Hepatitis C Virus Infection, but Not Hepatic Iron Overload Is the Dominant Risk Factor for the Manifestation of Hepatocellular Carcinoma Among Greek Thalassemic Patients

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.

Concise Review on the Frequency, Major Risk Factors and Surveillance of Hepatocellular Carcinoma (Hcc) in Β-Thalassemias: Past, Present and Future Perspectives

“…Similar results were also reported in 63 Greek thalassemia patients with HCC (median age: 45 years). 11 Comparing our data with the results of a previous publication, 22 it emerges that our subgroup of NTDT patients with HCC were older (56.8 vs.47 years). However, our series consisted of 6 NTDT patients vs.…”

“…However, several aspects remain to be explored further. HCC is more frequently diagnosed (at present) in men with TDT in their fourth -fifth decade and older in NTDT 11,22 with long-standing, untreated chronic hepatitis C (76%), irrespective of the content of hepatic iron load, estimated with MRI T2*. 11 One possible explanation is that patients with NTDT may have a milder process of iron overloading at late age and a lower incidence of chronic viral liver infections, mainly HCV.…”

“…Italy, Spain, and Greece have intermediate incidence rates of 10-20 per 100,000 individuals, while North and South America have a relatively low incidence (< 5 per 100,000 individuals). 10 Kourakli et al 11 analyzed all cases of malignant neoplastic disorders, occurring in 3,652 Greek thalassemic patients, diagnosed between 1985 and 2018. A total of 165 cases of malignant disorders were identified, (84 males and 81 females) with a median age at diagnosis of 45 years (range 9-73 years).…”

Hepatocellular carcinoma in adult thalassemia patients: an expert opinion based on current evidence

“…According to the 2019 AIOM report, 33.000 patients had HCC diagnosis in Italy between 2013 and 2018 [12]. Among beta-thalassemia patients, HCC prevalence ranged from 2.3% in Greece to 1% in Italy [1,13]. Another study reported that HCC prevalence in male patients with beta-thalassemia is 6 times higher than in non beta-thalassemia subjects [14].…”

“…HCC incidence, standardized by age in non beta-thalassemia patients can be estimated at 10.9/100.000 P/Y for male and 3.1/100.000 P/Y for female [ 13 ]. Incidence of 1.02/100.000 P/Y was estimated in the Italian Thalassemia Registry including 5855 patients [ 1 ].…”