Association between Hepatitis C Virus and Extrahepatic Tumors

Abstract

Hepatitis C virus (HCV), an oncogenic virus, is a well-known risk factor for hepatocellular carcinoma. Some studies have shown an increased risk of extrahepatic tumors in HCV patients, but the risk of different types of extrahepatic tumors remains controversial. Early prevention of extrahepatic tumors in HCV patients should be further explored. Therefore, this chapter aims to explore the association between HCV infection and extrahepatic tumors.

1. Introduction

Viral infections are closely related to cancers. The International Agency for Research on Cancer (IARC) estimates that about one in five cancer cases worldwide are caused by infections, most of which are caused by viruses, including hepatitis C virus (HCV) [1]. HCV is an RNA hepatotropic and lymphotropic virus that infects about 180 million people worldwide [2]. Compared with chronic hepatitis B virus (HBV), chronic HCV infection typically leads to liver fibrosis and cirrhosis, which leads to a higher risk of liver cancer and mortality [3, 4]. In addition, it has been shown that HCV may infect organs and tissues other than the liver, such as peripheral blood cells (i.e., neutrophils, T cells, and B cells), kidney, skin, oral mucosa, pancreas, heart, gallbladder, intestinal tract, and adrenal gland, where HCV can be detected as well as its associated antigens, genome and/or replicative sequences [5]. In recent years, epidemiological studies have found that HCV infection is closely related to the occurrence of extrahepatic tumors [6]. Therefore, this chapter summarizes the association between HCV infection and the risk of several extrahepatic tumors.

2. HCV infection and lymphoma

Lymphoma is a group of malignant neoplasms of lymphocytes that can be classified into non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) [7]. Lymphoma is associated with multiple factors, such as genetics, environment, and infection [8].

NHL is a hematologic malignancy with the highest prevalence worldwide, and its etiology is still unclear [9]. The relationship between HCV infection and NHL was first explored in 1994 by Ferri et al. [10]. The odds of HCV infection were higher in patients with NHL (34%) than those with HL (3%) and the healthy population (1.3%). A large number of studies have reported the relationship between HCV infection and NHL. The conclusions are mostly consistent in that patients with HCV are at a higher risk of developing NHL [11, 12]. For example, Zhu et al. conducted a meta-analysis, including 18 studies, during a period from 1999 to 2017 to explore the relationship between NHL and HCV [13]. They found that the risk of NHL was 69% higher among individuals with HCV infection compared to uninfected individuals. However, this study was mainly based on the European and American populations and ignored the impact of other factors, such as diet and living habits (e.g., high-fat diet, etc.), on the increased risk of NHL. In addition, Dal Maso et al. completed a meta-analysis of HCV infection and NHL based on 15 case–control studies and 3 prospective studies [14]. The etiologic fraction of NHL attributable to HCV varies greatly by country and may be up to 10% in areas where the HCV prevalence is high. By comparison, the studies included in this meta-analysis had several advantages. First, the studies included populations from the United States, Egypt, Italy, Japan, and Australia, and analyzed the differences among ethnicities. Second, some risk factors were adjusted, such as gender and age. Third, the diagnostic criteria of HCV infection were unified. In Southern and Eastern Europe, Japan, and the Southern United States, NHL and HCV have been reported to be highly correlated. There is no literature regarding the association of HCV infection with NHL in Central and Northern Europe, Canada, the Northern United States, and some Asian countries [15].

There are some potential mechanisms of HCV infection, leading to NHL. First, antiviral treatment appears to be effective in eliminating the clonal proliferation of B cells in patients with chronic HCV infection and may prevent the subsequent development of lymphoma [12]. Second, active replication of HCV in B cells may impair the cell cycle and mediate lymphomagenesis through the expression of HCV-related proteins, such as HCV core protein or nonstructural protein 3 (NS3). HCV enters B cells through the CD81 receptor, and the expression of viral core protein and NS3 in B cells leads to oxidative stress, which may eventually cause mutations and defective DNA repair [16]. Third, the E2 protein of HCV binds to the CD81 receptor and B-cell receptor (BCR) on B cells, and the complex formed after binding lowers the activation threshold of B cells, thereby promoting autoantibody production, which in turn leads to HCV-associated cryoglobulinemia. It is one of the extrahepatic manifestations caused by HCV infection, which can eventually progress to NHL [2, 17].

As for the association between HCV infection and HL, Franceschi et al. conducted a large prospective cohort study in 2011 and showed that the proportion of HCV infection in patients with HL was not significantly different from the general population [18]. Similarly, a meta-analysis conducted by Mullen et al. did not find any significant association between HCV infection and HL [19]. Therefore, further studies are needed to explore the association between HCV infection and HL.

3. HCV infection and breast cancer

Breast cancer is the leading cause of cancer incidence worldwide, representing 11.7% of all cancer cases, and is the fifth leading cause of cancer mortality worldwide. It is estimated that one in eight women in the world will develop breast cancer, but the exact cause of breast cancer is still unknown [20, 21].

The studies conducted by Larrey et al. [22], Omland et al. [23], and Swart et al. [24] did not show any association between HCV infection and breast cancer. However, Su et al. conducted a case–control study in 2011, which included a total of 1958 patients with newly diagnosed breast cancer during the period 2000–2008 [25], and showed no significant difference in the prevalence of HCV infection between breast cancer patients and control subjects (p = 0.48). However, patients aged <50 years with HCV infection had a 2-fold greater risk of developing breast cancer, suggesting that chronic HCV infection may be associated with early-onset breast cancer. However, given the retrospective nature of this study, there may be some false-positive and false-negative linkages. Thus, prospective studies are still needed to confirm their relationship.

The mechanism of the association between HCV infection and breast cancer is unclear. It is currently believed that HCV infection damages liver tissue and thus elevates estrogen in the blood, and the liver is the only organ of estrogen inactivation and metabolism, and elevated estrogen is strongly associated with the development of breast cancer [22, 26].

4. HCV infection and cancers of the digestive system

4.1 HCV infection and pancreatic cancer

Pancreatic cancer (PAC) is one of the most aggressive and lethal cancers in humans, with a high mortality rate and an overall five-year survival rate of <5%, resulting in approximately 250,000 deaths worldwide each year. The probability of PAC increases with aging and nearly 80% of these malignancies develop in subjects aged between 60 and 80 years old. In addition, smoking and family history are also strongly associated with an increased risk of PAC [23, 24, 27].

In a study conducted by Darvishian et al., based on the British Columbia Hepatitis Testers Cohort (BC-HTC), the risk of PAC was found to be significantly higher among HCV-infected individuals, irrespective of sex [28]. However, the information on smoking status was not collected in this study, so there was some potential bias. Similarly, Arafa et al. completed a meta-analysis of the association between HCV infection and PAC in 2020 [29]. A total of 16 studies were included, including 8 case–control studies and 8 cohort studies. Eventually, 7 studies (5 cohort and 2 case–control) showed a statistically significant association between HCV infection and PAC, while 9 studies (3 cohort and 6 case–control) did not. A meta-analysis of the 16 studies revealed that HCV-positive people had 51% higher risk of developing PAC than HCV negative people. However, this association was weakened among the studies that adjusted for potential risk factors for PAC, such as diabetes, chronic pancreatitis, and alcoholism. Therefore, prospective cohort studies with more information about potential confounders are needed to confirm the conclusion.

The mechanisms of HCV infection and PAC may be as follows. Fiorino et al. proposed a comprehensive and qualitative hypothetical model, namely “tensegrity model hypothesis” [30]. HCV-mediated perturbation of this interplay causes a substantial change of critical intracellular biochemical activities as well as that of genome expression that ultimately leads to the development of cancer. Specifically, HCV proteins, including HCV NS3, NS4A, NS5A, and NS5B, can interact with cytoplasmic enzymes and components of the cytoskeleton, leading to the disruption of cell structure, altered enzyme activity, and ultimately interference with several signaling pathways for important cell functions, such as proliferation, differentiation, energy production, and apoptosis, and qualitatively and quantitatively disrupt several intracellular biochemical activities associated with transcription, translation, and transduction of nuclear genes, leading to PAC [29, 30].

4.2 HCV infection and gastric cancer

Gastric cancer is the fifth most common cancer worldwide. Although the incidence of gastric cancer has decreased in recent years, it remains a major public health problem. Risk factors for gastric cancer include Helicobacter pylori infection, age, high salt intake, and low dietary intake of fruits and vegetables [31, 32].

Few studies reported the association between HCV infection and gastric cancer. Chen et al. found that HCV infection was a risk factor for gastric cancer development [33]. Since then, Yang et al. published a meta-analysis on the association between chronic hepatitis virus infection and gastric cancer in 2021, including 13 studies, five of which were on the association between HCV infection and gastric cancer [34]. The risk of gastric cancer in HCV-infected patients was increased by 88% compared with those without HCV infection (P = 0.001).

The mechanisms of HCV infection promoting gastric cancer can be elaborated from the following aspects. First, it has been shown that HCV acts as an indirect carcinogen of gastric cancer by promoting and maintaining a chronic inflammatory state at the site of infection, resulting in a gradual rearrangement of gastric tissue structure [5, 35]. Second, HCV inhibits antigen processing and presentation and induces a gastric mucosal oxidative stress response, which has been shown to be associated with the development of cancer. Therefore, it is reasonable to suspect that HCV infection may induce the development of gastric cancer [34, 36, 37]. Third, cirrhosis may also play an important role in the development of gastric cancer. The idea that HCV infection is a risk factor for cirrhosis has been well established, and studies have shown that cirrhosis is closely related to gastric cancer. Thus, patients with HCV infection can develop cirrhosis first, which can lead to the development of gastric cancer [38, 39].

4.3 HCV infection and cholangiocarcinoma

Cholangiocarcinoma (CCA) is a malignant neoplasm originating from biliary epithelial cells. CCA can be divided into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC), and epidemiological surveys show a gradual increase in their incidence and prevalence. Many risk factors, including primary sclerosing cholangitis, liver fluke infection, and liver stones, increase the risk of CCA [40, 41].

The earliest study on the relationship between HCV infection and CCA was conducted in Japan [42]. HCV-associated cirrhosis was a major risk factor for primary hepatobiliary cell carcinoma in Japan. Li et al. [40] and Tan et al. [43] performed meta-analyses of the relationship between HCV infection and CCA, and both of them showed that HCV infection significantly increased the risk of CCA. But a study by Zhou et al. did not find a significant correlation between them [44]. However, differences in tumor heterogeneity, misclassification, selection bias, incidence, and prevalence patterns in each country can cause bias in the meta-analysis results. Therefore, future prospective studies are needed to confirm these results.

HCV infects bile duct cells, and therefore the induction of transformation by viral oncoprotein activity may be a direct mechanism for the development and progression of CCA. Therefore, bile duct cells can express receptors and cytokines related to HCV infection susceptibility and HCV replication permissibility, leading to bile duct damage and loss, and ultimately bile duct carcinoma [45, 46, 47]. In addition, the modulation of epithelial-mesenchymal transition (EMT) and hedgehog (Hh) pathway by HCV and/or viral proteins and its resultant chronic biliary inflammation could be the indirect role of this viral infection on the process associated with fibrosis and CCA [46].

5. HCV infection and thyroid cancer

Thyroid cancer is the most common cancer of the endocrine system [48]. The incidence of thyroid cancer has steadily increased by approximately 4% per year. Important risk factors for thyroid cancer include a history of radiation exposure and a family history of thyroid cancer [49].

There are also some debates about the association between HCV and thyroid cancer. Some studies supported their association [50], while others did not [51]. To further clarify the correlation between HCV infection and thyroid cancer, Wang et al. conducted a meta-analysis in 2021, which included 6 articles, and showed that HCV infection was significantly associated with an increased risk of thyroid cancer [52]. However, only a few papers were included, and the lack of other factors, such as age and gender, may affect the incidence of thyroid cancer, thus interfering with the accuracy of statistical results.

The mechanism by which HCV promotes thyroid cancer remains unclear. However, some studies suggest that HCV may affect the immune system and the self-recognition of thyroid cells, in which HCV may directly damage thyroid tissue or mimic the structure of certain components of the thyroid gland, thereby triggering autoimmune disease. Therefore, the risk of thyroid disease may be increased after HCV infection [52, 53].

6. HCV infection and kidney cancer

Kidney cancer is the most common type of urogenital tract cancer. It has a mortality rate of 30–40% [54]. Risk factors for kidney cancer have not been identified, but high BMI, tobacco use, and hypertension influence the development of kidney cancer [55].

In recent years, there have been studies on the association between HCV infection and kidney cancer. Gonzalez et al. confirmed that HCV infection is an important risk factor for kidney cancer [56]. Wu et al. conducted a meta-analysis on the association between HCV infection and kidney cancer in 2021 [57]. The study population included 391,071 HCV patients and 38,333,839 non-HCV controls, from 9 different countries. Pooled results showed that HCV-infected patients had a significantly higher risk of developing kidney cancer. However, some well-known risk factors for kidney cancer, such as smoking, obesity, and high blood pressure, are not matched or adjusted. By contrast, in a Swedish study, no significant correlation was found between them [58]. Further clarification should be needed.

Although the mechanism by which HCV infection may lead to kidney cancer is not fully understood, HCV core protein has been found in the glomerular structures and tubular epithelial cells of the kidney in patients with HCV infection [59]. In addition, several other hypotheses have been proposed. First, it has been found that HCV infection may be related to the NY-REN protein, an alterable ubiquitin-related protein that impairs the autophagic response through ubiquitin protein ligase-related self-regulatory mechanisms, which in turn promotes tumorigenesis [60, 61]. Second, cytotoxic T-cell-dependent apoptosis plays a pilot role in the host immunity and normal tissue. HCV can disturb this process and lead to renal oncogenesis [61, 62]. Third, serine protease inhibitor Kazal (SPIK) is a cellular protein that inhibits serine proteaserelated apoptosis in kidney cancer tissue samples as an additional mechanism for HCV induced kidney cancer [61].

7. HCV infection and other extrahepatic tumors

Very few studies have also explored the association between HCV infection and other extrahepatic tumors, such as oral cancer, skin cancer, and colorectal cancer, but their finding has not been discussed in this chapter due to the paucity of relevant data or a substantial controversy of the current conclusions.

8. Conclusion

It has been well-recognized that HCV infection is a risk factor for hepatocellular carcinoma. Due to the risk of this virus on the development of cancer, many studies have indicated an increased risk of extrahepatic tumors in HCV-infected patients. However, it should be noted that the occurrence of cancer is attributed to a combination of multiple factors, such as family genetics, race, and lifestyle. Thus, the relationship between them is still challenging. Regardless, screening for various cancers is still necessary for patients with HCV infection, except for routine prevention of cirrhosis and liver cancer.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

None.