Does HPV Cause Ovarian Cancer? Key Facts and Emerging Research

Human papillomavirus (HPV) is widely recognized for its role in cervical cancer, but its potential link to other gynecological cancers, including ovarian cancer, remains under investigation. While HPV primarily infects epithelial cells, researchers are exploring whether it could contribute to ovarian malignancies through indirect mechanisms or direct infection of ovarian cells.

Understanding this possible connection is crucial for refining screening strategies and preventive measures. Emerging studies highlight the need for further research into how HPV might reach the ovaries and interact with ovarian tissue.

Pathways Of HPV Migration

The movement of HPV beyond its primary sites, such as the cervix and anogenital region, raises questions about how it might reach the ovaries. As a non-enveloped DNA virus with a strong affinity for epithelial cells, its presence in ovarian tissue suggests potential routes of migration beyond direct sexual transmission. One proposed mechanism is retrograde menstruation, where HPV-infected endometrial and cervical cells travel through the fallopian tubes into the peritoneal cavity. This process, which has been linked to the spread of endometriosis, could facilitate viral entry into the ovaries.

Another possibility is hematogenous or lymphatic dissemination, where HPV-infected cells or free viral particles enter the bloodstream or lymphatic system. While HPV is not traditionally considered bloodborne, studies have detected its DNA in peripheral blood mononuclear cells, suggesting systemic circulation as a transport method. The extensive lymphatic drainage of the cervix and uterus, which connects to the ovarian lymphatic network, could allow viral particles to reach the ovaries through immune cell trafficking or passive transport.

Surgical and procedural transmission is another consideration, particularly in cases where HPV DNA is found in unexpected anatomical locations. Gynecological procedures such as hysteroscopies, biopsies, or in vitro fertilization techniques could inadvertently transfer HPV-infected cells to the upper reproductive tract. Additionally, co-infection with pathogens like Chlamydia trachomatis may facilitate HPV migration by altering mucosal barriers and promoting viral persistence.

Interaction With Ovarian Cells

Once HPV reaches the ovaries, its ability to interact with ovarian cells becomes a key question. Unlike cervical epithelial cells, which are the primary targets of HPV, ovarian cells include epithelial, stromal, and germ cell populations. The ovarian surface epithelium (OSE), a single layer of mesothelial-like cells covering the ovary, is particularly relevant as the origin of most epithelial ovarian cancers.

Experimental studies suggest that HPV DNA can integrate into ovarian carcinoma cell genomes, disrupting tumor suppressor genes like TP53 and RB1 and leading to uncontrolled proliferation. However, the efficiency of viral entry into ovarian cells remains unclear, as the receptors facilitating HPV attachment—such as heparan sulfate proteoglycans and α6-integrins—are expressed at lower levels in OSE compared to cervical epithelium. This suggests that HPV may require additional cellular cofactors or microenvironmental conditions to establish infection in ovarian tissue.

Beyond direct infection, HPV may influence ovarian cells through paracrine signaling and extracellular vesicle-mediated communication. Studies have shown that HPV-infected cervical cells release exosomes containing viral oncoproteins, which can alter gene expression in neighboring uninfected cells and create a pro-tumorigenic environment. If similar mechanisms occur in the ovaries, HPV-derived factors could contribute to cellular dysregulation without direct viral replication. This aligns with findings where HPV DNA is detected in ovarian cancer specimens without evidence of productive infection, suggesting a role in tumorigenesis rather than classical viral replication.

Evidence Linking HPV To Ovarian Abnormalities

The detection of HPV DNA in ovarian tissue has prompted research into its potential role in ovarian abnormalities, including benign cysts, borderline tumors, and malignant neoplasms. While ovarian cancer is traditionally linked to genetic mutations such as BRCA1 and BRCA2, studies have found HPV DNA in ovarian tumors at varying prevalence rates, with some reporting viral sequences in up to 30% of samples. This raises questions about whether HPV is a bystander or an active participant in ovarian tumorigenesis.

Histopathological studies have identified molecular changes in HPV-positive ovarian tumors that mirror those seen in HPV-driven cervical cancers. The overexpression of p16INK4a, a marker for high-risk HPV activity, has been observed in some ovarian cancer specimens containing HPV DNA. Since p16 overexpression results from the inactivation of tumor suppressor pathways by HPV oncoproteins, its presence in ovarian tumors suggests HPV may contribute to disrupted cell cycle control. However, conflicting reports exist, with some studies failing to detect HPV DNA in ovarian cancer tissues, highlighting the need for standardized detection methods and larger cohort studies.

HPV has also been implicated in certain pre-neoplastic ovarian conditions. Some studies have identified HPV DNA in benign and borderline ovarian lesions, suggesting viral infection could be an early event in tumorigenesis. However, inconsistent evidence across populations indicates that if HPV contributes to ovarian pathology, it likely does so alongside other genetic or environmental factors rather than as a sole causative agent.

Strain Specific Associations

Different HPV strains exhibit distinct oncogenic potentials, with high-risk types such as HPV-16 and HPV-18 most strongly linked to cervical cancer. Identifying which strains are present in ovarian tumors is key to determining whether specific variants play a role in tumor development. Some studies have detected high-risk HPV strains in ovarian carcinoma samples, but the frequency and distribution vary widely across geographic regions and study populations. This suggests that if HPV is involved in ovarian malignancies, its role may be influenced by genetic or environmental factors affecting viral persistence and oncogenic transformation.

Strain-specific differences in viral integration could also affect how HPV interacts with ovarian cells. High-risk strains integrate into host DNA more frequently, disrupting tumor suppressor genes and promoting chromosomal instability. In contrast, low-risk strains like HPV-6 and HPV-11, primarily associated with benign lesions, are rarely found in malignant tissues. Some studies have reported HPV-33 and HPV-45 in ovarian cancer samples, but their significance remains unclear due to limited data. The presence of multiple HPV strains within a single tumor further complicates analysis, as co-infections may alter viral gene expression and impact carcinogenic pathways in unpredictable ways.