyond Milan criteria; the probability of recurrence at 5 years was 85% with fractional allelic imbalance > or = 0.27 vs. 10% when < 0.27 (p=0.0002). An algorithm including Milan criteria and fractional allelic imbalance status is 89% accurate in predicting tumor recurrence after transplantation. CONCLUSION Analysis of allelic imbalance of 9 microsatellites identifies a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have a low risk of posttransplant recurrence.
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Affiliation(s)
- Myron Schwartz
- Mount Sinai Liver Cancer Program, Department of Surgery, Recanati Miller Transplantation Institute, Division of Liver Disease, New York, NY 10029, USA.
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Facciuto ME, Koneru B, Rocca JP, Wolf DC, Kim-Schluger L, Visintainer P, Klein KM, Chun H, Marvin M, Rozenblit G, Rodriguez-Davalos M, Sheiner PA. Surgical treatment of hepatocellular carcinoma beyond Milan criteria. Results of liver resection, salvage transplantation, and primary liver transplantation. Ann Surg Oncol 2008; 15:1383-91. [PMID: 18320284 DOI: 10.1245/s10434-008-9851-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2008] [Revised: 02/04/2008] [Accepted: 02/04/2008] [Indexed: 12/12/2022]
Abstract
BACKGROUND There is no clear consensus regarding the best treatment strategy for patients with advanced hepatocellular carcinoma (HCC). METHODS Patients with cirrhosis and HCC beyond Milan who had undergone liver resection (LR) or primary orthotopic liver transplantation (OLT) between November 1995 and December 2005 were included in this study. Pathological tumor staging was based on the American Liver Tumor Study Group modified Tumor-Node-Metastasis classification. RESULTS A total of 23 HCC patients were primarily treated by means of LR, 5 of whom eventually underwent salvage OLT. An additional 32 patients underwent primary OLT. The overall actuarial survival rates at 3 and 5 years were 35% after LR, and 69% and 60%, respectively, after primary OLT. Recurrence-free survival at 5 years was significantly higher after OLT (65%) than after LR (26%). Of the patients who underwent LR, 11 (48%) experienced HCC recurrence only in the liver; 6 of these 11 presented with advanced HCC recurrence, poor medical status, or short disease-free intervals and were not considered for transplantation. Salvage OLT was performed in 5 patients with early stage recurrence (45% of patients with hepatic recurrence after LR and 22% of all patients who underwent LR). At a median of 18 months after salvage OLT, all 5 patients are alive, 4 are free of disease, and 1 developed HCC recurrence 16 months after salvage OLT. CONCLUSION For patients with HCC beyond Milan criteria, multimodality treatment-including LR, salvage OLT, and primary OLT-results in long-term survival in half of the patients. When indicated, LR can optimize the use of scarce donor organs by leaving OLT as a reserve option for early stage HCC recurrence.
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Affiliation(s)
- Marcelo E Facciuto
- Liver Transplant & Hepatobiliary Service, Westchester Medical Center, New York Medical College, 95 Grasslands Road, Valhalla, New York 10595, USA.
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Schwartz M, D'Amico F, Vitale A, Emre S, Cillo U. Liver transplantation for hepatocellular carcinoma: Are the Milan criteria still valid? Eur J Surg Oncol 2008; 34:256-62. [DOI: 10.1016/j.ejso.2007.07.208] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2007] [Accepted: 07/20/2007] [Indexed: 02/08/2023] Open
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Sun L, Wu H, Guan YS. Positron emission tomography/computer tomography: Challenge to conventional imaging modalities in evaluating primary and metastatic liver malignancies. World J Gastroenterol 2007; 13:2775-83. [PMID: 17569111 PMCID: PMC4395627 DOI: 10.3748/wjg.v13.i20.2775] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Computer tomography (CT) and magnetic resonance imaging (MRI), as conventional imaging modalities, are the preferred methodology for tumor, nodal and systemic metastasis (TNM) staging. However, all the noninvasive techniques in current use are not sufficiently able to identify primary tumors and even unable to define the extent of metastatic spread. In addition, relying exclusively on macromorphological characteristics to make a conclusion runs the risk of misdiagnosis due mainly to the intrinsic limitations of the imaging modalities themselves. Solely based on the macromorphological characteristics of cancer, one cannot give an appropriate assessment of the biological characteristics of tumors. Currently, positron emission tomography/computer tomography (PET/CT) are more and more widely available and their application with 18F-fluorodeoxyglucose (18F-FDG) in oncology has become one of the standard imaging modalities in diagnosing and staging of tumors, and monitoring the therapeutic efficacy in hepatic malignancies. Recently, investigators have measured glucose utilization in liver tumors using 18F-FDG, PET and PET/CT in order to establish diagnosis of tumors, assess their biologic characteristics and predict therapeutic effects on hepatic malignancies. PET/CT with 18F-FDG as a radiotracer may further enhance the hepatic malignancy diagnostic algorithm by accurate diagnosis, staging, restaging and evaluating its biological characteristics, which can benefit the patients suffering from hepatic metastases, hepatocellular carcinoma and cholangiocarcinoma.
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Affiliation(s)
- Long Sun
- Minnan PET Center, The First Hospital of Xiamen, Fujian Medical University, Xiamen, China
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17
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Pawlik TM, Gleisner AL, Anders RA, Assumpcao L, Maley W, Choti MA. Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy: implications for transplant eligibility. Ann Surg 2007; 245:435-42. [PMID: 17435551 PMCID: PMC1877015 DOI: 10.1097/01.sla.0000250420.73854.ad] [Citation(s) in RCA: 172] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To examine the diagnostic agreement of preoperative needle core biopsy (NCB) grading of hepatocellular carcinoma (HCC) compared with the final surgical pathologic tumor grade. SUMMARY BACKGROUND DATA Some centers have adopted protocols for selecting patients with HCC for transplantation based on tumor grade as determined by preoperative NCB. The validity of NCB to predict final tumor grade has not been previously assessed. METHODS A total of 211 patients who underwent hepatic resection, open radiofrequency, or transplantation for HCC between 1998 and 2004 were identified. Clinicopathologic, NCB, and surgical data were collected and analyzed using chi and kappa statistics. RESULTS A total of 120 (67.4%) of the 178 who underwent resection or transplantation had an NCB. On preoperative NCB, the majority of HCC cases were classified as well-differentiated (n = 35; 37.6%) or moderately differentiated (n = 44; 47.3%), while 14 (15.1%) cases were categorized as poorly differentiated. In contrast, when tumor grading was based on the final surgical specimen, there was a significantly higher proportion of HCC cases graded as poorly differentiated (well-differentiated, n = 34; 36.6%; moderately differentiated, n = 33; 35.5%; poorly differentiated, n = 26; 27.9%) (P < 0.05). The overall percent agreement of NCB and surgical pathology to determine tumor grade was poor (kappa = 0.18, P < 0.0001). Whereas final pathologic tumor grade predicted the presence of microscopic vascular invasion (well, 15.7%; moderate; 31.9%, poor; 58.4%; P = 0.001), NCB grade did not (well, 23.7%; moderate, 28.0%; poor, 25.4%; P = 0.65). CONCLUSIONS Selection of candidates for transplantation based on NCB tumor grade may be misleading, as NCB tumor grade often did not correlate with grade or presence of microscopic vascular invasion on final pathology. Clinicomorphologic criteria (tumor size, number) should remain the major determinants of eligibility for transplantation.
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Affiliation(s)
- Timothy M Pawlik
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 22187-6681, USA.
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18
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Parfitt JR, Marotta P, Alghamdi M, Wall W, Khakhar A, Suskin NG, Quan D, McAllister V, Ghent C, Levstik M, McLean C, Chakrabarti S, Garcia B, Driman DK. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl 2007; 13:543-51. [PMID: 17394152 DOI: 10.1002/lt.21078] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Milan and University of California at San Francisco (UCSF) criteria are used to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). Recurrent HCC is a significant cause of death. There is no widely accepted pathological assessment strategy to predict recurrent HCC after transplantation. This study compares the pathology of patients meeting Milan and UCSF criteria and develops a pathological score and nomogram to assess the risk of recurrent HCC after transplantation. All explanted livers with HCC from our center over the 18-yr period 1985 to 2003 were assessed for multiple pathological features and relevant clinical data were recorded; multivariate analysis was performed to determine features associated with recurrent HCC. Using pathological variables that independently predicted recurrent HCC, a pathological score and nomogram were developed to determine the probability of recurrent HCC. Of 75 cases analyzed, 50 (67%) met Milan criteria, 9 (12%) met only UCSF criteria and 16 (21%) met neither criteria based on explant pathology. There were 20 cases of recurrent HCC and the mean follow-up was 8 yr. Recurrent HCC was more common (67 vs. 12%; P < 0.001) and survival was lower (15 vs. 83% at 5 yr; 15 vs. 55% at 8 yr; P < 0.001) with those who met only UCSF criteria, compared to those who met Milan criteria. Cryptogenic cirrhosis (25 vs. 5%; P = 0.015), preoperative AFP >1,000 ng/mL (20 vs. 0%; P < 0.001) and postoperative OKT3 use (40 vs. 15%; P = 0.017) were more common among patients with recurrent HCC. While microvascular invasion was the strongest pathological predictor of recurrent HCC, tumor size >or=3 cm (P = 0.004; odds ratio [OR] = 7.42), nuclear grade (P = 0.044; OR = 3.25), microsatellitosis (P = 0.020; OR = 4.82), and giant/bizarre cells (P = 0.028; OR = 4.78) also predicted recurrent HCC independently from vascular invasion. The score and nomogram stratified the risk of recurrent HCC into 3 tiers: low (<5%), intermediate (40-65%), and high (>95%). In conclusion, compared to patients meeting Milan criteria, patients who meet only UCSF criteria have a worse survival and an increased rate of recurrent HCC with long-term follow-up, as well as more frequent occurrence of adverse histopathological features, such as microvascular invasion. Application of a pathological score and nomogram could help identify patients at increased risk for tumor recurrence, who may benefit from increased surveillance or adjuvant therapy.
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Affiliation(s)
- Jeremy R Parfitt
- Department of Pathology, London Health Sciences Centre and University of Western Ontario, London, Ontario, Canada
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20
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Suh KS, Cho EH, Lee HW, Shin WY, Yi NJ, Lee KU. Liver transplantation for hepatocellular carcinoma in patients who do not meet the Milan criteria. Dig Dis 2007; 25:329-33. [PMID: 17960068 DOI: 10.1159/000106913] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND To expand the Milan criteria, prognostic factors other than size and number of tumor may be necessary. We analyzed outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) exceeding Milan criteria to select favorable group of patients. METHODS Between November 1997 and December 2005, 104 cases of liver transplantation for patients with HCC were performed at our center. Twenty-four patients did not meet the Milan criteria preoperatively. Among these 24 patients, 19 had no major vascular invasion at the time of surgery. We analyzed the survival and prognostic factors of these 19 patients. The mean follow-up period was 33 months (range 6-89). RESULTS Three-year survival rate in 19 patients was 67.4%. Three-year survival rates were significantly higher when preoperative alpha-fetoprotein was less than 400 ng/ml (86.2 vs. 0%, p<0.001) when Edmonson-Steiner's histological grade 1 or 2 (100 vs. 40%, p = 0.036) and when microvascular invasion was absent (78.6 vs. 30%, p = 0.039). CONCLUSION If vascular invasion is absent in preoperative radiological studies, and the preoperative alpha-fetoprotein is less than 400 ng/ml, our findings suggest a good prognosis after liver transplantation for HCC patients who do not meet the Milan criteria.
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Affiliation(s)
- Kyung-Suk Suh
- Department of Surgery, Seoul National University, College of Medicine, Seoul, Korea.
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Wu L, Xu X, Shen J, Xie H, Yu S, Liang T, Wang W, Shen Y, Zhang M, Zheng S. MDR1 gene polymorphisms and risk of recurrence in patients With hepatocellular carcinoma after liver transplantation. J Surg Oncol 2007; 96:62-8. [PMID: 17443726 DOI: 10.1002/jso.20774] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND OBJECTIVES Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major cause of post-LT death. However, currently there is still lacking the markers to reliably predict recurrence. This study was undertaken to evaluate the association between three polymorphisms (C1236T, G2677A/T, C3435T) of Multidrug resistance 1 (MDR1) gene and the risk of recurrence after LT. METHODS Genomic DNA of 99 HCC patients undergoing LT was extracted from peripheral blood lymphocytes and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assay. Cox proportional hazard model was used to estimate the hazard ratios associated with polymorphisms. RESULTS During a mean follow-up of 14.9 months, 49 patients experienced recurrence. The association between recurrence-free and 2677A carrier (carrying at least one variant A allele) was significant (P = 0.019). However, no significant association was observed in other polymorphisms. Patients with 2677A carrier conferred a 63% reduction in recurrence risk compared with 2677A non-carrier (odds ratio: 0.374; 95% confidence interval: 0.177-0.788; P = 0.010). The median recurrence-free survival for 2677A carrier group was significantly longer than that for 2677A non-carrier group (44.2 vs. 10.5 months, P = 0.015). CONCLUSION The polymorphism of MDR1 gene may be a valuable molecular marker for HCC recurrence after LT.
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Affiliation(s)
- Liming Wu
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
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Khan MQ, Al-Ashgar H, Khuroo MS, Farahat K, Al-Omari M, Khalaf H, Al-Fadda M. Two cases of pulmonary metastasis after living donor liver transplantation for hepatocellular carcinoma. Ann Saudi Med 2006; 26:398-402. [PMID: 17019089 PMCID: PMC6074111 DOI: 10.5144/0256-4947.2006.398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/01/2005] [Indexed: 11/22/2022] Open
Affiliation(s)
- Mohammed Qaseem Khan
- Section of Gastroenterology and Hepatology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Hamad Al-Ashgar
- Section of Gastroenterology and Hepatology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - MS Khuroo
- Department of Hepatobiliary Surgery and Liver Transplantation, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Karim Farahat
- Section of Gastroenterology and Hepatology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Mohammed Al-Omari
- Department of Pathology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Hatem Khalaf
- Department of Hepatobiliary Surgery and Liver Transplantation, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Mohammed Al-Fadda
- Section of Gastroenterology and Hepatology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
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Yao FY. Selection criteria for liver transplantation in patients with hepatocellular carcinoma: beyond tumor size and number? Liver Transpl 2006; 12:1189-91. [PMID: 16868948 DOI: 10.1002/lt.20853] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Altimari A, Gruppioni E, Fiorentino M, Petraroli R, Pinna AD, Petropulacos K, Ridolfi L, Costa AN, Grigioni WF, Grigioni AD. Genomic Allelotyping for Distinction of Recurrent and De Novo Hepatocellular Carcinoma After Orthotopic Liver Transplantation. ACTA ACUST UNITED AC 2005; 14:34-8. [PMID: 15714062 DOI: 10.1097/01.pas.0000143609.85487.36] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Distinction between recurrent and de novo hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) bears important clinical and therapeutic implications. Techniques for molecular profiling of clinically suspected de novo and recurrent HCC are required since the histological/clinical discrimination of donor vs. recipient tumor origin is difficult. Multiple PCR amplification of 16 highly polymorphic short tandem repeat (STR) DNA sequences (routinely used for paternity and forensic assays) was applied in two patients who developed a second HCC after OLT. In both patients the technique provided reliable evidence that the two second HCC were recurrences of the primary tumor. Multiple STR genetic allelotyping is an effective tool for clear-cut discrimination of donor/recipient origin of a second HCC after OLT. Its application could be of great therapeutic relevance for such OLT patients.
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Affiliation(s)
- Annalisa Altimari
- Molecular and Transplantation Pathology Laboratory of the F. Addarii Institute of Oncology, Centro Riferimento Trapianti Emilia-Romagna, Bologna, Italy
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Ravaioli M, Grazi GL, Ercolani G, Fiorentino M, Cescon M, Golfieri R, Trevisani F, Grigioni WF, Bolondi L, Pinna AD. Partial necrosis on hepatocellular carcinoma nodules facilitates tumor recurrence after liver transplantation. Transplantation 2005; 78:1780-6. [PMID: 15614151 DOI: 10.1097/01.tp.0000145892.97114.ee] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The presence of partial necrosis in hepatocellular carcinoma (HCC) nodules is a common histologic finding after liver transplantation, but its correlation with tumor recurrence has never been investigated. METHODS we retrospectively reviewed the outcome of 54 patients with a single histologically proven HCC after liver transplantation. All cases had a survival of more than 6 months, and patients treated preoperatively had a transarterial chemoembolization (TACE) procedure. Since 1996, our center has applied the Milan criteria. Correlations between tumor recurrences and clinicopathologic variables, including the presence of partial necrosis, were performed. Etiologic factors for HCC partial necrosis were also investigated. RESULTS Sixteen of 54 (29.6%) HCC nodules presented partial necrosis, and 4 (25%) of them developed HCC recurrence compared with 1 of 38 (2.6%) cases without this histologic finding (P<0.05). Partial necrosis was related to TACE procedure (P<0.05), patient age less than 50 years (P<0.05), and tumor diameter greater than 2 cm (P<0.05). Multivariate analysis showed only TACE as an independent variable. The other variables related to the five (9.3%) tumor recurrences were HCC diameter greater than 2 cm (P<0.05), year of liver transplantation before 1996 (P<0.05), and the presence of satellite nodules (P<0.05). The Cox regression analysis showed the presence of partial necrosis as an independent variable related to tumor recurrence. The analysis of the recurrence-free survival confirmed the results of the recurrence rate. CONCLUSION Partial necrosis was a risk factor for tumor recurrence after liver transplantation. Patients and procedures should be selected while also bearing in mind the side-effect of incomplete necrosis of the nodules.
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Affiliation(s)
- Matteo Ravaioli
- Department of Liver and Multi-organ Transplantation, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy
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França AVC, Martinelli A, Silva OCE. Brain metastasis of hepatocellular carcinoma detected after liver transplantation. ARQUIVOS DE GASTROENTEROLOGIA 2005; 41:199-201. [PMID: 15678207 DOI: 10.1590/s0004-28032004000300012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
AIM We report the case of a patient with hepatocellular carcinoma submitted to liver transplantation, who subsequently manifested tumor recurrence initially as brain metastasis. CASE DESCRIPTION A 48-year-old male cirrhotic patient with hepatitis C infection, and two focal hepatic lesions, had a cytologic and histologic diagnosis of hepatocellular carcinoma. Before transplant, he was submitted to adjuvant treatment with a combination of arterial embolization and intratumoral ethanol injection. In the 3rd month post-liver transplantation, the patient developed headache, nausea and vomiting, without any neurological impairment. Brain computed tomography and magnetic resonance imaging identified an expansive hypervascular lesion with internal bleeding. Evaluation of the surgical explant revealed macroscopic invasion of portal vessels. CONCLUSION Brain metastasis of a hepatocellular carcinoma after liver transplantation may occur. This metastasis may have occurred before or soon after the transplant. Patients with hepatocellular carcinoma, awaiting liver transplant, should be screened for cerebral metastasis. Vascular invasion may indicate hematogenic dissemination of the tumor.
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Affiliation(s)
- Alex Vianey Callado França
- Liver Transplant Group, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil.
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Cillo U, Navaglia F, Vitale A, Molari A, Basso D, Bassanello M, Brolese A, Zanus G, Montin U, D'Amico F, Ciarleglio FA, Carraro A, Bridda A, Burra P, Carraro P, Plebani M, D'Amico DF. Clinical significance of alpha-fetoprotein mRNA in blood of patients with hepatocellular carcinoma. Clin Chim Acta 2004; 347:129-38. [PMID: 15313150 DOI: 10.1016/j.cccn.2004.04.032] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2004] [Revised: 04/08/2004] [Accepted: 04/14/2004] [Indexed: 02/08/2023]
Abstract
BACKGROUND Alpha-fetoprotein (AFP) messenger RNA (mRNA) in the blood reflects the presence of circulating hepatocellular carcinoma (HCC) cells and is a sensitive marker of HCC extrahepatic metastases. The specificity of this molecular marker and its correlation with the main HCC clinical-pathological parameters remains controversial, however. METHODS AFPmRNA was determined in 50 HCC patients and in 50 patients with diagnosis of cirrhosis (6), or colon (24) or, pancreatic (20) carcinoma. HCC patients with clinically evident extrahepatic metastasis were excluded. HCC diagnosis was confirmed in all patients by histology on percutaneous biopsies or surgical specimens; pathological grading was assessed at the same time. RESULTS AFPmRNA was positive in 20 HCC patients (40%) and in 18 patients without HCC (36%). The presence of AFPmRNA in the blood correlated significantly with cholestatic indices (p<0.01), nodule size (p=0.03), vascular invasion (p=0.006) and moderately or poorly differentiated HCC (p<0.0001). Moreover, survival analysis showed a significant impact of AFPmRNA detection on overall (p=0.04) and recurrence-free survival (p=0.0007) after a median follow-up of 17 months. CONCLUSIONS Although AFPmRNA is frequently detected in the blood, even in benign liver diseases or gastroenteric tumors, in HCC patients without clinical evidence of extrahepatic metastases it seemed to identify the biologically more aggressive tumors.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Colonic Neoplasms/blood
- DNA Primers
- DNA, Neoplasm/biosynthesis
- DNA, Neoplasm/isolation & purification
- Electrophoresis, Agar Gel
- Female
- Humans
- Liver Cirrhosis/blood
- Liver Neoplasms/blood
- Liver Neoplasms/pathology
- Male
- Middle Aged
- Neoplasm Recurrence, Local/blood
- Pancreatic Neoplasms/blood
- Prognosis
- Prospective Studies
- RNA, Messenger/blood
- Reverse Transcriptase Polymerase Chain Reaction
- Survival Analysis
- alpha-Fetoproteins/biosynthesis
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Affiliation(s)
- Umberto Cillo
- Clinica Chirurgica I, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Via Giustiniani 2, Policlinico III Piano, 35128 Padova, Italy
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Ravaioli M, Ercolani G, Cescon M, Vetrone G, Voci C, Grigioni WF, D'Errico A, Ballardini G, Cavallari A, Grazi GL. Liver transplantation for hepatocellular carcinoma: further considerations on selection criteria. Liver Transpl 2004; 10:1195-202. [PMID: 15350014 DOI: 10.1002/lt.20239] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The selection criteria in liver transplantation for HCC are a matter of debate. We reviewed our series, comparing two periods: before and after 1996, when we started to apply the Milan criteria. The study population was composed of patients with a preoperative diagnosis of HCC, confirmed by the pathological report and with a survival of >1 year. Preoperative staging as revealed by radiological imagining was distinguished from postoperative data, including the variable of tumor volume. After 1996 tumor recurrences significantly decreased (6 out of 15 cases, 40% vs. 3 out of 48, 6.3%, P < .005) and 5-year patient survival improved (42% vs. 83%, P < .005). Not meeting the Milan criteria was significantly related to higher recurrence rate (37.5% vs. 12.7%, P < .05) and to lower 5-year patient survival (38% vs. 78%, P < .005%) in the preoperative analysis, but not in the postoperative one. The alfa-fetoprotein level of more than 30 ng/dL and the preoperative tumor volume of more than 28 cm3 predicted HCC recurrences in the univariate and mutivariate analysis (P < .005 and P < .05, respectively). The ROC curve showed a linear correlation between preoperative tumor volume and HCC recurrence. Milan criteria significantly reduced tumor recurrences after liver transplantation, improving long-term survival. In conclusion, the efficacy of tumor selection criteria must be analyzed with the use of preoperative data, to avoid bias of the postoperative evaluation. Tumor volume and alfa-fetoprotein level may improve the selection of patients.
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Affiliation(s)
- Matteo Ravaioli
- Department of Surgery and Transplantation, Surgical Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
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Fiorentino M, Altimari A, Ravaioli M, Gruppioni E, Gabusi E, Corti B, Vivarelli M, Bringuier PP, Scoazec JY, Grigioni WF, D'Errico-Grigioni A. Predictive value of biological markers for hepatocellular carcinoma patients treated with orthotopic liver transplantation. Clin Cancer Res 2004; 10:1789-1795. [PMID: 15014033 DOI: 10.1158/1078-0432.ccr-1149-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE To help stratify candidates with hepatocellular carcinoma (HCC) for orthotopic liver transplantation (OLT), biomarkers are needed that are capable of predicting recurrence of disease (ROD). We investigated the prognostic role in this setting of immunohistochemical markers reported previously to predict poor prognosis in HCC patients treated with resection. EXPERIMENTAL DESIGN Eighty-three patients with HCC who underwent OLT between 1987 and 2001 with a minimum clinical follow up of 12 months were included in this retrospective study. We analyzed immunohistochemical expression of the adhesion molecules E-cadherin and beta-catenin (membrane/nuclear localization), MIB-1 proliferative index and the cyclin-dependent kinase inhibitor p27, alongside the main clinical-pathological variables. RESULTS At univariate analysis, vascular thrombosis, high MIB-1 index, lower membrane expression of E-cadherin and beta-catenin, and nuclear beta-catenin localization were associated with ROD. At multivariate analysis, only MIB-1 index, low equal E-cadherin (with respect to non-neoplastic surrounding tissue), and nuclear beta-catenin appeared as independent predictors of ROD. The logistic regression analysis model indicated that detection of any one parameter was associated with at least 88% estimated risk of ROD (up to 99% for all three). CONCLUSIONS We propose these three molecular parameters as an additional tool for rational selection of OLT candidates among HCC patients (stratification according to the risk of ROD might help provide a similar life expectancy for cirrhotic candidates with and without HCC).
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Affiliation(s)
- Michelangelo Fiorentino
- Pathology Unit of the "F. Addarii" Institute of Oncology, Department of Oncology and Hematology, Hopital Edouard Herriot, Lyon, France
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Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, Burra P, Fagiuoli S, Farinati F, Rugge M, D'Amico DF. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004; 239:150-9. [PMID: 14745321 PMCID: PMC1356206 DOI: 10.1097/01.sla.0000109146.72827.76] [Citation(s) in RCA: 255] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate. METHODS Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC. RESULTS On histologic examination, 38% of the entire group of 48 patients did not meet the "Milan criteria" and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates. CONCLUSIONS The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.
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Affiliation(s)
- Umberto Cillo
- Clinica Chirurgica I, Dipartimento di Scienze Chirurgiche e Gastroenterlogiche, Italy.
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31
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Kim JW, Ye Q, Forgues M, Chen Y, Budhu A, Sime J, Hofseth LJ, Kaul R, Wang XW. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology 2004; 39:518-527. [PMID: 14768006 DOI: 10.1002/hep.20053] [Citation(s) in RCA: 110] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Several types of aggressive cancers, including hepatocellular carcinoma (HCC), often arise as a multifocal primary tumor. This suggests a high rate of premalignant changes in noncancerous tissue before the formation of a solitary tumor. Examination of the messenger RNA expression profiles of tissue samples derived from patients with cirrhosis of various etiologies by complementary DNA (cDNA) microarray indicated that they can be grossly separated into two main groups. One group included hepatitis B and C virus infections, hemochromatosis, and Wilson's disease. The other group contained mainly alcoholic liver disease, autoimmune hepatitis, and primary biliary cirrhosis. Analysis of these two groups by the cross-validated leave-one-out machine-learning algorithms revealed a molecular signature containing 556 discriminative genes (P <.001). It is noteworthy that 273 genes in this signature (49%) were also significantly altered in HCC (P <.001). Many genes were previously known to be related to HCC. The 273-gene signature was validated as cancer-associated genes by matching this set to additional independent tumor tissue samples from 163 patients with HCC, 56 patients with lung carcinoma, and 38 patients with breast carcinoma. From this signature, 30 genes were altered most significantly in tissue samples from high-risk individuals with cirrhosis and from patients with HCC. Among them, 12 genes encoded secretory proteins found in sera. In conclusion, we identified a unique gene signature in the tissue samples of patients with cirrhosis, which may be used as candidate markers for diagnosing the early onset of HCC in high-risk populations and may guide new strategies for chemoprevention. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
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Affiliation(s)
- Jin Woo Kim
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Nart D, Arikan C, Akyildiz M, Yuce G, Demirpolat G, Zeytunlu M, Karasu Z, Aydogdu S, Killi R, Yuzer Y, Tokat Y, Kilic M. Hepatocellular carcinoma in liver transplant era: a clinicopathologic analysis. Transplant Proc 2003; 35:2986-2990. [PMID: 14697957 DOI: 10.1016/j.transproceed.2003.10.076] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors in the world, and the prognosis is usually poor. Today, liver transplantation (LT) is a radical but frequently curative treatment modality for HCC. In selected patients, it cures HCC and the underlying cirrhosis at the same time. The present clinicopathological study examined the importance of tumor characteristics for their effects on recurrence and survival rates after LT for HCC. Forty-two native hepatectomy specimens among 250 consecutive orthotopic liver transplantations contained HCC. Patients were predominantly men (30 men, 12 women), ranging in age from 1 to 61 years (median 51). While 20 patients received cadaveric organs, 22 were transplanted from living donors. In 14 patients (33%) HCC presented as a solitary nodule, 5 (12%) as two nodules; 2 (5%) as three nodules; and 21 patients (50%) as more than three nodules. The maximal diameter of the largest tumor not larger than 3 cm in 28 patients (66%), exceeding this size in 14 patients (34%). There was a significant correlation between nodule number and tumor size (r = 0.36, P = 0.05). While 23 patients had no sign of vascular involvement, 17 tumors showed microscopic invasion and two large vessel involvement. There was a positive correlation between vascular invasion and nodule number (r = 0.41, P = 0.05). The histopathological grade of differentiation of the tumors was assessed as "well" in seven patients (14%), moderate in 28 (72%), and poor in 7 (14%). The differentiation was significantly poorer when vascular invasion was observed (r = 0.43, P =.01). According to the TNM classification, 11 patients (26%) were stage I, 6 (14%) stage II, 13 (31%) stage III, and 12 (29%) stage IV. After a median follow-up of 10 months (1-50 months), the overall mortality was 18% (n = 8). Patient survival at 6 month, 1, and 4 years was 88%, 80%, and 60%, respectively. The outcome was significantly poorer for TNM stage IV versus stage I,II, and III tumors to (P =.02). Tumor recurred in three patients at 4,6, and 50 months after liver transplantation. The sites of recurrence were bone, lung, and adrenal glands. In conclusion, liver transplantation represents a safe and feasible treatment for hepatocellular carcinoma with excellent outcomes compared with other treatment modalities. Liver transplantation offers excellent survival rates and chance for cure in stages I, II, and III hepatocellular carcinoma in cirrhotic patients.
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Affiliation(s)
- D Nart
- Department of Pathology, Ege University Medical School, 35100 Bornova, Izmir, Turkey.
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Yoo HY, Patt CH, Geschwind JF, Thuluvath PJ. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 2003; 21:4329-35. [PMID: 14581446 DOI: 10.1200/jco.2003.11.137] [Citation(s) in RCA: 179] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE We hypothesized that the outcome of liver transplantation in patients with hepatocellular carcinoma (HCC) has improved over the past decade because of the application of published criteria for patient selection. In this study, we compared the outcome of liver transplantation in patients with and without HCC at different time periods using the United Network for Organ Sharing data. PATIENTS AND METHODS We excluded children, patients with multiple organ transplantation or retransplantation, and those with incomplete survival data. The study period was arbitrarily divided into three time intervals: 1987 to 1991, 1992 to 1996, and 1997 to 2001. RESULTS During the study period, 985 patients with HCC (HCC group), and 33,339 without HCC underwent liver transplantation (control group). Kaplan-Meier patient and graft survivals were significantly lower for the HCC group compared with the control group. Cox regression analysis (after adjusting for other confounding variables) confirmed a lower patient survival in the HCC group (1-year survival, 77.0% v 86.7%; hazard ratio [HR], 1.7; 95% CI, 1.5 to 2.0; P <.0001) compared with the control group (5-year survival, 48.2% v 74.7%; HR, 2.2; 95% CI, 1.9 to 2.4; P <.0001); HCC was an independent predictor of survival. Kaplan-Meier analysis showed a significant improvement in 5-year patient survival with time in patients with HCC (1987 to 1991, 25.3%; 1992 to 1996, 46.6%; 1997 to 2001, 61.1%; P <.0001). During the same period, there was only minimal improvement in survival among the control group. CONCLUSION Five-year survival of patients transplanted for HCC is excellent, with a steady improvement in survival over the past decade. It is possible that the published criteria for patient selection may have contributed to the better outcome.
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Affiliation(s)
- Hwan Y Yoo
- Division of Gastroenterology and Hepatology, Johns Hopkins University Hospital, 1830 East Monument Street, Suite 428, Baltimore, MD 21205, USA.
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Salizzoni M, Romagnoli R, Lupo F, David E, Mirabella S, Cerutti E, Ottobrelli A. Microscopic vascular invasion detected by anti-CD34 immunohistochemistry as a predictor of recurrence of hepatocellular carcinoma after liver transplantation. Transplantation 2003; 76:844-8. [PMID: 14501865 DOI: 10.1097/01.tp.0000083555.06337.8e] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Vascular invasion (VI) is the strongest risk factor for recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT). However, unlike macroscopic VI, microscopic VI has not been acknowledged as a predictor of recurrence in individual patients. This study aimed to determine whether immunohistochemical staining of the vessels could change the judgment on microscopic VI in such a way as to confer clinical relevance to the feature. METHODS Antibodies against the CD34 antigen (endothelial cell marker of hepatocarcinogenesis) were applied to sections from all the HCC nodules found in 136 patients who underwent LT for HCC arising from cirrhosis between 1990 and 2000. Microscopic VI at the periphery of the nodules was searched blindly by the same pathologist who had already examined hematoxylin-eosin slides. Several characteristics of the patients and of the cancers were analyzed to define their respective influence on recurrence. RESULTS Recurrent HCC was diagnosed in nine patients. Although 6 of the 22 patients in whom microscopic VI had been detected by hematoxylin-eosin staining developed recurrence, 8 of the 16 in whom microscopic VI was detected by anti-CD34 immunohistochemistry developed recurrence, accounting for 5-year cumulative incidences of recurrence of 34% and 70%, respectively. At multivariate analysis, relative risk for recurrence was the highest for microscopic VI found with anti-CD34 antibodies. CONCLUSIONS Microscopic VI detected by anti-CD34 immunohistochemistry implies an extremely high risk for HCC to recur after LT. Trials focusing on patients with evidence of microscopic VI are needed to test the efficacy of adjuvant therapies to prevent recurrence.
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MESH Headings
- Adult
- Aged
- Antibodies
- Antigens, CD34/analysis
- Antigens, CD34/immunology
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Female
- Humans
- Immunohistochemistry
- Incidence
- Liver Neoplasms/blood supply
- Liver Neoplasms/epidemiology
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Liver Transplantation
- Male
- Microcirculation
- Middle Aged
- Neoplasm Recurrence, Local/blood supply
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/pathology
- Neovascularization, Pathologic/epidemiology
- Neovascularization, Pathologic/pathology
- Predictive Value of Tests
- Proportional Hazards Models
- Risk Factors
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Affiliation(s)
- Mauro Salizzoni
- Chirurgia Generale 8, Centro Trapianto di Fegato, San Giovanni Battista Hospital, Turin, Italy.
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Fernández JA, Robles R, Marin C, Sánchez-Bueno F, Ramirez P, Pons JA, Garre MC, Pérez D, Parrilla A, Navalón JC, Parrilla P. Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size? Transplant Proc 2003; 35:1818-1820. [PMID: 12962807 DOI: 10.1016/s0041-1345(03)00723-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Due to the scarcity of donors and the fact that size is the main prognostic factor, Milan criteria have been used since 1996 to select hepatocellular carcinoma (HCC) patients for liver transplantation. In 2001 UCSF criteria showed that including layer tumors did not reduce the survival results. The objective of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence survival rates. PATIENTS AND METHODS Between May 1988 and July 2001, 53 patients were transplanted due to HCC and cirrhosis. The etiology of cirrhosis was HCV in 23 cases and HBV in 6. In 11 cases the HCC were incidental by discovered namely, a mean/ diameter of 1.8 cm (versus 2.6 cm in nonincidental HCC). Sixty-two percent of tumors met the Milan criteria, and 68% the USCF criteria. RESULTS The actuarial survival was 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of those with nonincidental HCC (78% at 1 year and 57% at 5 years, P<.05). According to Milan criteria, the survival patients with early tumors was 82% at 1 year and 68% at 5 years, and for advanced tumors (NS), 75% and 54%, respectively. Comparison of early versus advanced tumors according to UCSF criteria showed survivals of 84% versus 64% at 1 year (P<.05) and 67% versus 48% at 5 years (P<.05), respectively. CONCLUSION Increasing the HCC size among LT according to the California criteria did not reduce survival rates compared with the Milan criteria.
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Affiliation(s)
- J A Fernández
- Department of Surgery, Hospital Universitario Virgen de la Arrixaca, El Palmar S/N (Murcia), Spain.
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Yamamoto S, Tomita Y, Nakamori S, Hoshida Y, Nagano H, Dono K, Umeshita K, Sakon M, Monden M, Aozasa K. Elevated expression of valosin-containing protein (p97) in hepatocellular carcinoma is correlated with increased incidence of tumor recurrence. J Clin Oncol 2003; 21:447-52. [PMID: 12560433 DOI: 10.1200/jco.2003.06.068] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
PURPOSE Valosin-containing protein (VCP; also known as p97) has been shown to be associated with antiapoptotic function and metastasis via activation of the nuclear factor-kappaB signaling pathway. In this study, association of VCP expression with recurrence of hepatocellular carcinoma (HCC) and patient survival was examined. PATIENTS AND METHODS VCP expression in 170 patients (139 male and 31 female) with ages ranging from 31 to 81 years (median, 61 years) was analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. RESULTS Immunohistochemically, 57 patients (35.2%) showed level 1, and 105 patients (64.8%) showed level 2, VCP expression. Quantitative RT-PCR analysis revealed higher VCP mRNA expression in level 2 patients (n = 7) than level 1 (n = 4) (P <.05). Patients with VCP-level 2 HCC showed higher rate of portal vein invasion in the tumor (P <.01) and poorer disease-free and overall survival (P <.0001 and P <.05, respectively) compared with level 1 patients. Multivariate analysis revealed VCP expression level, tumor multiplicity, and degree of fibrosis in the noncancerous liver tissue to be independent prognosticators for disease-free and overall survival. VCP level was an indicator for disease-free survival in each early- (I and II) and advanced- (III and IV) stage group of pathologic tumor-node-metastasis classification (P <.001 and P <.01, respectively). CONCLUSION VCP expression level has prognostic significance for disease-free and overall survival of patients with HCC.
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Affiliation(s)
- Shinji Yamamoto
- Departments of Surgery and Clinical Oncology, and Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
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Libbrecht L, Meerman L, Kuipers F, Roskams T, Desmet V, Jansen P. Liver pathology and hepatocarcinogenesis in a long-term mouse model of erythropoietic protoporphyria. J Pathol 2003; 199:191-200. [PMID: 12533832 DOI: 10.1002/path.1257] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Erythropoietic protoporphyria (EPP) is an inherited disease of haem synthesis caused by a mutation in one of the alleles of the enzyme ferrochelatase. This mutation leads to partial deficiency of the enzyme, resulting in increased concentrations of protoporphyrin (PP) in blood, liver, and faeces. Five to ten per cent of patients with EPP develop severe liver disease characterized by the presence of PP deposits. This study used histochemistry and immunohistochemistry to investigate the histopathological features present in the livers of 44 mice with a heterozygous or homozygous point mutation in the ferrochelatase gene (fch/+ and fch/fch mice, respectively). Some fch/+ mouse livers showed mixed steatosis and large cell dysplasia. The livers of fch/fch mice showed periportal or septal fibrosis accompanied by an atypical ductular reaction. These findings suggest that the obstruction and damage of a proportion of large and small bile ducts by PP deposits cause an accumulation of PP in the parenchyma, which leads to damage and loss of hepatocytes due to the toxic effects of PP. The classical stages of hepatocarcinogenesis were observed and hepatic progenitor cells appear to be involved in this process. PP acts as the promoting agent and is probably also the initiating agent.
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Affiliation(s)
- Louis Libbrecht
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
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Osada S, Saji S, Kuno T. Clinical significance of combination study of apoptotic factors and proliferating cell nuclear antigen in estimating the prognosis of hepatocellular carcinoma. J Surg Oncol 2003; 85:48-54. [PMID: 14696087 DOI: 10.1002/jso.20006] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Hepatocellular carcinoma (HCC) is one of the most common recurrence diseases, which affects the patient's prognosis. The aim of this report is to evaluate recurrence risk after primary treatment by the combination study with the clinical features and immunohistological findings. METHODS 153 removable HCCs were examined by immunohistochemical study of the proliferating cell nuclear antigen (PCNA), p53, or Bax. The relationships of these factors with histological grades, the presence of intra-hepatic metastasis (IM), tumor size, value of serum alpha-fetoprotein (AFP), and prognosis were studied. PCNA labeling index (LI) was calculated to count positive nuclei in 1,000 cells. RESULTS PCNALI was significantly higher in cancer and correlated with tumor size. PCNALI and the tumor diameter in themselves could be a good predictor for patient prognosis and the combination study of them was an even stronger indicator. The value of AFP was significantly higher in positive p53 cases. The incidence of p53 was associated with histological types. The presence of IM was found in negative Bax cases of main tumors. The appearance of Bax was not correlated with histological types. The incidence of p53 or Bax was indicated to distinguish the patient prognosis of the lower grade histological cases, in which differences could not be found by the routine histological study. CONCLUSIONS The combination study of the immunohistochemical findings and the clinical features could be one of the most important aids in interpreting the status of HCC.
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Affiliation(s)
- Shinji Osada
- Second Department of Surgery, Gifu University School of Medicine, Tsukasamachi, Gifu City, Japan.
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Chau GY, Lui WY, Wu CW. Spectrum and significance of microscopic vascular invasion in hepatocellular carcinoma. Surg Oncol Clin N Am 2003; 12:25-34, viii. [PMID: 12735127 DOI: 10.1016/s1055-3207(02)00077-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Microscopic vascular invasion frequently occurs in patients with hepatocellular carcinoma (HCC). It is a biologic characteristic of HCC to consider when selecting patients for surgical treatment. In addition, microscopic vascular invasion is important to consider in the development of strategies to prevent cancer recurrence after potentially curative therapy.
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Affiliation(s)
- Gar-Yang Chau
- Department of Surgery, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan, 112
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Jonas S, Steinmüller T, Tullius SG, Thelen A, Settmacher U, Berg T, Radtke C, Neuhaus P. Increased mortality after liver transplantation for hepatocellular carcinoma in hepatitis B-associated cirrhosis. Transpl Int 2002. [PMID: 12545339 DOI: 10.1111/j.1432-2277.2003.tb00220.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Transplant patients suffering from hepatocellular carcinoma in cirrhosis are selected according to tumor nodule number and diameter. Vascular invasion and histopathological grading are predictive of outcome. The prognostic influence of hepatitis B-cirrhosis has been investigated after resection and after local tumor treatment, but not after transplantation. Of the 1,188 transplantations performed between 1989 and 2000, 120 were on patients with hepatocellular carcinoma in cirrhosis (HCC) (follow-up: 57 months; 1-140 months). Within this group, 25 patients (21%) suffered from hepatitis B. Pre-transplant selection criteria were a maximum diameter of 5 degrees cm in uni-nodular tumors, or 3 degrees cm for two to three tumor nodules. The rate of tumors with 2-3 tumor nodules was increased in the hepatitis-B group (52% vs. 29%; P<0.05). Other tumor characteristics did not differ. In the hepatitis-B group, more patients died post-transplantation (44% vs.22%; P<0.05). This difference was due to unspecific causes, not to tumor recurrence or re-infection. These findings may be indicative of a more complicated course in patients suffering from hepatitis B in general.
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Affiliation(s)
- Sven Jonas
- Department of General, Visceral, and Transplantation Surgery, Charité Campus Virchow Klinikum, Humboldt University Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
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41
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Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 2002; 8:765-74. [PMID: 12200775 DOI: 10.1053/jlts.2002.34892] [Citation(s) in RCA: 311] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We previously proposed modified staging criteria for predicting acceptable outcome after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). These were solitary tumor < or = 6.5 cm, or three or fewer nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm, without gross vascular invasion (University of California, San Francisco [UCSF] criteria). In this study, we further evaluated the performance of the Milan criteria (solitary tumor < or = 5 cm, or three or fewer lesions none > 3 cm), the UCSF criteria, and the Pittsburgh modified tumor-node-metastasis (TNM) criteria. Pathologic HCC staging according to each set of criteria was performed in 70 patients. The difference in survival when comparing 24 patients with HCC exceeding Milan criteria versus 46 patients meeting Milan criteria did not reach statistical significance (HR, 2.0; P = .12). Using our definition for acceptable 2-year survival to be > or = 70%, the 14 patients (20%) meeting UCSF criteria but exceeding Milan criteria had a 2-year survival of 86% (95% CI, 54% to 96%). Survival for Pittsburgh stage I, II, and IIIA patients as a group was significantly better than for stages IIIB and IVA patients combined (HR, 4.2; P = .007), and similar to survival for patients meeting UCSF criteria. Advanced tumor exceeding UCSF criteria served reasonably well as a surrogate marker for poorly differentiated grade and microvascular invasion. In conclusion, our analyses suggest that UCSF criteria better predict acceptable posttransplant outcome than Milan criteria. UCSF criteria confer a different advantage over Pittsburgh criteria, which require information on microvascular invasion that is difficult to ascertain preoperatively without the attendant risk of biopsy.
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Affiliation(s)
- Francis Y Yao
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0538, USA.
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Molmenti EP, Klintmalm GB. Liver transplantation in association with hepatocellular carcinoma: an update of the International Tumor Registry. Liver Transpl 2002; 8:736-48. [PMID: 12200772 DOI: 10.1053/jlts.2002.34879] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is an epithelial tumor derived from hepatocytes that accounts for more than 80% of all primary hepatic tumors. The severity of the underlying disease is almost always the key factor in deciding whether to consider liver resection or transplantation as its treatment. Data in our registry corresponding to almost 800 patients from transplant centers throughout the world showed that patient survival after liver transplantation was significantly affected by histologic grade, tumor size >5 cm, and the presence of positive nodes. Recurrence-free survival showed a correlation with tumor size >5 cm, positive nodes, bilobar spread, and vascular invasion. At the present time, 59% of patients in our registry are alive, 84% of whom are free of tumor. Of those who died, half did so without evidence of tumor.
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Affiliation(s)
- Ernesto P Molmenti
- Baylor University Medical Center, Transplantation Services, Dallas, TX 75246, USA
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43
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Affiliation(s)
- John Fung
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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44
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Hess D, Humar A, Sielaff TD. Living related liver transplantation for recurrent hepatocellular carcinoma in a normal liver. Clin Transplant 2002; 16:240-2. [PMID: 12010151 DOI: 10.1034/j.1399-0012.2002.01135.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The role of liver transplantation for hepatocellular carcinoma (HCC) is evolving. In patients with advanced liver disease and early stage HCC, transplantation offers the best hope for cure. A living donor offers the optimal approach to a timely transplant, before disease progression obviates the potential benefit. But extending the indications beyond those designated by the United Network for Organ Sharing (UNOS) for liver transplantation for HCC is controversial [Hepatology 2001: 33: 1073; Liver Transplant 2000: 6: S1]. Cadaver split techniques and use of living donors are potentially compelling ways to test the limitations of liver transplantation for HCC, without notably reducing the cadaver organ pool. Herein, we report a rare case of a patient who developed a well-differentiated HCC in a normal liver. After resection of the index lesion and, later, of a remote recurrent lesion, a living donor liver transplant was offered. The natural history of this lesion and the management of transplantation in this setting are discussed.
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Affiliation(s)
- Donavon Hess
- Department of Surgery, University of Minnesota, Minneapolis 55455, USA
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45
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Liver transplantation for hepatocellular carcinoma. Curr Opin Organ Transplant 2002. [DOI: 10.1097/00075200-200206000-00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
The number of papers published regarding hepatocellular carcinoma increased remarkably over the previous year. The 1-year survival for hepatocellular carcinoma has only improved slightly over the past 20 years, while the overall survival has remained unchanged. Hepatitis B genotypes, specifically genotype B, correlate with better response and survival in patients with hepatocellular carcinoma caused by this chronic infection. A consensus conference recommended that patients with Child-Turcotte-Pugh class A or B cirrhosis should be screened with ultrasound and alpha-fetoprotein measurement every 6 months. Using microarray technology, several groups established the gene expression for human hepatocellular carcinoma including the identification of potential genes involved in hepatic carcinogenesis. Dynamic gadolinium MRI is the preferred imaging of choice for the evaluation of hepatocellular carcinoma, but contrast-enhanced power Doppler ultrasound is a new imaging technique able to differentiate neoplastic from nonneoplastic liver lesions. Overall, transplantation is the best long-term therapeutic option, but in patients without portal hypertension and well-preserved liver function, resection may be preferable.
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Affiliation(s)
- Mary Ann Huang
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
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47
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Lefkowitch JH. Hepatobiliary pathology. Curr Opin Gastroenterol 2002; 18:290-8. [PMID: 17033299 DOI: 10.1097/00001574-200205000-00002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Technologic advances using cDNA microarray hybridization, liver diseases characterized by mitochondrial DNA depletion, and new work characterizing bile salt transport problems in familial intrahepatic cholestasis syndromes were some of the major highlights of this past year. Analysis of normal livers by cDNA microarrays disclosed 2418 unique gene transcripts encoding a host of cellular structural and functional proteins. This technique was also applied to hepatocellular carcinoma, where enhanced expression of a number of genes involved in antiapoptosis and cell transformation may shed additional light on the process of hepatocarcinogenesis. Mitochondrial DNA depletion seen in Navajo neurohepatopathy and in respiratory chain disorders of infancy was associated with cholestasis and cirrhosis in the former and microvesicular steatosis and oncocytic transformation (mitochondrial hyperplasia) in the latter. Pathologists who routinely examine liver biopsies after liver or bone marrow transplantation should be aware of unusual biopsy features that mimic other diseases, such as the autoimmune hepatitis-like syndrome that may follow liver transplantation and chronic graft-versus-host disease that clinically and pathologically resembles acute hepatitis.
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Affiliation(s)
- Jay H Lefkowitch
- College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
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Cheng SJ, Freeman RB, Wong JB. Predicting the probability of progression-free survival in patients with small hepatocellular carcinoma. Liver Transpl 2002; 8:323-8. [PMID: 11965574 DOI: 10.1053/jlts.2002.31749] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Allocation of cadaveric livers to patients based on such objective medical urgency data as the Model for End-Stage Liver Disease (MELD) score may not benefit patients with small hepatocellular carcinomas (HCCs). To ensure that these patients have a fair opportunity of receiving a cadaveric organ, the risk for death caused by HCC and tumor progression beyond 5 cm should be considered. Using a Markov model, two hypothetical cohorts of patients with small hepatomas were assumed to have either (1) Gompertzian tumor growth, in which initial exponential growth decreases as tumor size increases; or (2) rapid exponential growth. The model tracked the number of patients who either died or had tumor progression beyond 5 cm. These results were used to back-calculate an equivalent MELD score for patients with small HCCs. All probabilities in the model were varied simultaneously using a Monte Carlo simulation. The Gompertzian growth model predicted that patients with a 1- and 4-cm tumor have 1-year progression-free survival rates of 70% (HCC-specific MELD score 6) and 66% (HCC-specific MELD score 8), respectively. When assuming rapid exponential growth, patients with a 1- and 4-cm tumor have progression-free survival rates of 69% (HCC-specific MELD score 6) and 12% (HCC-specific MELD score 24), respectively. Our model predicted that the risk for death caused by HCC or tumor progression beyond 5 cm should increase with larger initial tumor size in patients with small hepatomas. To ensure that these patients have a fair opportunity to receive a cadaveric organ, HCC-specific scores predicted by our model could be added to MELD scores of patients with HCC.
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Affiliation(s)
- Steve J Cheng
- Department of Medicine, Division of Clinical Decision Making, New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
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