Hepatitis C Virus Infection, but Not Hepatic Iron Overload Is the Dominant Risk Factor for the Manifestation of Hepatocellular Carcinoma Among Greek Thalassemic Patients
Authors: Kourakli Alexandra , Diamantidis Michael D. , Skafidas Myrto-Evangelia , Delicou Sophia , Pantelidou Despoina , Fragodimitri Christina , Vlachaki Efthymia , Lafioniatis Stylianos , Petropoulou Fotini , Eftychiadis Eftychios , Kapsali Eleni , Kalpaka Anastasia , Zissis Christos , Koutsouka Frideriki , Vasileiadi Artemis , Goula Anastasia , Giasari Panagiota , Katsatou Marianna , Lafiatis Ioannis , Klironomos Evangelos , Kaiafas Panagiotis , Kyriacopoulou Dimitra , Lazaris Vasileios , Maragkos Konstantinos , Fotiou Paraskevi , Chalkia Panagiota , Schiza Vasiliki , Kattamis Antonis , Symeonidis Argiris 
Published: October 2019

Abstract

Background: Effective iron chelation and other supportive treatment have a substantial impact on survival prolongation of thalassemic patients, who may reach late adulthood, and therefore, may manifest various neoplastic disorders. However, no systemic analysis of the prevalence of neoplastic disorders in this patient population has been performed.
Aims: We systematically analyzed all cases of malignant neoplastic disorders, occurred in a large cohort of Greek thalassemic patients and investigated for possible underlying predisposing factors.
Patients and methods: Data of 3652 patients with hemoglobinopathies (Group I: beta-thalassemia homozygous N=1981, Group II: thalassemia Intermedia N=746, Group III: sickle-cell disease +/- beta-Thalassemia n=751, Group IV: hemoglobinopathy-H N=174) were retrieved, followed up at 24 specific Hospital Units, between 1985 and 2018. Totally, 165 cases of a malignant disorder were identified (overall prevalence 4.52%). The significance of the following predisposing factors was investigated: familial history of neoplasia, occupational exposure to known mutagens, previous autoimmunity, previous splenectomy, tobacco smoking, alcohol use, HBV, HCV or HIV infection, iron overload, hydroxyurea treatment, previous irradiation for extramedullary hematopoietic tumors and systemic use of androgens/estrogens.
Results: Patients were 84 males and 81 females with a median age at diagnosis of the neoplastic disorder of 45 years (range 9-73 years). Higher prevalence of neoplasia was noted among patients of Groups I and II (4.99% vs 3.03% among patients of Groups III and IV, p<0.05). Table 1 shows histological diagnosis of the 165 neoplastic disorders, of which 139 (84.2%) were solid tumors and 26 (15.8%) hematological malignancies. The dominant malignancy was hepatocellular carcinoma, diagnosed in 63 patients, followed by thyroid cancer (17 cases), non-Hodgkin's lymphoma (13 cases), and renal cell carcinoma (10 cases). There was a strong positive association between hepatitis C virus infection and hepatocellular carcinoma, and a negative one between HCV infection and thyroid and renal cancer. Active HCV infection was found in 81 patients (49.1%) compared to an estimated prevalence of about 25% among the whole thalassemic patient population. Hepatocellular carcinoma was more frequently diagnosed in men (M/F ratio 1.86) of the fourth and fifth decade (median age 45 years) with thalassemia homozygous or intermedia (89% of the cases), with long-standing, untreated HCV infection (76%), irrespective of the burden of hepatic iron load, estimated with MRI T2*. Indeed, no difference in the occurrence of hepatocellular carcinoma, as well as of any other type of cancer was found, in relation to Liver Iron Concentration (LIC). Moreover, no preponderance of any HCV genotype was identified, but interestingly, all 1b HCV genotype-associated neoplasms were hepatocellular carcinoma (7 cases). Finally, no association between any of the remaining potential risk factors with the manifestation of any specific neoplastic disorder was observed.
Discussion: In our large thalassemic patient cohort, representative of the whole country of Greece, we have identified increased prevalence of four types of cancer. Besides hepatocellular carcinoma, we have unexpectedly encountered high prevalence of thyroid and renal cancer, as well as of all types of lymphomas. These primary findings deserve further investigation, since, excluding hepatocellular carcinoma, no prominent or speculative causality can be currently attributed for the remaining malignancies.

Disclosures
Kattamis: Vifor Pharma: Consultancy; ApoPharma: Honoraria; CELGENE: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.