Human papillomavirus (HPV), a double-stranded DNA virus belonging to the Papillomaviridae family, is known for its tropism for epithelial tissues. More than 200 HPV genotypes have been identified, categorized into high-risk (oncogenic) and low-risk (non-oncogenic) types. High-risk HPV types, such as HPV-16 and HPV-18, are implicated in the development of several malignancies, including cervical, anogenital, and oropharyngeal cancers. The HPV’s oncogenic potential arises from its ability to integrate into the host genome, leading to the disruption of critical cellular pathways involved in proliferation, apoptosis, and immune evasion (
1).
The HPV genome encodes several early proteins, notably E6 and E7, which play pivotal roles in carcinogenesis. The E6 facilitates the degradation of the tumor suppressor protein p53, impairing DNA repair mechanisms and promoting genomic instability. Meanwhile, E7 binds to the retinoblastoma protein (pRb), releasing E2F transcription factors that drive unchecked cell cycle progression. Collectively, these interactions disrupt cellular homeostasis and promote malignant transformation (
2).
While the association between high-risk HPV and cervical cancer is well-established, growing evidence suggests that HPV’s oncogenic mechanisms may extend to non-traditional anatomical sites, including the thyroid gland. Several studies have reported the presence of HPV DNA in thyroid tumor tissues, particularly in papillary thyroid carcinoma (PTC), raising significant questions about HPV’s role in thyroid carcinogenesis (
3). The detection of high-risk HPV in thyroid cancer specimens has spurred interest in understanding its potential causal relationship and the molecular mechanisms by which HPV may contribute to thyroid tumorigenesis.
In addition to the role of HPV in genomic instability, persistent HPV infection is associated with chronic inflammation, creating a microenvironment conducive to oncogenesis. Chronic inflammation can lead to oxidative stress, DNA damage, and the secretion of pro-inflammatory cytokines, all of which facilitate tumor development. In the thyroid, conditions such as Hashimoto’s thyroiditis, which involve chronic inflammation, have been linked to an increased risk of malignancy. This suggests that HPV-induced inflammation may similarly predispose the thyroid gland to cancer development. Moreover, HPV’s ability to evade the host immune system is a critical factor in its carcinogenic potential (
4,
5). By downregulating major histocompatibility complex (MHC) class I expression and interfering with antigen presentation, HPV escapes immune surveillance, allowing infected cells to proliferate without restraint. In the thyroid gland, immune evasion could contribute to the persistence of infected cells, increasing the likelihood of malignant transformation (
6).
The integration of HPV DNA into the host genome is a hallmark of its oncogenic activity. In thyroid cells, this integration may disrupt genetic regulatory elements, leading to the activation of oncogenes or inactivation of tumor suppressor genes. Integrated HPV DNA has been identified in thyroid cancer samples, particularly in PTCs, suggesting that HPV may directly contribute to malignancy (
7,
8). Furthermore, the unique endocrine function of the thyroid gland may interact with HPV-mediated oncogenic pathways, as dysregulation of thyroid hormones has been shown to influence cell proliferation and apoptosis — processes also affected by HPV proteins. This interplay between thyroid hormone regulation and HPV-driven oncogenesis may amplify the carcinogenic effects of the virus in thyroid tissue, although this hypothesis remains to be fully explored (
9).
Numerous studies have attempted to establish a correlation between HPV infection and thyroid cancer. Molecular analyses have detected high-risk HPV DNA in a subset of thyroid cancer tissues, with some studies reporting prevalence rates as high as 30%. Notably, the presence of HPV has been more frequently observed in PTC than in other thyroid cancer subtypes, suggesting a potential subtype-specific association. However, these findings are not universally consistent, as some studies have failed to detect HPV in thyroid tumors. This inconsistency highlights the need for standardized methodologies and larger cohort studies to draw definitive conclusions about the relationship between HPV and thyroid cancer (
10).
One of the primary challenges in studying the role of HPV in thyroid cancer is the variability in detection methods. Techniques such as polymerase chain reaction (PCR) and in situ hybridization (ISH) have been employed to identify HPV DNA in thyroid tissues, but differences in sensitivity and specificity can lead to inconsistent results. Furthermore, distinguishing between causal infection and incidental presence remains a significant hurdle. The prevalence of HPV-associated thyroid cancer varies geographically, with higher detection rates reported in some regions. This variation may reflect differences in HPV prevalence, environmental factors, or genetic predispositions among populations (
11,
12). While the presence of HPV in thyroid cancer tissues is intriguing, establishing a causal relationship requires robust experimental and longitudinal data. The coexistence of HPV DNA with thyroid malignancies does not definitively establish causality, as other cofactors, such as iodine deficiency, radiation exposure, and genetic mutations, must also be considered. Therefore, understanding the role of HPV in thyroid cancer requires not only molecular studies but also epidemiological and clinical data to establish a clearer connection.
If a causal link between HPV and thyroid cancer is established, it could have significant clinical implications. The HPV vaccination programs, already known to reduce the burden of cervical and oropharyngeal cancers, could potentially reduce the incidence of HPV-associated thyroid cancer. Additionally, identifying HPV-positive thyroid cancers could have prognostic and therapeutic implications, as these tumors may respond differently to conventional treatments.
To address the existing knowledge gaps, future research should focus on the following areas: Conducting large-scale, multi-center studies to determine the prevalence of HPV in thyroid cancer across diverse populations; elucidating the molecular mechanisms by which HPV contributes to thyroid tumorigenesis using in vitro and in vivo models; investigating potential interactions between HPV and other risk factors, such as genetic mutations and environmental exposures; and assessing the impact of HPV vaccination on thyroid cancer incidence in vaccinated cohorts. Bridging these knowledge gaps will require interdisciplinary collaboration, integrating virology, endocrinology, and oncology perspectives (
13,
14).
Thyroid cancer is one of the most rapidly growing malignancies worldwide, with rising incidence rates and significant morbidity across diverse populations. Epidemiological data consistently show an increasing prevalence, with differentiated thyroid cancer (DTC), including papillary and follicular subtypes, dominating clinical diagnoses. Despite relatively high survival rates, the escalating global burden of thyroid cancer necessitates urgent exploration of innovative diagnostic, therapeutic, and preventive strategies. Contributing to this trend is not only improved detection through advanced imaging technologies but also the potential role of environmental, genetic, and viral factors, including HPV, in thyroid cancer pathogenesis (
15).
Among these factors, viral infections, particularly HPV, have garnered increasing attention as potential contributors to thyroid tumorigenesis. Recent evidence has linked HPV and herpes virus infections to the progression of thyroid cancer, highlighting the need for further research to clarify their clinical and molecular roles. This focus is critical given the multifactorial nature of thyroid cancer, which integrates hormonal imbalances, environmental exposures, and immune dysregulation. The thyroid gland’s role in endocrine regulation, influencing metabolic processes, growth, thermogenesis, and neurophysiological stability, underscores the systemic impact of thyroid malignancy and the importance of investigating HPV’s potential involvement in this process.
In addition to its direct impact on thyroid cancer, viral infections like HPV may also contribute to the development of sleep-related disorders in thyroid cancer patients, particularly obstructive sleep apnea (OSA). The OSA, characterized by repeated episodes of partial or complete airway obstruction during sleep, has been strongly associated with thyroid disorders, exacerbating the challenges faced by thyroid cancer patients.