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Development of Hepatitis C Virus-Related Cancers

A Special Issue of Cancers (ISSN 2072-6694) belonging to the section "Clinical Research in Cancer".

Deadline for manuscript submissions: 20 September 2026 | Viewed by 1177

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Guest Editor
Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy
Interests: viral hepatitis; hepatic and extrahepatic manifestations of hepatitis viruses; mixed cryoglobulinemia; lymphoproliferative disorders; mechanisms of viral oncogenesis

Special Issue Information

Dear Colleagues,

Chronic infection with hepatitis C virus (HCV) is a well-established risk factor for hepatocellular carcinoma. However, a growing body of evidence has demonstrated that HCV is also associated with a wide range of non-hepatic malignancies. Epidemiological and clinical studies have linked HCV infection with lymphoproliferative disorders, such as non-Hodgkin lymphoma, as well as certain solid tumors, including those of the pancreas, kidney, and oral cavity.

The mechanisms underlying these associations are multifactorial and may include chronic immune activation, sustained inflammation, and direct oncogenic effects of viral proteins. Understanding the broader oncogenic potential of HCV is essential for developing comprehensive screening, surveillance, and management strategies—especially in the era of direct-acting antivirals (DAAs), where long-term outcomes post SVR remain a key area of investigation.

This Special Issue aims to provide an updated overview of the oncogenic risks associated with HCV, taking into account both hepatic and extrahepatic sites, with a focus on the available pathogenetic data, the clinical relevance of these associations, and their implications for patient care.

Prof. Dr. Anna linda Zignego
Guest Editor

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Keywords

  • hepatitis C virus (HCV)
  • hepatocellular carcinoma (HCC)
  • extrahepatic malignancies
  • lymphoproliferative disorders
  • viral oncogenesis
  • chronic inflammation and cancer
  • direct-acting antivirals (DAAs)
  • cancer surveillance in HCV patients

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Published Papers (2 papers)

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Review

24 pages, 1070 KB  
Review
From Antigenic Drive to Clonal Autonomy: An Update on Molecular Mechanisms of HCV-Related B-Cell Lymphomagenesis
by Silvia Marri, Maria Concetta Scavuzzo, Gabriella Cavallini and Laura Gragnani
Cancers 2026, 18(17), 2761; https://doi.org/10.3390/cancers18172761 - 25 Aug 2026
Viewed by 286
Abstract
Chronic hepatitis C virus (HCV) infection is an established risk factor for B-cell lymphoproliferative disorders and represents a paradigmatic model of infection-driven lymphomagenesis. Although direct-acting antivirals have markedly reduced the burden of HCV-related disease, HCV-associated lymphomas continue to occur. Moreover, HCV screening remains [...] Read more.
Chronic hepatitis C virus (HCV) infection is an established risk factor for B-cell lymphoproliferative disorders and represents a paradigmatic model of infection-driven lymphomagenesis. Although direct-acting antivirals have markedly reduced the burden of HCV-related disease, HCV-associated lymphomas continue to occur. Moreover, HCV screening remains incomplete in some geographical areas and healthcare settings, leaving a substantial proportion of infected individuals unaware of their status. This narrative review integrates current evidence on the mechanisms linking chronic HCV infection to mixed cryoglobulinemia and overt B-cell non-Hodgkin lymphoma. HCV lymphotropism and persistent antigenic stimulation could initially promote the selection and expansion of autoreactive B-cell clones, while mixed cryoglobulinemia represents the most informative pre-lymphomatous risk condition. Cytokine-mediated survival signals, particularly those involving B-cell activating factor, reinforce clonal persistence and cooperate with host genetic susceptibility, impaired apoptotic control, and activation-induced cytidine deaminase-mediated genomic instability. The progressive acquisition of somatic driver mutations, copy-number alterations, and epigenetic and transcriptomic changes may enable selected clones to escape functional anergy and become increasingly independent of the original viral stimulus that, in turn, represents an initial trigger of the lymphoproliferative process. Recurrent abnormalities converge on NF-κB, NOTCH, chromatin-regulatory, apoptotic, and cell-cycle pathways, although HCV-associated lymphomas remain molecularly heterogeneous. Emerging microRNA profiles further contribute to the molecular characterization of the transition from chronic infection and cryoglobulinemia to lymphoma. Despite the availability of highly effective antiviral therapies, HCV-associated lymphomagenesis remains clinically relevant and continues to provide an especially informative model for understanding how chronic viral infection can drive human cancer development. Full article
(This article belongs to the Special Issue Development of Hepatitis C Virus-Related Cancers)
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16 pages, 310 KB  
Review
The Role of Direct-Acting Antivirals (DAAs) in Hepatitis C Virus-Associated Lymphoproliferative Disorders
by Cesare Mazzaro, Riccardo Bomben, Laura Gragnani, Marcella Visentini, Paolo Agostinis, Silvia Marri, Anna Linda Zignego and Valter Gattei
Cancers 2026, 18(15), 2501; https://doi.org/10.3390/cancers18152501 - 4 Aug 2026
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Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15–30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated [...] Read more.
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15–30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated with a broad spectrum of extrahepatic manifestations, particularly mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Persistent viral infection induces chronic antigenic stimulation of B lymphocytes, a key pathogenic mechanism underlying the progression from MC to overt B-NHL. These observations have important therapeutic implications and support the use of antiviral therapy as a cornerstone of treatment. The efficacy of direct-acting antivirals (DAAs) has been well established in patients with HCV-related MC and cryoglobulinemic vasculitis. Several studies have shown that DAAs achieve sustained virologic response rates exceeding 90%, often approaching 100% in contemporary cohorts. Viral eradication is frequently associated with clinical and immunological improvement, as well as regression of cryoglobulinemia. Encouraging outcomes have also been reported in patients with HCV-associated indolent B-NHL, particularly marginal zone lymphoma, although confirmation in larger studies with longer follow-up is needed. In patients with HCV-positive aggressive lymphomas, DAAs have been safely administered in combination with immunochemotherapy, yielding promising results. This review summarizes the current evidence on HCV-associated MC and B-NHL and discusses the impact of DAA therapy on the clinical course and management of these disorders. Full article
(This article belongs to the Special Issue Development of Hepatitis C Virus-Related Cancers)
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