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Singh A, Singh C, Dhaliwal A, Singh N, Kumar V, Sohal A, Schneider J. Incidence, screening, and management of de novo malignancies in liver transplant patients: A review. World J Transplant 2025; 15:101046. [DOI: 10.5500/wjt.v15.i3.101046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 04/18/2025] Open
Abstract
Liver transplantation (LT) is the definitive treatment for end-stage liver disease, acute liver failure, and liver cancer. Although advancements in surgical techniques, postoperative care, and immunosuppressive therapies have significantly improved outcomes, the long-term use of immunosuppression has increased the risk of complications, including infections, cardiovascular disease, and cancer. Among these, de novo malignancies (DNMs) are a major concern, accounting for 20%-25% of deaths in LT recipients surviving beyond the early post-transplant period. Non-melanoma skin cancers, particularly squamous cell carcinoma are the most prevalent DNMs. Other significant malignancies include Kaposi's sarcoma, post-transplant lymphoproliferative disorders, and various solid organ cancers, including head and neck cancers. Compared to the general population, LT patients face a twofold increase in solid organ malignancies and a 30-fold increase in lymphoproliferative disorders. Risk factors for DNM include chronic immunosuppression, alcohol or tobacco use, viral infections, and underlying liver disease. Emerging evidence emphasizes the importance of tailored cancer screening and prevention strategies, including regular dermatological examinations, targeted screenings for high-risk cancers, and patient education on lifestyle modifications. Early detection through enhanced surveillance protocols has been shown to improve outcomes. Management of DNMs involves a combination of standard oncological therapies and adjustments to immunosuppressive regimens, with promising results from the use of mTOR inhibitors in select patients. The review highlights the critical need for ongoing research to refine risk stratification, optimize screening protocols, and improve treatment approaches to mitigate the burden of DNMs in LT recipients. By implementing personalized preventive and therapeutic strategies, we can enhance long-term outcomes and quality of life for this vulnerable population.
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Affiliation(s)
- Anmol Singh
- Department of Medicine, Tristar Centennial Medical Center, Nashville, TN 37203, United States
| | - Carol Singh
- Department of Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Armaan Dhaliwal
- Division of Hematology and Oncology, Lehigh Valley Health Network, Allentown, PA 18103, United States
| | - Navdeep Singh
- Department of Medicine, Government Medical College, Amritsar 143001, Punjab, India
| | - Vikash Kumar
- Division of Gastroenterology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
| | - Aalam Sohal
- Division of Gastroenterology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
| | - Jonathan Schneider
- Division of Gastroenterology, Tristar Centennial Medical Center, Nashville, TN 37203, United States
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2
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Lim W, Moon S, Lee NR, Shin HG, Yu SY, Lee JE, Kim I, Ko KP, Park SK. Group I pharmaceuticals of IARC and associated cancer risks: systematic review and meta-analysis. Sci Rep 2024; 14:413. [PMID: 38172159 PMCID: PMC10764325 DOI: 10.1038/s41598-023-50602-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/21/2023] [Indexed: 01/05/2024] Open
Abstract
We aimed to summarize the cancer risk among patients with indication of group I pharmaceuticals as stated in monographs presented by the International Agency for Research on Cancer working groups. Following the PRISMA guidelines, a comprehensive literature search was conducted using the PubMed database. Pharmaceuticals with few studies on cancer risk were identified in systematic reviews; those with two or more studies were subjected to meta-analysis. For the meta-analysis, a random-effects model was used to calculate the summary relative risks (SRRs) and 95% confidence intervals (95% CIs). Heterogeneity across studies was presented using the Higgins I square value from Cochran's Q test. Among the 12 group I pharmaceuticals selected, three involved a single study [etoposide, thiotepa, and mustargen + oncovin + procarbazine + prednisone (MOPP)], seven had two or more studies [busulfan, cyclosporine, azathioprine, cyclophosphamide, methoxsalen + ultraviolet (UV) radiation therapy, melphalan, and chlorambucil], and two did not have any studies [etoposide + bleomycin + cisplatin and treosulfan]. Cyclosporine and azathioprine reported increased skin cancer risk (SRR = 1.32, 95% CI 1.07-1.62; SRR = 1.56, 95% CI 1.25-1.93) compared to non-use. Cyclophosphamide increased bladder and hematologic cancer risk (SRR = 2.87, 95% CI 1.32-6.23; SRR = 2.43, 95% CI 1.65-3.58). Busulfan increased hematologic cancer risk (SRR = 6.71, 95% CI 2.49-18.08); melphalan was associated with hematologic cancer (SRR = 4.43, 95% CI 1.30-15.15). In the systematic review, methoxsalen + UV and MOPP were associated with an increased risk of skin and lung cancer, respectively. Our results can enhance persistent surveillance of group I pharmaceutical use, establish novel clinical strategies for patients with indications, and provide evidence for re-categorizing current group I pharmaceuticals into other groups.
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Affiliation(s)
- Woojin Lim
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
- Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Republic of Korea
| | - Sungji Moon
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
- Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea
- Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Na Rae Lee
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, 04933, Republic of Korea
| | - Ho Gyun Shin
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, 04933, Republic of Korea
| | - Su-Yeon Yu
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, 04933, Republic of Korea
| | - Jung Eun Lee
- Department of Food and Nutrition, Seoul National University College of Human Ecology, Seoul, 08826, Republic of Korea
| | - Inah Kim
- Department of Occupational and Environmental Medicine, Hanyang University College of Medicine, Seoul, 04763, Republic of Korea
| | - Kwang-Pil Ko
- Clinical Preventive Medicine Center, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
- Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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Altieri M, Sérée O, Lobbedez T, Segol P, Abergel A, Blaizot X, Boillot O, Boudjema K, Coilly A, Conti F, Chazouillères O, Debette-Gratien M, Dharancy S, Durand F, Duvoux C, Francoz C, Gugenheim J, Hardwigsen J, Houssel-Debry P, Kamar N, Latournerie M, Lebray P, Leroy V, Neau-Cransac M, Pageaux GP, Radenne S, Salamé E, Saliba F, Samuel D, Vanlemmens C, Besch C, Launoy G, Dumortier J. Risk factors of de novo malignancies after liver transplantation: a French national study on 11004 adult patients. Clin Res Hepatol Gastroenterol 2021; 45:101514. [PMID: 33714907 DOI: 10.1016/j.clinre.2020.07.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 07/13/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND After liver transplantation (LT),de novo malignancies are one of the leading causes of late mortality. The aim of the present retrospective study was to identify the risk factors of de novo malignancies in a large cohort of LT recipients in France, using Fine and Gray competing risks regression analysis. METHODS The study population consisted in 11004 adults transplanted between 2000 and 2013, who had no history of pre-transplant malignancy, except primary liver tumor. A Cox model adapted to the identification of prognostic factors (competitive risks) was used. RESULTS From the entire cohort, one (or more)de novo malignancy was reported in 1480 L T recipients (13.45%). The probability to develop a de novo malignancy after LT was 2.07% at 1 year, 13.30% at 5 years, and 28.01% at 10 years. Of the known reported malignancies, the most common malignancies were hematological malignancy (22.36%), non-melanoma skin cancer (19.53%) and lung cancer (12.36%). According to Fine and Gray competing risks regression multivariate analysis, were significant risk factors for post-LT de novo malignancy: recipient age (Subdistribution Hazard Ratio (SHR) = 1.03 95%CI 1.03-1.04), male gender (SHR = 1.45 95%CI 1.27-1.67), non-living donor (SHR = 1.67 95%CI 1.14-2.38), a first LT (SHR = 1.35 95%CI 1.09-1.69) and the type of initial liver disease (alcohol-related liver disease (SHR = 1.63 95%CI 1.22-2.17), primary sclerosing cholangitis (SHR = 1.98 95%CI 1.34-2.91), and primary liver tumor (SHR = 1.88 95%CI 1.41-2.54)). Initial immunosuppressive regimen had no significant impact. CONCLUSION The present study confirms that LT recipient characteristics are associated with the risk ofde novo malignancy and this underlines the need for personalized screening in order to improve survival.
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Affiliation(s)
- Mario Altieri
- Hôpital Côte de Nacre, Service d'Hépato-Gastroentérologie, Nutrition et Oncologie Digestive, Caen, France; UFR Santé Caen France: U1086 INSERM- "ANTICIPE", Caen, France
| | - Olivier Sérée
- Réseau Régional de Cancérologie OncoBasseNormandie, Caen, France
| | - Thierry Lobbedez
- Hôpital Côte de Nacre, Néphrologie, CUMR CAEN CEDEX, France, Normandie Université, Unicaen UFR de Médecine, RDPLF, Caen, France
| | - Philippe Segol
- Hôpital Côte de Nacre, Service de chirurgie digestive et générale, Caen, France
| | - Armand Abergel
- CHU Estaing, Médecine Digestive, Institut Pascal., UMR 6602 UCA CNRS SIGMA, Clermont-Ferrand, France
| | - Xavier Blaizot
- Réseau Régional de Cancérologie OncoBasseNormandie, Caen, France
| | - Olivier Boillot
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation Hépatique, et Université Claude Bernard Lyon 1, France
| | - Karim Boudjema
- Hôpital Universitaire de Pontchaillou, Service d'Hépatologie et Transplantation Hépatique, Rennes, France
| | - Audrey Coilly
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Villejuif, France
| | - Filomena Conti
- APHP - Hôpital de la Pitié Salpétrière, Service d'Hépatologie et Transplantation Hépatique, Paris, France
| | - Olivier Chazouillères
- AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, INSERM UMR S 938, CDR Saint-Antoine, Centre de Référence « Maladies inflammatoire des voies biliaires et hépatite auto-immune », Filière FILFOIE, Université Paris 6, UMR_S 938, CDR Saint-Antoine, Paris, France
| | - Maryline Debette-Gratien
- CHU Limoges, Service d'hépato-Gastroentérologie,, INSERM, U850, Université Limoges, Limoges, France
| | | | - François Durand
- APHP, Hôpital Beaujon, Service d'Hépatologie et Transplantation Hépatique - Université Paris Diderot - INSERM U1149, Clichy, France
| | | | - Claire Francoz
- APHP, Hôpital Beaujon, Service d'Hépatologie et Transplantation Hépatique - Université Paris Diderot - INSERM U1149, Clichy, France
| | - Jean Gugenheim
- Hôpital Universitaire de Nice, Service de Chirurgie Digestive et de Transplantation Hépatique - Université de Nice-Sophia-Antipolis, Nice, France
| | - Jean Hardwigsen
- APHM, Hôpital La Timone, Service Chirurgie Générale et Transplantation Hépatique Marseille, France
| | - Pauline Houssel-Debry
- Hôpital Universitaire de Pontchaillou, Service d'Hépatologie et Transplantation Hépatique, Rennes, France
| | - Nassim Kamar
- CHU Rangueil, Département de Néphrologie et Transplantation d'Organes, Toulouse, France
| | - Marianne Latournerie
- CHU Dijon, Service d'Hépato-gastroentérologie et Oncologie Digestive, Inserm EPICAD LNC-UMR1231, Université de Bourgogne-Franche Comté, Dijon, France
| | - Pascal Lebray
- CHU Dijon, Service d'Hépato-gastroentérologie et Oncologie Digestive, Inserm EPICAD LNC-UMR1231, Université de Bourgogne-Franche Comté, Dijon, France
| | - Vincent Leroy
- CHU Grenoble-Alpes, Service d'hépato-gastroentérologie, La Tronche, France
| | - Martine Neau-Cransac
- CHU de Bordeaux, Hôpital Haut Lévêque, Service de Chirurgie Hépatobiliaire et de Transplantation Hépatique, Bordeaux, France
| | | | - Sylvie Radenne
- Hospices civils de Lyon, Hôpital de la Croix-Rousse, Service d'Hépato-Gastroentérologie, Lyon, France
| | - Ephrem Salamé
- CHU Tours, Hôpital Trousseau Service de chirurgie digestive, oncologique et endocrinienne, Transplantation hépatique, Tours, France
| | - Faouzi Saliba
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Villejuif, France
| | - Didier Samuel
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Villejuif, France
| | - Claire Vanlemmens
- Hôpital Jean Minjoz, Service d'Hépatologie et Soins Intensifs Digestifs, Besançon, France
| | - Camille Besch
- CHRU Hautepierre, Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Strasbourg, France
| | - Guy Launoy
- UFR Santé Caen France: U1086 INSERM- "ANTICIPE", Caen, France
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation Hépatique, et Université Claude Bernard Lyon 1, France.
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Choudhary NS, Saigal S, Saraf N, Soin AS. Extrahepatic Malignancies and Liver Transplantation: Current Status. J Clin Exp Hepatol 2021; 11:494-500. [PMID: 34276155 PMCID: PMC8267344 DOI: 10.1016/j.jceh.2020.10.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022] Open
Abstract
Recipients of liver transplantation (LT) remain at higher risk (adjusted for other risk factors) of de novo malignancies (DNMs). The higher risk can be attributed to the effect of immunosuppression and patient-related risk factors (age, tobacco, alcohol, etiology of liver disease). DNMs are an important cause of late mortality in liver transplant recipients. The pattern (type) of posttransplant malignancies reflects pattern in local population. The common types include skin cancers, solid organ malignancies, and post-transplant lymphoproliferative disorders. Counseling of patients about risk factors and surveillance protocols may help in the prevention and diagnosis at early stage. We also discuss the results of LT in patients with a history of extrahepatic malignancy in the pretransplant period.
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Affiliation(s)
| | - Sanjiv Saigal
- Address for correspondence: Dr Sanjiv Saigal DM, MRCP Senior Director, Hepatology and Liver Transplantation, Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Sector 38, Gurgaon, PIN 122001, India.
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5
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Ritter A, Badir S, Mansour M, Segal Z, Ad-El D, Bachar G, Shpitzer T, Popovtzer A, Mizrachi A. Solid organ transplantation worsens the prognosis of patients with cutaneous squamous cell carcinoma of the head and neck region-Comparison between solid organ transplant recipients and immunocompetent patients. Head Neck 2020; 43:884-894. [PMID: 33247523 DOI: 10.1002/hed.26546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 10/25/2020] [Accepted: 11/09/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Cutaneous squamous cell carcinoma of the head and neck (CSCC-HN) appears to behave more aggressively in immunosuppressed patients. We aimed to investigate this hypothesis by comparing solid organ transplant recipients (SOTR) with CSCC-HN to immunocompetent patients. METHODS A retrospective comparative study was conducted for SOTR and immunocompetent patients who were treated for CSCC-HN. RESULTS A total of 177 SOTR and 157 immunocompetent patients with CSCC-HN were included. Lymph node metastases were more common in the SOTR group (9% vs 3%), and distant metastases occurred only in SOTR (3% of patients). SOTR had a higher rate of recurrences (19% vs 10%), which were mostly regional (7%) and distant (3%). The 2-year disease-specific survival of SOTR was lower (93% vs 100%). CONCLUSIONS SOTR with CSCC-HN has significantly worse outcomes compared to immunocompetent patients. Solid-organ transplantation should be regarded as a negative prognostic factor in patients with CSCC-HN.
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Affiliation(s)
- Amit Ritter
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Samih Badir
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Muhammad Mansour
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Zvi Segal
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Dean Ad-El
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Gideon Bachar
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Thomas Shpitzer
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aron Popovtzer
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
| | - Aviram Mizrachi
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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6
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Gitto S, Aspite S, Golfieri L, Caputo F, Vizzutti F, Grandi S, Patussi V, Marra F. Alcohol use disorder and liver transplant: new perspectives and critical issues. Korean J Intern Med 2020; 35:797-810. [PMID: 32241080 PMCID: PMC7373982 DOI: 10.3904/kjim.2019.409] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 03/03/2020] [Indexed: 12/13/2022] Open
Abstract
Alcoholic liver disease is a consolidated indication for liver transplantation, but many unsolved issues can be highlighted. Patients with alcohol use disorder develop peculiar comorbidities that can become contraindications for transplantation. Moreover, a number of social and psychological patterns should be evaluated to select candidates with a low risk of alcohol relapse and adequate post-transplant adherence. In this context, the 6-month rule is too rigid to be widely applied. A short period of abstinence (1 to 3 months) is useful to estimate recovery of liver function and, possibly to avoid transplant. Cardiovascular disorders and extra-hepatic malignancies represent the main clinical issues after transplant. Patients transplanted due to alcoholic disease are a major risk for other liver diseases. Severe corticosteroid-resistant alcoholic acute hepatitis is a debated indication for transplant. However, available data indicate that well-selected patients have excellent post-transplant outcomes. Behavioral therapy, continued psychological support and a multidisciplinary team are essential to achieve and maintain complete alcohol abstinence during the transplant process. Alcoholic liver disease is an excellent indication for a liver transplant but patients with alcohol use disorder deserve a personalized approach and dedicated resources.
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Affiliation(s)
- Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Silvia Aspite
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Lucia Golfieri
- Department of Psychology, University of Bologna, Bologna, Italy
| | - Fabio Caputo
- Department of Internal Medicine, SS Annunziata Hospital, University of Ferrara, Cento, Italy
| | - Francesco Vizzutti
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Silvana Grandi
- Department of Psychology, University of Bologna, Bologna, Italy
| | | | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- Research Center Denothe, University of Florence, Italy
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Singh A, De A, Singh V. Post-transplant malignancies in alcoholic liver disease. Transl Gastroenterol Hepatol 2020; 5:30. [PMID: 32258534 DOI: 10.21037/tgh.2019.11.18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 11/21/2019] [Indexed: 01/20/2023] Open
Abstract
Post-transplant malignancy is emerging as an important cause of mortality in patients with cirrhosis undergoing liver transplant (LT). However, establishing the exact relationship between the two needs further evaluation. It has been observed that approximately 30% deaths after 10 years of hepatic transplantation occur due to de novo malignancies. Various known risk factors include immunosuppression, age of patient, alcoholic liver disease (ALD) or primary sclerosing cholangitis, smoking, and oncogenic viral infections. There is scanty literature on the post-transplant malignancy risk in patients with alcoholic cirrhosis. The current evidence suggests a particularly increased risk of oropharyngeal and lung cancers in patients transplanted for ALD. Abstinence from alcohol, smoking and other tobacco-containing products along with optimization of immunosuppression are paramount for decreasing the risk of post-transplant malignancies.
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Affiliation(s)
- Akash Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Virendra Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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8
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Molecular Biology of Basal and Squamous Cell Carcinomas. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1268:171-191. [PMID: 32918219 DOI: 10.1007/978-3-030-46227-7_9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The prevalent keratinocyte-derived neoplasms of the skin are basal cell carcinoma and squamous cell carcinoma. Both so-called non-melanoma skin cancers comprise the most common cancers in humans by far. Common risk factors for both tumor entities include sun exposure, DNA repair deficiencies leading to chromosomal instability, or immunosuppression. Yet, fundamental differences in the development of the two different entities have been and are currently unveiled. The constitutive activation of the sonic hedgehog signaling pathway by acquired mutations in the PTCH and SMO genes appears to represent the early basal cell carcinoma developmental determinant. Although other signaling pathways are also affected, small hedgehog inhibitory molecules evolve as the most promising basal cell carcinoma treatment options systemically as well as topically in current clinical trials. For squamous cell carcinoma development, mutations in the p53 gene, especially UV-induced mutations, have been identified as early events. Yet, other signaling pathways including epidermal growth factor receptor, RAS, Fyn, or p16INK4a signaling may play significant roles in squamous cell carcinoma development. The improved understanding of the molecular events leading to different tumor entities by de-differentiation of the same cell type has begun to pave the way for modulating new molecular targets therapeutically with small molecules.
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9
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Manzia TM, Angelico R, Gazia C, Lenci I, Milana M, Ademoyero OT, Pedini D, Toti L, Spada M, Tisone G, Baiocchi L. De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature. World J Gastroenterol 2019; 25:5356-5375. [PMID: 31558879 PMCID: PMC6761240 DOI: 10.3748/wjg.v25.i35.5356] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 08/08/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy. RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.
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Affiliation(s)
- Tommaso Maria Manzia
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Roberta Angelico
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Carlo Gazia
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, United States
| | - Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | | | - Domiziana Pedini
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Luca Toti
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Marco Spada
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Giuseppe Tisone
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
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10
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Haney MO, Ordin YS, Arkan G. Skin Cancer-Sun Knowledge and Sun Protection Behaviors of Liver Transplant Recipients in Turkey. JOURNAL OF CANCER EDUCATION : THE OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER EDUCATION 2019; 34:137-144. [PMID: 28887780 DOI: 10.1007/s13187-017-1279-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The aim of this study was to compare liver transplant recipients (LTRs) with the general population regarding their knowledge of skin cancer, sun health, sun protection behaviors, and affecting factors. This cross-sectional study was conducted in Turkey between March 2016 and September 2016 with 104 LTRs and 100 participants from the general population group (GPG). The mean age of the LTRs was 53.2 ± 11.8 and that of the GPG was 42.7 ± 14.5. The LTRs' skin cancer and sun knowledge were significantly lower than in the GPG, but there was no difference between the two groups in terms of their sun protection behavior scores. The most commonly used sun protection behaviors of LTRs were not being outside and not sunbathing between 10 a.m. and 4 p.m., wearing clothing that covers the skin, and avoiding the solarium. Behaviors commonly practiced by the GPG were wearing sunglasses, wearing sunscreen with a sun protection factor of 15 or higher before going outside, wearing sunscreen at the beach, while swimming or doing physical activity outside, and reapplying it every 2 h. Results of our study will contribute to the development of education and training programs for LTRs on skin cancer. The results also demonstrated the importance of practicing adequate sun protection behaviors which will certainly impact their future health.
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Affiliation(s)
- Meryem Ozturk Haney
- Public Health Nursing Department, Dokuz Eylul University Faculty of Nursing, Izmir, Turkey
| | - Yaprak Sarigol Ordin
- Surgical Nursing Department, Dokuz Eylul University Faculty of Nursing, Izmir, Turkey
| | - Gulcihan Arkan
- Public Health Nursing Department, Dokuz Eylul University Faculty of Nursing, Dokuz Eylul University Health Campus, Inciralti, 35340, Izmir, Turkey.
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11
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Ritter A, Bachar G, Feinmesser R, Shpitzer T, Popovtzer A, Rabinovics N. Nonmelanoma skin cancer of the head and neck region in solid organ transplant recipients. Head Neck 2018; 41:374-380. [DOI: 10.1002/hed.25467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 08/17/2018] [Indexed: 01/20/2023] Open
Affiliation(s)
- Amit Ritter
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Gideon Bachar
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Raphael Feinmesser
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Thomas Shpitzer
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Aron Popovtzer
- Institute of Oncology, Davidoff CenterRabin Medical Center Petach Tikva Israel
| | - Naomi Rabinovics
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
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12
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Tanaka T, Voigt MD. Decision tree analysis to stratify risk of de novo non-melanoma skin cancer following liver transplantation. J Cancer Res Clin Oncol 2018; 144:607-615. [PMID: 29362916 DOI: 10.1007/s00432-018-2589-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/17/2018] [Indexed: 01/15/2023]
Abstract
PURPOSE Non-melanoma skin cancer (NMSC) is the most common de novo malignancy in liver transplant (LT) recipients; it behaves more aggressively and it increases mortality. We used decision tree analysis to develop a tool to stratify and quantify risk of NMSC in LT recipients. METHODS We performed Cox regression analysis to identify which predictive variables to enter into the decision tree analysis. Data were from the Organ Procurement Transplant Network (OPTN) STAR files of September 2016 (n = 102984). RESULTS NMSC developed in 4556 of the 105984 recipients, a mean of 5.6 years after transplant. The 5/10/20-year rates of NMSC were 2.9/6.3/13.5%, respectively. Cox regression identified male gender, Caucasian race, age, body mass index (BMI) at LT, and sirolimus use as key predictive or protective factors for NMSC. These factors were entered into a decision tree analysis. The final tree stratified non-Caucasians as low risk (0.8%), and Caucasian males > 47 years, BMI < 40 who did not receive sirolimus, as high risk (7.3% cumulative incidence of NMSC). The predictions in the derivation set were almost identical to those in the validation set (r2 = 0.971, p < 0.0001). Cumulative incidence of NMSC in low, moderate and high risk groups at 5/10/20 year was 0.5/1.2/3.3, 2.1/4.8/11.7 and 5.6/11.6/23.1% (p < 0.0001). CONCLUSIONS The decision tree model accurately stratifies the risk of developing NMSC in the long-term after LT.
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Affiliation(s)
- Tomohiro Tanaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, USA.
| | - Michael D Voigt
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, USA
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13
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Bajetta E, Platania M, Catena L, Bichisao E, Fabbri A, Procopio G, De Dosso S, Buzzoni R. Merkel Cell Carcinoma after Liver Transplantation: A Case Report. TUMORI JOURNAL 2018; 93:323-6. [PMID: 17679476 DOI: 10.1177/030089160709300321] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background Merkel cell carcinoma is a rare and aggressive neuroendocrine skin cancer with a very low incidence in the general population. MCC seems to be common in transplant recipients and 52 cases have been reported in the literature. Methods and results This report describes a Merkel cell carcinoma which developed in a liver transplant recipient. To our knowledge, this is the second such case reported, as Merkel cell carcinoma most commonly occurs after kidney and heart transplants. The treatment approach is described and the literature on the subject is reviewed. Conclusion There is currently no consensus regarding the optimal therapeutic approach to Merkel cell carcinoma. In transplant recipients, such tumors are more common and more aggressive but their treatment does not differ from the treatment of Merkel cell carcinomas in the general population.
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Affiliation(s)
- Emilio Bajetta
- Unit of Medical Oncology 2, Centro di Riferimento per lo Studio e la Cura del Carcinoide e dei Tumori Neuroendocrini (CeRiCa), Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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14
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Ge L, Chee SN, Robledo KP, Lowe P. Comparison of skin cancers in liver and renal transplant recipients: Results of a prospective study in an Australian tertiary referral centre. Australas J Dermatol 2018; 59:291-296. [DOI: 10.1111/ajd.12759] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/21/2017] [Indexed: 01/11/2023]
Affiliation(s)
- Ludi Ge
- Department of Dermatology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
- Sydney Medical School; University of Sydney; Sydney New South Wales Australia
| | - Shien-Ning Chee
- Department of Dermatology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
| | - Kristy P Robledo
- National Health and Medical Research Council; Clinical Trials Centre; University of Sydney; Sydney New South Wales Australia
| | - Patricia Lowe
- Department of Dermatology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
- Sydney Medical School; University of Sydney; Sydney New South Wales Australia
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15
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Campos GR, Boin IDFSF, Campos IDD, Cintra ML. Study of factors affecting the incidence of skin cancer in patients after liver transplant. An Bras Dermatol 2017; 92:492-498. [PMID: 28954097 PMCID: PMC5595595 DOI: 10.1590/abd1806-4841.20175946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 12/10/2016] [Indexed: 01/08/2023] Open
Abstract
Background Many factors are currently being identified as potential inductors of skin
cancer in patients after a liver transplant, among them, immunosuppressive
regimen. Objective To study the factors that influence the incidence of skin cancer in patients
after liver transplant. Methods We have carried out a retrospective and observational study with 170
transplanted patients who had undergone transplantation from 1997 to 2010.
We have adjusted the multiple logistic regression model (saturated model) to
the ensemble of collected data using skin cancer as dependent variable,
indicated in anatomopathological analysis between 1997 and 2014. Results Incidence of skin cancer was 9.4%. Predictors were incidence of diabetes in
the third year after the transplantation (p=0.047), not using tacrolimus in
the first year after the transplantation (p=0.025) and actinic keratosis
(p=0.003). Study Limitations An important limitation is that the interpretation of the results was based
on information collected of patients undergoing transplantation at a single
center. Future research, multicentric and involving larger and more diverse
populations, are needed. Conclusions Factors found might contribute to Brazilian surveillance programs associated
with decreased incidence of skin cancer.
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Affiliation(s)
- Gabriela Rached Campos
- Post-Graduation Program in Surgery Sciences of School of Medical Sciences of Universidade Estadual de Campinas (FCM-Unicamp) - Campinas (SP), Brazil
| | | | - Ivan Dias de Campos
- Post-Graduation Program in Surgery Sciences of School of Medical Sciences of Universidade Estadual de Campinas (FCM-Unicamp) - Campinas (SP), Brazil
| | - Maria Letícia Cintra
- Department of Pathologic Anatomy of School of Medical Sciences of Universidade Estadual de Campinas (FCM-Unicamp) - Campinas (SP), Brazil
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16
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Liu ZN, Wang WT, Yan LN. De Novo Malignancies After Liver Transplantation With 14 Cases at a Single Center. Transplant Proc 2016; 47:2483-7. [PMID: 26518956 DOI: 10.1016/j.transproceed.2015.08.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/27/2015] [Accepted: 08/03/2015] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To analyze the clinical characteristics, risk factors, and prevention of de novo malignant tumors after liver transplantation. METHODS Fourteen patients who underwent liver transplantation were identified as having de novo malignancies. The clinical characteristics and survival of these patients were retrospectively reviewed. RESULTS Fourteen cases of de novo malignancies after liver transplantation occurred for an incidence rate of 1.94% (14/722), including 11 men (78.6%, mean age, 48 y) and 3 women (21.4%, mean age, 50 y). The mean period from transplantation to cancer diagnosis was 55 ± 35 months. The distribution of tumor histologic types included colon cancer, lung cancer, esophageal cancer, nasopharyngeal cancer, liver cancer, parotid carcinoma, bone cancer, post-transplantation lymphoproliferative disorder, stomach cancer, bladder cancer, and laryngeal cancer. Twelve cases (85.7%) had hepatitis B. Five patients (35.7%) underwent operations, and the other 9 patients underwent chemotherapy or radiotherapy. During a mean follow-up period of 37 ± 26 months after the diagnosis of de novo malignancy, 8 patients (57.1%) died, with only 1 dying of causes not related to the de novo malignancy. The survival analysis showed 1-, 5-, and 7-year survival rates of 85.7%, 71.4%, and 42.9%, respectively. CONCLUSIONS De novo malignancies after organ transplantation have been suggested to be a major cause of late mortality. De novo malignancy after orthotopic liver transplantation was found to be related to smoking, sex, and low immune function due to immunosuppressive agents. Solid tumors should be removed, and the patient should receive chemotherapy or radiotherapy as early as possible. Early diagnosis and treatment are very important for improving the prognosis.
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Affiliation(s)
- Z-N Liu
- Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - W-T Wang
- Liver Surgery, West China Hospital of Sichuan University, Chengdu, China.
| | - L-N Yan
- Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
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17
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Doycheva I, Amer S, Watt KD. De Novo Malignancies After Transplantation: Risk and Surveillance Strategies. Med Clin North Am 2016; 100:551-67. [PMID: 27095645 DOI: 10.1016/j.mcna.2016.01.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
De novo malignancies are one of the leading causes of late mortality after liver and kidney transplantation. Nonmelanoma skin cancer is the most common malignancy, followed by posttransplant lymphoproliferative disorder and solid organ tumors. Immunosuppression is a key factor for cancer development, although many other transplant-related and traditional risk factors also play a role. In this review, the authors summarize risk factors and outcomes of frequently encountered de novo malignancies after liver and kidney transplantation to stratify recipients at highest risk. Future efforts in prospectively validated, cost-effective surveillance strategies that improve survival of these complex patients are greatly needed.
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Affiliation(s)
- Iliana Doycheva
- Division of Gastroenterology and Hepatology, Medical University-Sofia, 1 G. Sofiisky Boulevard, Sofia 1431, Bulgaria
| | - Syed Amer
- Division of Internal Medicine, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, CH-10, 200 First Street Southwest, Rochester, MN 55905, USA.
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18
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Mukthinuthalapati PK, Gotur R, Ghabril M. Incidence, risk factors and outcomes of de novo malignancies post liver transplantation. World J Hepatol 2016; 8:533-544. [PMID: 27134701 PMCID: PMC4840159 DOI: 10.4254/wjh.v8.i12.533] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 03/08/2016] [Accepted: 04/06/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is associated with a 2 to 7 fold higher, age and gender adjusted, risk of de novo malignancy. The overall incidence of de novo malignancy post LT ranges from 2.2% to 26%, and 5 and 10 years incidence rates are estimated at 10% to 14.6% and 20% to 32%, respectively. The main risk factors for de novo malignancy include immunosuppression with impaired immunosurveillance, and a number of patient factors which include; age, latent oncogenic viral infections, tobacco and alcohol use history, and underlying liver disease. The most common cancers after LT are non-melanoma skin cancers, accounting for approximately 37% of de novo malignancies, with a noted increase in the ratio of squamous to basal cell cancers. While these types of skin cancer do not impact patient survival, post-transplant lymphoproliferative disorders and solid organ cancer, accounting for 25% and 48% of malignancies, are associated with increased mortality. Patients developing these types of cancer are diagnosed at more advanced stages, and their cancers behave more aggressively compared with the general population. Patients undergoing LT for primary sclerosing cholangitis (particularly with inflammatory bowel disease) and alcoholic liver disease have high rates of malignancies compared with patients undergoing LT for other indications. These populations are at particular risk for gastrointestinal and aerodigestive cancers respectively. Counseling smoking cessation, skin protection from sun exposure and routine clinical follow-up are the current approach in practice. There are no standardized surveillance protocol, but available data suggests that regimented surveillance strategies are needed and capable of yielding cancer diagnosis at earlier stages with better resulting survival. Evidence-based strategies are needed to guide optimal surveillance and safe minimization of immunosuppression.
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19
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Burra P, Rodriguez-Castro KI. Neoplastic disease after liver transplantation: Focus on de novo neoplasms. World J Gastroenterol 2015; 21:8753-8768. [PMID: 26269665 PMCID: PMC4528018 DOI: 10.3748/wjg.v21.i29.8753] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 05/31/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma (HCC) recurrence have been reported with the use of mTOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs mTOR-inhibitor-free immunosuppression is more efficacious in reducing HCC recurrence.
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20
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Carenco C, Faure S, Herrero A, Assenat E, Duny Y, Danan G, Bismuth M, Chanques G, Ursic-Bedoya J, Jaber S, Larrey D, Navarro F, Pageaux GP. Incidence of solid organ cancers after liver transplantation: comparison with regional cancer incidence rates and risk factors. Liver Int 2015; 35:1748-55. [PMID: 25488375 DOI: 10.1111/liv.12758] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/04/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Increased rates of solid organ cancers post-liver transplantation have been reported, but the contribution of environmental factors and immunosuppressive therapy is not clear. This study's aims were to compare the incidence of de novo solid organ cancers after liver transplantation; identify risk factors independent of immunosuppressive therapy associated with these cancers; and assess the influence of calcineurin inhibitors on the appearance of these cancers. METHODS This single-centre study from 1991 to 2008 included 465 liver recipients who had survived for ≥1 year. Gross incidence rates were standardized by age and sex, using the global population as a reference. In addition, 322 of the 465 patients treated for ≥1 year with calcineurin inhibitors were studied. RESULTS Sixty-five (13.9%) of the 465 patients developed de novo solid cancers. The overall relative risk was 3.7. Significantly increased relative risks were observed for digestive, oesophageal, colorectal, oral and lung cancers, but not for genito-urinary and breast cancers. Among the 65 patients who developed solid organ cancers, 43 died (66.1%), 41 from cancer. The two independent risk factors were pretransplant smoking [P < 0.0001; odds ratio = 5.5 (.5; 12)] and obesity [P = 0.0184; odds ratio = 2.2 (1.1; 4.3)]. Of the 322 patients on calcineurin inhibitors, 55 (17%) developed de novo solid cancers. Tacrolimus exposure level was a risk factor for de novo solid cancers [P < 0.0001; OR = 15.3 (4.5; 52.2)]. CONCLUSIONS We recommend a change in immunosuppressive protocols with lifestyle/dietary guidelines and smoking cessation.
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Affiliation(s)
- Christophe Carenco
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Stéphanie Faure
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Astrid Herrero
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Eric Assenat
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Yohan Duny
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Guillaume Danan
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Michaël Bismuth
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Gérald Chanques
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - José Ursic-Bedoya
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Samir Jaber
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Dominique Larrey
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
| | - Francis Navarro
- Digestive department, Liver Transplantation Unit - Saint-Eloi Hospital, Monterpellier, France
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Jiménez-Romero C, Justo-Alonso I, Cambra-Molero F, Calvo-Pulido J, García-Sesma &A, Abradelo-Usera M, Caso-Maestro O, Manrique-Municio A. Incidence, risk factors and outcome of de novo tumors in liver transplant recipients focusing on alcoholic cirrhosis. World J Hepatol 2015; 7:942-953. [PMID: 25954477 PMCID: PMC4419098 DOI: 10.4254/wjh.v7.i7.942] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 09/15/2014] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett’s esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.
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Cordero-Coma M, Salazar-Méndez R, Yilmaz T. Treatment of severe non-infectious uveitis in high-risk conditions (Part I): pregnancy and malignancies, management and safety issues. Expert Opin Drug Saf 2015; 14:1071-86. [DOI: 10.1517/14740338.2015.1044969] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Carenco C, Assenat E, Faure S, Duny Y, Danan G, Bismuth M, Herrero A, Jung B, Ursic-Bedoya J, Jaber S, Larrey D, Navarro F, Pageaux GP. Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship. Am J Transplant 2015; 15:678-86. [PMID: 25648361 DOI: 10.1111/ajt.13018] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 09/11/2014] [Accepted: 09/12/2014] [Indexed: 01/25/2023]
Abstract
Although increased rates of solid organ cancers have been reported following liver transplantation (LT), the impact of quantitative exposure to calcineurin inhibitors (CNI) remains unclear. We have therefore probed the relationship between the development of solid organ cancers following LT and the level of CNI exposure. This prospective single-center study was conducted between 1995 and 2008 and is based on 247 tacrolimus-treated liver transplant recipients who survived at least 1 year following surgery. The incidence of cancer was recorded, and the mean blood concentration of tacrolimus (TC) was determined at 1 and 3 years following LT. The study results indicate that 43 (17.4%) patients developed de novo solid cancers. Mean TC during the first year after LT was significantly higher in patients who developed solid organ tumors (10.3 ± 2.1 vs. 7.9 ± 1.9 ng/mL, p < 0.0001). Independent risks factors in multivariate analysis were tobacco consumption before LT (OR = 5.42; 95% CI [1.93-15.2], p = 0.0014) and mean annual TC during the first year after LT (p < 0.0001; OR = 2.01; 95% CI [1.57-2.59], p < 0.0001). Similar effects were observed in 216 patients who received tacrolimus continuously for ≥3 years. It appears therefore that CNI should be used with caution after LT, and that new immunosuppressive therapies could deliver significant clinical benefits in this regard.
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Affiliation(s)
- C Carenco
- Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier I, Montpellier, France
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Management of de novo malignancies after liver transplantation. Transplant Rev (Orlando) 2015; 29:38-41. [DOI: 10.1016/j.trre.2014.11.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Revised: 10/21/2014] [Accepted: 11/13/2014] [Indexed: 12/19/2022]
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25
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Skin cancers after liver transplantation: retrospective single-center study on 371 recipients. Transplantation 2014; 98:335-40. [PMID: 24621534 DOI: 10.1097/tp.0000000000000051] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The increased risk of skin cancer is well known in heart and kidney transplant recipients, but fewer data exist on liver-transplant recipients (LTRs). The aim of this study was to analyze the prevalence, clinical features and risk factors of skin cancers in LTR treated mainly with tacrolimus. METHODS We selected LTR grafted in our hospital between January 1996 and December 2008, aged 20 years or more at the time of the study. Data were collected from the patients' medical files and with a questionnaire. RESULTS Three hundred seventy-one LTR were included. The median follow-up period was 8.2 years. The overall prevalence of skin cancers was 13.5%. The prevalence of melanoma was 1.3%. The squamous cell carcinoma to basal cell carcinoma ratio was 1:3. Both the overall cumulative patient risk of de novo skin malignancies and the squamous cell carcinoma-to-basal cell carcinoma ratio increased with time postgraft. The duration of immunosuppression was a risk factor, in addition to those common in the general population. No association was found between the primary liver disease and the development of skin cancer. CONCLUSION Contrasting with previous data of the literature, our findings suggest that, for a similar follow-up time, the risk of skin cancer in LTR is comparable to that of kidney transplant recipients.
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Desai R, Neuberger J. Donor transmitted and de novo cancer after liver transplantation. World J Gastroenterol 2014; 20:6170-6179. [PMID: 24876738 PMCID: PMC4033455 DOI: 10.3748/wjg.v20.i20.6170] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 12/02/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
Cancers in solid organ recipients may be classified as donor transmitted, donor derived, de novo or recurrent. The risk of donor-transmitted cancer is very low and can be reduced by careful screening of the donor but cannot be abolished and, in the United Kingdom series is less than 0.03%. For donors with a known history of cancer, the risks will depend on the nature of the cancer, the interventions given and the interval between diagnosis and organ donation. The risks of cancer transmission must be balanced against the risks of death awaiting a new graft and strict adherence to current guidelines may result increased patient death. Organs from selected patients, even with high-grade central nervous system (CNS) malignancy and after a shunt, can, in some circumstances, be considered. Of potential donors with non-CNS cancers, whether organs may be safely used again depends on the nature of the cancer, the treatment and interval. Data are scarce about the most appropriate treatment when donor transmitted cancer is diagnosed: sometimes substitution of agents and reduction of the immunosuppressive load may be adequate and the impact of graft removal should be considered but not always indicated. Liver allograft recipients are at increased risk of some de novo cancers, especially those grafted for alcohol-related liver disease and hepatitis C virus infection. The risk of lymphoproliferative disease and cancers of the skin, upper airway and bowel are increased but not breast. Recipients should be advised to avoid risk behavior and monitored appropriately.
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EXP CLIN TRANSPLANTExp Clin Transplant 2014; 12. [DOI: 10.6002/ect.25liver.p11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Wimmer CD, Angele MK, Schwarz B, Pratschke S, Rentsch M, Khandoga A, Guba M, Jauch KW, Bruns C, Graeb C. Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: a single center experience with 609 patients. Transpl Int 2013; 26:999-1006. [PMID: 23952102 DOI: 10.1111/tri.12165] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 05/05/2013] [Accepted: 07/21/2013] [Indexed: 12/18/2022]
Abstract
De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long-term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long-term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow-up (median 4.78 years), 87 de novo malignancies occurred in 71 patients (mean age 47.5 ± 13.3 years, mean time after liver transplantation 5.7 ± 3.7 years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15 years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post-transplant lymphoid disease, oropharyngeal cancer (n = 6, 6.9%), upper gastrointestinal tract cancer (n = 4, 4.6%), lung cancer (n = 4, 4.6%), gynecological malignancies (n = 4, 4.6%), and kidney cancer (n = 3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus-based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus-based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials.
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Affiliation(s)
- Cosmas D Wimmer
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany
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Thomas BR, Barnabas A, Agarwal K, Aluvihare V, Suddle AR, Higgins EM, O'Grady JG, Heaton ND, Heneghan MA. Patient perception of skin-cancer prevention and risk after liver transplantation. Clin Exp Dermatol 2013; 38:851-6. [DOI: 10.1111/ced.12159] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2013] [Indexed: 11/28/2022]
Affiliation(s)
| | | | | | | | | | - E. M. Higgins
- Department of Dermatology; King's College Hospital; London UK
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Chandok N, Watt KD. Burden of de novo malignancy in the liver transplant recipient. Liver Transpl 2012; 18:1277-89. [PMID: 22887956 DOI: 10.1002/lt.23531] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 07/04/2012] [Indexed: 12/12/2022]
Abstract
Recipients of liver transplantation (LT) have a higher overall risk (2-3 times on average) of developing de novo malignancies than the general population, with standardized incidence ratios ranging from 1.0 for breast and prostate cancers to 3-4 for colon cancer and up to 12 for esophageal and oropharyngeal cancers. Aside from immunosuppression, other identified risk factors for de novo malignancies include the patient's age, a history of alcoholic liver disease or primary sclerosing cholangitis, smoking, and viral infections with oncogenic potential. Despite outcome studies showing that de novo malignancies are major causes of mortality and morbidity after LT, there are no guidelines for cancer surveillance protocols or immunosuppression protocols to lower the incidence of de novo cancers. Patient education, particularly for smoking cessation and excess sun avoidance, and regular clinical follow-up remain the standard of care. Further research in epidemiology, risk factors, and the effectiveness of screening and management protocols is needed to develop evidence-based guidelines for the prevention and treatment of de novo malignancies.
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Affiliation(s)
- Natasha Chandok
- Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada
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Spanogle JP, Kudva YC, Dierkhising RA, Kremers WK, Roenigk RK, Brewer JD, Prieto M, Otley CC. Skin cancer after pancreas transplantation. J Am Acad Dermatol 2012; 67:563-9. [DOI: 10.1016/j.jaad.2011.11.939] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 11/08/2011] [Indexed: 10/28/2022]
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Nam SH, Ji XY, Park JS. Investigation of Tacrolimus Loaded Nanostructured Lipid Carriers for Topical Drug Delivery. B KOREAN CHEM SOC 2011. [DOI: 10.5012/bkcs.2011.32.3.956] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Singh MK, Brewer JD. Current Approaches to Skin Cancer Management in Organ Transplant Recipients. ACTA ACUST UNITED AC 2011; 30:35-47. [DOI: 10.1016/j.sder.2011.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Evolution and management of de novo neoplasm post-liver transplantation: a 20-year experience from a single European centre. Hepatol Int 2010; 5:707-15. [PMID: 21484107 DOI: 10.1007/s12072-010-9231-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Accepted: 11/26/2010] [Indexed: 12/15/2022]
Abstract
PURPOSE Survival post-liver transplantation (LT) has improved; however, patients are considered at the, risk of malignancy due to prolonged immunosuppression. The long-term outcome of patients developing de novo neoplasm (DN) at our centre was evaluated. METHODS Between October 1988 and December 2007, 800 LT were performed in 742 patients. Patients were divided into two study periods according to the time of LT; first: October 1988-December 1995; second: January 1996-December 2007. RESULTS After a mean follow-up of 5 ± 4.6 years, 71 DN (9.5%) were detected in 742 patients. The cumulative risk of DN development increased with the time from LT although no differences at 3, 5, and 10 years were found when first and second periods were compared (3, 7, 16% vs. 2, 4, 11%, respectively; p = 0.4). DN incidence was higher in the first compared with the second period (10.7 vs. 7.8%; p < 0.04); no significant differences were observed in mortality rate (50 vs. 27%; p = 0.052). Actuarial patient survival post-DN at 1, 3, and 5 years: 67, 48, 45% versus 82, 71, 65%, in the first versus second period, respectively, p < 0.04. CONCLUSIONS DN incidence has decreased in recent years; however, as survival post-LT increases, so does the incidence of DN. Surveillance programmes are necessary to diagnose DN at early stages.
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Leung J, Dowling L, Obadan I, Davis J, Bonis PA, Kaplan MM, Casey D, Viveiros K. Risk of non-melanoma skin cancer in autoimmune hepatitis. Dig Dis Sci 2010; 55:3218-23. [PMID: 20165977 DOI: 10.1007/s10620-010-1145-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2009] [Accepted: 01/26/2010] [Indexed: 12/09/2022]
Abstract
BACKGROUND Most patients with autoimmune hepatitis (AIH) require long-term immunosuppressive therapy (IS). While it is well established that solid organ transplant recipients have a high risk of developing non-melanoma skin cancer (NMSC) as a result of immunosuppression, little is known about the risk of NMSC associated with IS in patients with AIH. OBJECTIVES The aim of this study is to determine the incidence and risk factors for NMSC in patients on IS for AIH. METHODS We reviewed the medical records of all patients with AIH seen at a tertiary care medical center between 1998 and 2008. We compared the incidence of NMSC to an age- and sex-matched control population and analyzed risk factors for NMSC. RESULTS A total of forty-five patients with AIH were identified. Twenty NMSC lesions were found in eight patients. Compared to the age and sex-matched general population, the risk of SCC and BCC were increased as quantified by elevated standardized incidence ratios (28.5 and 5.0, respectively). Patients who developed NMSC were on average 24 years older (78.4 vs. 54.2 years old, p < 0.0001) and had AIH diagnosed at a more advanced age (66.0 vs. 45.4 years old, p = 0.0003). CONCLUSION The risk of NMSC is significantly increased in patients with AIH on immunosuppression. Independent risk factors include current age and age at diagnosis of AIH.
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Affiliation(s)
- John Leung
- Division of Gastroenterology, Tufts Medical Center, 800 Washington Street, Boston, MA, USA.
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Chak E, Saab S. Risk factors and incidence of de novo malignancy in liver transplant recipients: a systematic review. Liver Int 2010; 30:1247-58. [PMID: 20602682 DOI: 10.1111/j.1478-3231.2010.02303.x] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Orthotopic liver transplant (OLT) is an established life saving procedure for both acute and chronic liver failure, but incidences and risk factors for development of these malignancies are yet to be established. To determine the incidences and risk factors associated with de novo malignancy after OLT. We performed a systematic review of relevant epidemiological studies available on MEDLINE, which provided information on the incidences and risk factors for the development malignancies in adult OLT recipients published from 1983 to 2009. All data was compiled from retrospective studies. Independent risk factors for the development of de novo malignancy in adult OLT recipients were identified to be statistically significant including immunosuppression, hepatitis C virus infection, smoking, alcoholic cirrhosis and sun exposure. OLT recipients with smoking and alcohol history are of particular risk for head and neck and lung cancers. Primary sclerosing cholangitis and inflammatory bowel disease were found to be independent risk factors for colon cancer. Adult OLT recipients are at increased risk for the development of post-transplant malignancies and obviates the need for surveillance protocols that are safe and cost-effective. OLT recipients should be advised on taking proper precautions in the sun, smoking cessation, and eliminating alcohol consumption. Given the emergence of alcoholic cirrhosis as a leading indication for liver transplantation, the early detection of lung and head and neck cancers is of particular importance.
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Affiliation(s)
- Eric Chak
- Department of Medicine, UCLA-Oliver View Medical Center, Pfleger Liver Institute, Sylmar, Los Angeles, CA 90095, USA
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Tjon ASW, Sint Nicolaas J, Kwekkeboom J, de Man RA, Kazemier G, Tilanus HW, Hansen BE, van der Laan LJW, Tha-In T, Metselaar HJ. Increased incidence of early de novo cancer in liver graft recipients treated with cyclosporine: an association with C2 monitoring and recipient age. Liver Transpl 2010; 16:837-46. [PMID: 20583092 DOI: 10.1002/lt.22064] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The goal of this study was to determine the risk factors for de novo cancer after liver transplantation (LTx). Retrospective analyses were performed in 385 LTx patients who underwent transplantation between 1986 and 2007. In total, 50 (13.0%) recipients developed de novo malignancy. The cumulative incidence of de novo cancer at 1, 5, 10, and 15 years after LTx was 2.9% +/- 0.9%, 10.5% +/- 1.8%, 19.4% +/- 3.0%, and 33.6% +/- 6.8%, respectively. The standardized incidence ratio of malignancy in LTx patients compared to the general population was 2.2 (95% confidence interval: 1.6-2.8). After excluding posttransplant lymphoproliferative disorder and skin cancer, patients with de novo cancer had a significantly lower survival rate compared to recipients who remained cancer-free. The identified univariate risk factors for de novo cancer were cyclosporine A (CsA) treatment, time period of LTx, and recipient age. In multivariate analysis, only CsA treatment emerged as an independent risk factor for de novo cancer, which was attributed to more aggressive cancer types. A surprising finding was that CsA treatment specifically enhanced cancer risk in patients who underwent transplantation after 2004, when C(2) monitoring (blood concentration at 2 hours postdose) was introduced. In addition, these patients showed a significantly lower acute rejection rate, which might reflect a more robust immunosuppressive status caused by the CsA-C(2) regimen. When age was considered, only patients < or =50 years had a higher cancer rate when treated with CsA compared to treatment with tacrolimus. Our data suggest that, compared to tacrolimus treatment, CsA treatment with C(2) monitoring or in younger patients of < or =50 years is associated with a higher early de novo cancer risk after LTx.
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Affiliation(s)
- Angela S W Tjon
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
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Kim NN, Boone SL, Ortiz S, Mallett K, Stapleton J, Turrisi R, Yoo S, West DP, Rademaker AW, Robinson JK. Squamous cell carcinoma in solid organ transplant recipients: influences on perception of risk and optimal time to provide education. ACTA ACUST UNITED AC 2009; 145:1196-7. [PMID: 19841415 DOI: 10.1001/archdermatol.2009.247] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
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Lanza LL, Wang L, Simon TA, Irish WD. Epidemiologic critique of literature on post-transplant neoplasms in solid organ transplantation. Clin Transplant 2009; 23:582-8. [DOI: 10.1111/j.1399-0012.2009.01061.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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42
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Proby CM, Wisgerhof HC, Casabonne D, Green AC, Harwood CA, Bouwes Bavinck JN. The epidemiology of transplant-associated keratinocyte cancers in different geographical regions. Cancer Treat Res 2009; 146:75-95. [PMID: 19415194 DOI: 10.1007/978-0-387-78574-5_7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Affiliation(s)
- Charlotte M Proby
- Division of Surgery and Oncology, College of Medicine, Dentistry and Nursing, University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, United Kingdom
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Affiliation(s)
- Carlos Ferrándiz
- Department of Dermatology, Hospital Universitario Germans Trias i Pujol, Badalona, Spain
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45
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Euvrard S, Claudy A. Post-transplant skin cancer: the influence of organ and pre-transplant disease. Cancer Treat Res 2009; 146:65-74. [PMID: 19415193 DOI: 10.1007/978-0-387-78574-5_6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Affiliation(s)
- Sylvie Euvrard
- Department of Dermatology, Hôpital Edouard Herriot, 69437 Lyon, Cedex 03, France
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46
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Kempen JH, Gangaputra S, Daniel E, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster CS, Jabs DA, Helzlsouer KJ. Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: a critical assessment of the evidence. Am J Ophthalmol 2008; 146:802-12.e1. [PMID: 18579112 PMCID: PMC2614443 DOI: 10.1016/j.ajo.2008.04.035] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Revised: 04/24/2008] [Accepted: 04/29/2008] [Indexed: 12/17/2022]
Abstract
PURPOSE To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting. DESIGN Focused evidence assessment. METHODS Relevant publications were identified by MEDLINE and EMBASE queries and reference list searches. RESULTS Extrapolation from transplant, rheumatology, skin disease, and inflammatory bowel disease cohorts to the ocular inflammation setting suggest that: 1) alkylating agents increase hematologic malignancy risk and cyclophosphamide increases bladder cancer risk, but less so with < or =18 months' duration of therapy and hydration, respectively; 2) calcineurin inhibitors and azathioprine probably do not increase total cancer risk to a detectable degree, except perhaps some other risk factors (uncommon in ocular inflammation patients) might interact with the former to raise risk; 3) tumor necrosis factor (TNF) inhibitors may accelerate diagnosis of cancer in the first six to 12 months, but probably do not increase long-term cancer risk; and 4) changes in risk with methotrexate, mycophenolate mofetil, and daclizumab appear negligible, although nontransplant data are limited for the latter agents. Immunosuppression in general may increase skin cancer risk in a sun exposure-dependent manner. CONCLUSION Use of alkylating agents for a limited duration seems justifiable for severe, vision-threatening disease, but otherwise cancer risk may be a relevant constraint on use of this approach. Antimetabolites, daclizumab, TNF inhibitors, and calcineurin inhibitors probably do not increase cancer risk to a degree that outweighs the expected benefits of therapy. Monitoring for skin cancer may be useful for highly sun-exposed patients. Data from ocular inflammation patients are needed to confirm the conclusions made in this analysis by extrapolation.
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Affiliation(s)
- John H Kempen
- Ocular Inflammation Service, Scheie Eye Institute, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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Boin I, Leonardi MI, Stucchi RB, Ataide EC, Almeida JR, Barros RH, Leonardi LS. De novo posttransplantation nonlymphoproliferative malignancies in liver transplant recipients. Transplant Proc 2008; 39:3284-6. [PMID: 18089372 DOI: 10.1016/j.transproceed.2007.07.084] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2006] [Revised: 03/19/2007] [Accepted: 07/28/2007] [Indexed: 11/19/2022]
Abstract
The risk of developing de novo malignancies after liver transplantation is around 1% per year. The incidence varies from 3% to 15%; it is greater than that in the general population. The potential causes for cancer after solid organ grafting are: chronic immunosuppression and human herpes viral infection. The objective of this paper was to review the medical literature about the subject to verify the incidence of de novo malignancies in our service. We performed retrospective analysis of the medical files of 325 successive patients undergoing orthotopic liver transplantation from September 1991 to December 2006. We analyzed the type of tumor, the risk factors, the treatment modality, and the patient survivals. Recurrences of hepatocellular carcinoma were excluded. There were 5 (1.54%) men of average age 50.2 years, and an 80% mortality rate. Their survival time was affected by the nature of the tumor and by the late manifestations of intestinal obstruction allowing adequate surgical treatment. Four of the patients displayed heavy alcohol and tobacco consumption before transplantation. Screening for premalignant lesions must be strongly encouraged to achieve better postoperative results.
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Affiliation(s)
- I Boin
- State University of Campinas, Unit of Liver Transplantation, Sao Paolo, Brazil.
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50
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Lira MG, Mazzola S, Tessari G, Malerba G, Ortombina M, Naldi L, Remuzzi G, Boschiero L, Forni A, Rugiu C, Piaserico S, Girolomoni G, Turco A. Association of functional gene variants in the regulatory regions of COX-2 gene (PTGS2) with nonmelanoma skin cancer after organ transplantation. Br J Dermatol 2007; 157:49-57. [PMID: 17578436 DOI: 10.1111/j.1365-2133.2007.07921.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Overexpression of cyclooxygenase-2 (COX-2), resulting in excessive prostaglandin production, has been observed in human epidermal keratinocytes after ultraviolet B injury, in squamous cell skin carcinoma (SCC), in actinic keratoses, and in the early stages of carcinogenesis in a wide variety of tissues. The dysregulation of COX-2 expression can in part be due to functional changes affecting regulatory elements in the promoter or 3' untranslated region (UTR) of the gene. Two common polymorphisms (-765G-->C, and -1195A-->G) in the promoter region of the COX-2 gene (now PTGS2), and one common polymorphism in the 3' UTR (8473T-->C) have been described, and reported as associated with various malignancies. OBJECTIVES To determine if common known polymorphisms in the regulatory region of the COX-2 gene (PTGS2) can be associated with nonmelanoma skin cancer (NMSC) predisposition after organ transplantation, to evaluate if cancer risks are associated with specific COX-2 gene (PTGS2) haplotypes containing these polymorphisms, and to identify possible new genetic polymorphisms in the proximal 5' or 3' regulatory regions of the gene associated with disease. METHODS The frequency of the three polymorphisms was determined in 240 Northern Italian transplant recipient patients (107 cases and 133 controls) with polymerase chain reaction-restriction fragment length polymorphism analysis. The proximal 5' and 3' regulatory regions of the gene were screened by heteroduplex analysis. RESULTS Stratification by age at transplant and type of tumours [SCC or basal cell carcinoma (BCC)] demonstrated that allele -765C represented a protective factor in BCC cases undergoing transplantation before 50 years of age (CC + CG vs. GG, Fisher exact test P = 0.003). One rare polymorphism, -62C-->G, was detected in the 5' flanking region. The allele frequency of -62G was 0.019, and no difference in genotype between cases and controls was observed. No other variants were found, suggesting that sequence variations in these regions are not likely to contribute to NMSC risk in this population. Haplotype analysis showed that the haplotype containing all major alleles represents a protective factor in patients with SCC undergoing transplantation after 50 years of age [P = 0.009; OR = 0.37 (0.18-0.79)] and that variant -1195A-->G may represent a risk factor in this subgroup of patients [P = 0.01; OR = 4.77 (1.47-16.41)]. Haplotype analysis in patients with BCC revealed that variant -765C might be a protective factor in patients undergoing transplantation before 50 years of age. Variant 8473T-->C, located in the 3' UTR region of the gene, showed no association with NMSC risk after transplantation. CONCLUSIONS COX-2 common variants -765G-->C and -1195A-->G appear to be associated with risk of NMSC, although in different ways in the SCC and BCC subgroups, indicating that environmental and genetic risk factors may play different roles in the outcome leading to these two phenotypes.
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Affiliation(s)
- M Gomez Lira
- Department of Mother and Child, Section of Biology and Genetics, University of Verona, Verona, Italy.
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