Delayed onset of HPV-associated uterine malignancies: seven pathogenetic factors in contrast to cervical cancer

Human papillomaviruses (HPVs) are a diverse group of small, non-enveloped deoxyribonucleic acid (DNA) viruses with over 200 identified genotypes, of which approximately 14 are classified as high-risk HPV (hrHPV) due to their oncogenic potential [ 1 ]. Globally, HPV is responsible for nearly all cervical cancers and contributes to a significant proportion of other anogenital and oropharyngeal malignancies. The burden is unevenly distributed, with the highest incidence in low- and middle-income countries where screening and vaccination programs are limited [ 2 ]. HPV infects basal epithelial cells through microabrasions in the mucosa. The viral life cycle is tightly linked to the differentiation program of the host epithelium, with initial episomal replication followed by late-stage production of capsid proteins in terminally differentiated cells [ 3 ]. hrHPV types persist by evading immune detection through modulating interferon (IFN) responses, Toll-like receptor (TLR) signaling, and antigen presentation pathways [ 4 ]. Distinct HPV variant lineages exhibit differences in pathogenicity. For example, Asian-American HPV-16 variants demonstrate higher oncogenic potential than European lineages, while certain HPV-18 E6 variants more effectively activate the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling cascade [ 5 ]. These molecular variations influence persistence, immune evasion, and malignant transformation rates. The carcinogenic capacity of hrHPV is primarily mediated by the viral oncoproteins E6 and E7, which respectively inactivate p53 and retinoblastoma (Rb) tumor suppressors [ 5 ]. This disruption leads to unchecked cell proliferation, genomic instability, and accumulation of mutations. Additional oncogenic alterations include modulation of telomerase activity, interference with apoptotic pathways, and constitutive activation of survival signaling networks [ 6 ]. HPV-driven cervical carcinogenesis benefits from direct viral access to the transformation zone, a site of high cell turnover and hormonal sensitivity. In contrast, the endometrium presents anatomical and physiological barriers to viral persistence, including the cyclical shedding of the functional layer, lower exposure to external pathogens, and differences in immune microenvironment. Consequently, while cervical cancer can develop within a decade of persistent hrHPV infection, endometrial malignancies linked to HPV may require longer periods of genomic instability and co-factors to emerge [ 7 ]. This paper will outline seven pathogenetic factors explaining the delayed onset and underrecognized role of HPV in endometrial malignancies compared to cervical cancer, integrating anatomical, hormonal, immune, genetic, and infectious co-factors into a unified model and showcases morphological microscopic findings.

This research received no external funding.

The collective evidence showcased in this work indicates that HPV can have a role in endometrial malignancies, but this role differs fundamentally from its well-established etiological dominance in cervical cancer. The progression from infection to malignancy in the endometrium is shaped by a complex interplay of anatomical barriers, cyclical tissue turnover, prolonged viral latency, pre-existing genetic instability, hormonal influences, immune modulation, co-infections, and, in some cases, the persistence of virus-harboring ectopic endometrial tissue such as in endometriosis. Unlike in the cervix, where hrHPV types act as primary carcinogens, endometrial malignancies likely emerge from multifactorial pathogenesis in which HPV functions as a co-factor rather than the singular initiating event. The virus’s oncogenic proteins (E6/E7) may synergize with pre-existing mutations in tumor suppressor genes (e.g., PTEN, PIK3CA, MMR defects) and with chronic estrogen-driven proliferation, leading to transformation over a decades-long latency. This prolonged trajectory helps explain why HPV-associated endometrial tumors often appear late in life and sometimes in the context of multiple prior HPV-related malignancies. Morphological evidence, including rare cases of women developing HPV-related cervical and vulvar carcinomas, followed years later by endometrial malignancies highlights the possibility of HPV’s long-term field effect across the female genital tract. Furthermore, the identification of HPV DNA in endometriotic lesions supports the hypothesis that ectopic endometrial tissue may serve as a viral reservoir, sheltering the virus from cyclical shedding and immune clearance. HPV should be considered a potential but underestimated contributor to a subset of endometrial malignancies. Its role is most plausibly that of a synergistic agent operating in conjunction with genetic, hormonal, and environmental risk factors. Future research, combining molecular virology, immunopathology, and long-term clinical follow-up is essential to clarify HPV’s precise contribution, refine screening strategies, and fully assess the preventive value of vaccination beyond cervical cancer.

The delayed onset of HPV-associated endometrial malignancies, when compared to cervical cancer, can be explained by a multifactorial interplay between anatomical, physiological, immunological, hormonal, genetic, and infectious factors. Our synthesis of the seven pathogenetic mechanisms demonstrates that the extended latency period is not attributable to a single barrier, but rather to cumulative layers of defense and differential carcinogenic trajectories. Anatomical separation of the endometrium from the site of viral entry substantially limits initial infection. The cervical canal and mucus act as both physical and biochemical filters [ 9 ], and the rarity of retrograde viral ascent means that viral genomes may take years to reach endometrial epithelial basal cells. This contrasts sharply with the cervical transformation zone, where viral inoculation is direct and frequent [ 10 ]. Physiologically, the menstrual cycle provides a periodic “reset” of the functional endometrium, disrupting the ability of HPV to maintain continuous persistence [ 11 ]. While cervical epithelium remains stable, offering HPV an uninterrupted reservoir, endometrial turnover forces repeated re-establishment of infection [ 4 ]. Disruption of this cycle, due to obesity, PCOS, or exogenous hormones, may erode this protection [ 2 ]. Latency in the endometrium is prolonged by the lower frequency of viral reactivation and a hormonally modulated immune microenvironment [ 23 ]. In cervical cancer, viral genome integration occurs earlier, often driving genomic instability and oncogene activation within a decade [ 24 ]. Endometrial latency, however, often spans decades before enough mutational “hits” accumulate to drive carcinogenesis [ 12 ]. Molecular susceptibility also differs. Endometrial carcinomas frequently harbor PTEN, PIK3CA, and MMR gene mutations that are absent in most cervical cancers [ 25 ]. In HPV-positive endometrial tumors, the virus may act as a late-stage cofactor rather than the primary driver of transformation [ 6 ]. Hormonal influences amplify this difference. Chronic unopposed estrogen exposure promotes proliferation of potentially HPV-infected cells, while luteal-phase progesterone induces immune tolerance that can allow viral persistence [ 26 ]. Experimental work shows that estrogen can synergize with HPV E6/E7 to accelerate tumorigenesis [ 13 ]. The immune microenvironment of the endometrium, which is designed to tolerate implantation, has cyclical periods of reduced antiviral immunity [ 14 ]. HPV exploits these windows via immune evasion strategies, including MHC downregulation and IFN pathway suppression [ 16 ]. Finally, co-infections can breach cervical barriers and alter immune responsiveness, facilitating HPV ascent to the endometrium [ 17 ]. Ct [ 18 ] and HSV-2 [ 7 ] infections are particularly relevant, as they cause chronic inflammation, epithelial disruption, and immunomodulation. In integrating these factors, it becomes clear that HPV’s role in endometrial carcinogenesis is often underestimated because it rarely acts alone. The virus must navigate a more hostile anatomical and physiological environment, relying on co-existing genetic instability, hormonal conditions, immune tolerance, and microbial interactions to exert its oncogenic potential. This results in a protracted carcinogenic course that may span decades from infection to malignancy, contrasting sharply with the more direct pathway in cervical cancer. Emerging evidence suggests that endometriosis may not only predispose women to chronic inflammation and neoplastic transformation, but could also serve as a reservoir for HPV, thus creating conditions favorable for long-term viral persistence and eventual carcinogenesis. Several studies have detected HPV DNA within endometriotic lesions. A study by Oppelt et al. found high- and medium-risk HPV in 11.3% of endometriosis lesions, suggesting these ectopic tissues are not impervious to infection [ 7 ]. Rocha et al. reported HPV DNA positivity in 82.8% of endometriosis patients versus 38.7% in controls [odds ratio (OR) 6.64], indicating a strong association between endometriosis and HPV presence along the female reproductive tract [ 27 , 28 ]. A meta-analysis further reinforced this link, showing that women exposed to HPV had nearly twice the risk of developing endometriosis compared to unexposed individuals [ 29 ]. However, population-level data provide a more nuanced picture. A large-scale U.S. survey [National Health and Nutrition Examination Survey (NHANES)] found no significant association between self-reported endometriosis and HPV prevalence after adjusting for confounders [adjusted prevalence ratio (aPR) 0.84 for any HPV, 0.71 for hrHPV] [ 27 ]. This inconsistency may reflect selection biases, differences in detection methods, or the sensitivity of tissue versus population sampling. Endometriosis establishes ectopic endometrial implants outside the uterus, which do not undergo regular menstrual shedding, unlike the eutopic endometrium. This anatomical advantage could allow HPV, once established, to persist in a stable microenvironment. Indeed, Rocha et al. demonstrated that hrHPV types found in lower genital tract (LGT) sites also appeared in the UGT, including endometriotic lesions, in patients, thus highlighting the potential for viral continuity across reproductive tract regions [ 27 ]. Chronic inflammation within endometriosis is well documented and may predispose tissues to neoplastic transformation via oxidative stress, angiogenesis, and altered immune surveillance [ 30 ]. If HPV is present in these lesions, its oncoproteins (E6/E7) could synergize with the inflammatory milieu, increasing the likelihood of genomic instability and malignant progression. Further supporting this concept, Nazari et al. observed HPV in endometrial polyps, benign but potentially pre-malignant overgrowths, suggesting that benign endometrial proliferation may harbor HPV even in the absence of overt malignancy [ 31 ]. Integrating these findings, endometriotic implants appear to offer an environment where HPV can evade shedding-related clearance, persist over time, and exist alongside chronic inflammation, which are conditions conducive to delayed malignant transformation. That this may contribute to rarer and delayed endometrial malignancies (e.g., sarcomas) aligns with the long-latency model proposed for HPV in endometrium. Given the conflicting prevalence data, further prospective HP, molecular, and longitudinal studies are needed to clarify: (i) whether HPV contributes to the pathogenesis of endometriosis; (ii) if endometriosis independently increases risk of HPV-associated endometrial malignancy; and (iii) whether HPV-positive endometriotic lesions evolve into malignancy more frequently than HPV-negative ones. Understanding this reservoir function holds significant implications for screening, monitoring, and preventive strategies in women with endometriosis, potentially informing long-term surveillance and risk stratification.

The progression from HPV infection to malignancy is a complex, multistep process influenced by viral, host, and environmental factors. In the case of endometrium, several unique barriers and modifying influences lead to a prolonged latency period compared to cervical carcinogenesis. Below are the seven principal pathogenetic factors identified in this review. The cervix is uniquely vulnerable to HPV infection because its transformation zone which is the junction between the squamous epithelium of the ectocervix and the columnar epithelium of the endocervix and is directly accessible during sexual contact. In contrast, the endometrium lies within the uterine cavity, anatomically separated from the external genital tract by the cervical canal and protected by several structural and functional barriers. This anatomical distance significantly reduces the likelihood of initial HPV colonization in the endometrial lining [ 8 ]. For HPV to reach the endometrium, the virus must ascend through the cervical mucus, which contains immunoglobulins (notably secretory IgA) and antimicrobial peptides that inhibit viral penetration [ 7 ]. The mucus also varies in viscosity throughout the menstrual cycle, becoming thinner during ovulation under estrogen influence but otherwise maintaining a dense gel-like consistency that hinders pathogen migration. Moreover, cervical epithelial cells themselves can mount an antiviral response through IFN signaling and TLR activation, further limiting viral ascent. Mechanical ascent of HPV into the upper genital tract (UGT) is rare under normal physiological conditions but may occur in certain scenarios. Retrograde menstruation, the backward flow of menstrual blood through the Fallopian tubes into the peritoneal cavity, has been proposed as one possible route for the dissemination of HPV-infected cells, although evidence remains circumstantial [ 9 ]. Gynecological interventions such as curettage, hysteroscopy, or intrauterine device (IUD) insertion may also facilitate the upward transport of viral particles by mechanically bypassing mucosal barriers. Another consideration is that the cervical microenvironment is richer in basal keratinocytes, the primary HPV target cells, due to its constant exposure to micro-abrasions during intercourse. In contrast, the endometrium is less frequently injured in a way that exposes basal epithelial layers, making initial viral entry more challenging [ 10 ]. The combination of limited direct exposure, protective cervical mucus barrier, and the relative scarcity of exposed basal epithelial cells reduces the efficiency of HPV infection in the endometrium compared to the cervix. The physical separation of the endometrium from the site of viral inoculation, combined with multiple protective anatomical and immunological barriers, contributes to the delayed onset of HPV-associated endometrial malignancies. While these defenses are not absolute, their cumulative effect significantly slows the timeline for viral persistence and oncogenic progression in the uterine lining, especially when compared to the cervix. One of the most distinctive protective mechanisms of the endometrium against persistent HPV infection is its cyclical process of shedding and regeneration. During each menstrual cycle, the functional layer of the endometrium is sloughed off in response to progesterone withdrawal, physically removing epithelial cells, including any transiently infected by HPV, from the uterine cavity [ 11 ]. This natural turnover reduces the window of opportunity for HPV to establish long-term episomal persistence, a prerequisite for carcinogenic transformation. The cervical epithelium, by contrast, does not undergo such wholesale renewal. Instead, it maintains a relatively stable epithelial layer, allowing persistent HPV infection to continue unchecked for months or years. This is a critical difference in the pathogenesis of cervical versus endometrial malignancies: in the cervix, viral persistence often begins within a few months of infection, whereas in the endometrium, repeated shedding forces the virus to “re-establish” infection multiple times before persistence is achieved [ 4 ]. However, this protective mechanism is not absolute. Factors that reduce or disrupt regular endometrial shedding can enhance the risk of viral persistence. Chronic anovulation, as seen in polycystic ovary syndrome (PCOS), obesity-related endocrine disruption, or prolonged progesterone deficiency, leads to unopposed estrogen exposure and continuous endometrial proliferation without regular shedding. This creates a more stable epithelial environment where HPV-infected cells can survive longer and accumulate oncogenic mutations [ 10 ]. Menstrual cycle length also plays a role. Women with longer cycles experience fewer shedding events per year, potentially increasing the time HPV has to establish itself before infected cells are lost. A population-based study linked prolonged cycle length and later menopause to increased risk of endometrial carcinoma, possibly by extending the cumulative estrogenic exposure and reducing the clearance frequency of potentially infected cells [ 1 ]. Another consideration is the regenerative capacity of the endometrium. Each cycle’s proliferative phase relies on the rapid replication of residual basal layer cells. HPV infection during this phase could result in integration into stem/progenitor cell populations, which are not removed during menstruation. This would enable the virus to persist across cycles, albeit less efficiently than in cervical tissue where basal cell exposure is constant [ 11 ]. The cyclical shedding of the endometrium serves as a biological “reset” that significantly hinders HPV persistence compared to the cervix. However, when menstrual regularity is disrupted, either by hormonal imbalance, metabolic conditions, or reproductive aging, the protective effect diminishes, allowing HPV greater opportunity to integrate and contribute to carcinogenesis. This interplay between viral persistence and menstrual physiology is a key reason why HPV-associated endometrial malignancies often emerge years, or even decades, after initial exposure. Latency is a hallmark of HPV biology, allowing the virus to remain hidden within epithelial basal cells for extended periods without producing detectable infection or symptoms. In the endometrium, this latency period is often prolonged compared to the cervix due to a combination of anatomical, physiological, and cellular factors that restrict viral replication and antigen presentation [ 4 ]. HPV establishes latency by maintaining its genome in episomal form within basal epithelial cells. In the cervix, the high turnover of the transformation zone epithelium and frequent microtraumas facilitate cycles of reactivation and low-level viral replication, which in turn drive faster progression toward persistent infection and oncogenesis. In the endometrium, however, viral replication is more sporadic, partly due to the cyclical shedding of infected cells and a less favorable microenvironment for continuous viral activity [ 1 ]. The virus’s ability to remain dormant is aided by its suppression of host immune surveillance mechanisms. HPV oncoproteins E6 and E7 downregulate IFN pathways and antigen-presenting machinery, reducing recognition by cytotoxic T-cells [ 10 ]. This immune evasion is effective in both cervical and endometrial tissues, but in the endometrium, latency can be prolonged because the virus has fewer opportunities to reactivate – a reflection of the lower frequency of direct pathogen contact, and mechanical disruption in the UGT. Viral latency in the endometrium is further influenced by the hormonal environment. During the luteal phase, progesterone-driven modulation of the immune system promotes local tolerance, which may allow latent HPV to persist without clearance. In postmenopausal women, changes in the endometrial immune landscape, combined with reduced cell turnover, can prolong latency until other oncogenic triggers, such as genetic instability or chronic inflammation, initiate malignant transformation [ 6 ]. Importantly, latency does not mean the virus is biologically inactive. Studies suggest that even during latent phases, HPV genomes may undergo low-level transcription, producing occasional E6/E7 expression that can subtly drive genomic instability over years. This “smoldering” activity allows for the gradual accumulation of DNA damage in endometrial epithelial cells without eliciting strong immune responses [ 12 ]. The delayed onset of HPV-associated endometrial malignancies can be partly attributed to the extended latency phase. The anatomical isolation of the endometrium, the cyclical removal of infected cells, and the unique hormonal and immune microenvironment work together to limit reactivation frequency. As a result, progression from infection to clinically significant disease often requires decades which is a stark contrast to the more rapid timeline seen in the cervix. The genetic landscape of endometrial carcinoma differs markedly from that of cervical cancer, and this divergence plays a pivotal role in the delayed onset of HPV-associated endometrial malignancies. While HPV’s oncogenic proteins E6 and E7 can inactivate p53 and Rb pathways in both tissues, the initiation of malignant transformation in the endometrium often requires the accumulation of additional, non-HPV-driven mutations over decades [ 4 ]. Endometrial carcinoma is frequently associated with mutations in phosphatase and tensin homolog (PTEN), a tumor suppressor gene involved in the regulation of the PI3K/Akt signaling pathway. Loss of PTEN function results in uncontrolled cell proliferation and survival, creating a permissive background for HPV-mediated transformation. PTEN mutations are detected in up to 83% of type I endometrial carcinomas, but they often arise independently of HPV infection. When HPV does infect such genetically compromised cells, the virus’s E6/E7 oncoproteins can synergize with existing signaling dysregulation to accelerate oncogenesis, but only after a prolonged mutational evolution [ 11 ]. Another common alteration in endometrial malignancies is activating mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), the gene encoding the catalytic subunit of PI3K. These mutations drive persistent activation of Akt and mammalian target of rapamycin (mTOR) pathways, which promote cell cycle progression and metabolic reprogramming. HPV’s E7 protein can exacerbate these effects by liberating E2F transcription factors from Rb-mediated repression, further amplifying proliferative signaling [ 11 ]. Mismatch repair (MMR) deficiency is also a notable feature of endometrial cancer, particularly in tumors with microsatellite instability (MSI). MMR deficiency leads to hypermutation, increasing the likelihood of acquiring driver mutations necessary for malignant transformation. While cervical cancer typically follows a viral oncogenesis-driven pathway with fewer additional mutations required, endometrial carcinoma in the context of HPV infection often represents a “dual-hit” model: viral oncogenesis layered on top of a genetically unstable background [ 12 ]. In addition to somatic mutations, germline variants may modulate susceptibility to HPV-mediated transformation. For example, women with Lynch syndrome, caused by inherited MMR gene mutations, have a significantly increased risk of endometrial carcinoma, and while HPV is not the primary driver in these cases, co-infection could theoretically accelerate tumorigenesis in already genetically compromised tissue [ 10 ]. Overall, the mutational trajectory of endometrial cancer requires more cumulative genetic damage than that of cervical cancer. HPV infection may act as a late-stage accelerant rather than the sole initiator. This means that the latency period from initial HPV exposure to endometrial cancer presentation is extended, as decades may pass before the necessary constellation of mutations is in place for the virus to exert its full oncogenic potential. Hormonal regulation of the endometrium is a central factor in both its physiology and its susceptibility to malignant transformation. Unlike the cervix, the endometrium is highly responsive to cyclical fluctuations in estrogen and progesterone, which control cell proliferation, differentiation, and shedding. These hormonal changes not only shape the tissue’s structural environment but also influence immune function and viral persistence, making them critical in the context of HPV-associated carcinogenesis [ 4 ]. Estrogen, particularly when unopposed by progesterone, promotes proliferation of endometrial epithelial cells, increasing the number of potential HPV target cells. Conditions associated with prolonged unopposed estrogen exposure (such as obesity, PCOS, nulliparity, and late menopause) have all been linked to an increased risk of endometrial carcinoma. In obesity, peripheral conversion of androgens to estrogens in adipose tissue leads to chronic estrogenic stimulation without sufficient progesterone counterbalance. This not only promotes endometrial hyperplasia but may also provide an environment where HPV-infected cells can survive and proliferate [ 11 ]. Progesterone exerts protective effects by inducing differentiation of endometrial cells and downregulating estrogen receptor expression, thereby reducing proliferative signaling. However, during the luteal phase, progesterone also modulates the immune microenvironment, dampening cytotoxic T-cell responses to maintain uterine receptivity for potential implantation. This immunomodulatory effect could inadvertently aid in the persistence of latent HPV infections by reducing antiviral immune surveillance [ 6 ]. Hormonal influences may also interact with viral oncogenic mechanisms at the molecular level. Estrogen receptor signaling can synergize with HPV E6/E7 oncoproteins to promote transcription of genes involved in cell cycle progression and DNA synthesis. Experimental models have shown that estrogen can enhance HPV-driven tumorigenesis in the reproductive tract, likely by sustaining proliferation of HPV-infected cells while simultaneously reducing immune clearance [ 10 ]. Additionally, the hormonal milieu changes with age. In perimenopause and menopause, fluctuating estrogen and progesterone levels alter both the endometrial architecture and immune responsiveness. Postmenopausal endometrium is typically atrophic, with reduced cell turnover – conditions that can prolong HPV latency but also allow for the slow accumulation of genetic damage until oncogenic transformation occurs. This may partially explain why HPV-associated endometrial malignancies are more often diagnosed in older women, frequently years or decades after the presumed initial infection [ 11 ]. Hormonal influences act as both gatekeepers and enablers in HPV-associated endometrial carcinogenesis. Cyclical progesterone and estrogen fluctuations typically protect against persistent infection through endometrial shedding and immune modulation, but chronic hormonal imbalances, particularly those involving prolonged unopposed estrogen exposure, can shift the balance toward viral persistence and eventual malignant transformation. The immune microenvironment of the endometrium is uniquely adapted to balance pathogen defense with reproductive tolerance. This dual function has critical implications for the persistence of HPV infections and the delayed onset of associated malignancies. Unlike the cervix, where immune surveillance is constantly challenged by exposure to the external environment, the endometrium operates within a more controlled and periodically immune-tolerant setting [ 13 ]. Throughout the menstrual cycle, immune cell populations in the endometrium fluctuate in response to hormonal cues. In the proliferative phase, there is an increased presence of cytotoxic cluster of differentiation (CD)8+ T-cells and natural killer (NK) cells, which are important for recognizing and destroying virus-infected cells. However, during the luteal phase, progesterone promotes a shift toward immune tolerance to facilitate potential embryo implantation. This includes a reduction in NK cell cytotoxicity, increased regulatory T-cell activity, and elevated anti-inflammatory cytokine production [ 14 ]. While essential for reproduction, this cyclical immunosuppression can create windows during which latent HPV can evade immune clearance and persist within the endometrium. HPV further exploits this environment by downregulating antigen presentation pathways, particularly through E6 and E7 oncoprotein-mediated suppression of IFN signaling and major histocompatibility complex (MHC) expression [ 8 ]. In the endometrium, where immune activation is already hormonally dampened for significant portions of the cycle, this viral immune evasion may be even more effective than in the cervix. The immune microenvironment is also altered in certain pathological or physiological states. Aging, for instance, is associated with immunosenescence, a decline in both innate and adaptive immune responses, which reduces the clearance efficiency of HPV-infected cells. Similarly, systemic immunosuppression due to chronic disease, corticosteroid therapy, or organ transplantation can enhance HPV persistence. In women with immunodeficiency, persistent hrHPV infection is a stronger predictor of endometrial cancer risk compared to the general population [ 15 ]. In addition, localized changes in the vaginal and uterine microbiota may influence immune responsiveness to HPV. A disrupted microbial balance, often caused by chronic inflammation or co-infections, can impair epithelial barrier function and skew cytokine production toward a more tolerogenic profile, further supporting viral persistence [ 16 ]. The endometrium’s immune microenvironment, shaped by hormonal cycles, reproductive imperatives, aging, and microbiota composition, provides a unique setting in which HPV can establish prolonged latency. The cyclical immune suppression inherent to uterine physiology may slow viral clearance and extend the time required for oncogenic transformation, contributing to the later onset of HPV-associated endometrial malignancies compared to cervical cancer. Co-infections with other pathogens can significantly influence the persistence, pathogenicity, and oncogenic potential of HPV in the endometrium. These additional infections may alter the mucosal barrier, modulate immune responses, and create a chronic inflammatory microenvironment that facilitates HPV’s ascent to the UGT and its integration into host DNA [ 17 ]. One well-studied example is Chlamydia trachomatis (Ct), an intracellular bacterium that can cause chronic cervicitis and pelvic inflammatory disease. Ct infection disrupts epithelial tight junctions, exposes basal cells, and induces long-term mucosal inflammation, thereby increasing the susceptibility of these tissues to HPV infection and persistence [ 18 ]. The inflammatory cytokines produced during Ct infection, including interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), can promote a microenvironment conducive to DNA damage and cell proliferation, both of which enhance HPV’s carcinogenic potential. Herpes simplex virus type 2 (HSV-2) has also been implicated as a co-factor in HPV-mediated oncogenesis. HSV-2 can cause recurrent mucosal ulcerations, which disrupt the epithelial barrier and allow HPV direct access to basal keratinocytes which are the primary target cells for viral infection. Moreover, HSV-2 infection has been shown to modulate local immune responses, particularly through the induction of IL-17-mediated pathways that may impair antiviral T-cell activity [ 15 ]. Co-infections are not limited to sexually transmitted pathogens. Alterations in the vaginal and uterine microbiota, whether from bacterial vaginosis, fungal overgrowth, or other chronic microbial imbalances, can lead to persistent inflammation and disruption of epithelial defenses. Such dysbiosis has been linked to impaired antigen presentation and skewed cytokine profiles, favoring viral persistence [ 14 ]. The effect of co-infections may be particularly pronounced in the endometrium due to its relative anatomical isolation. Normally, the cervical mucus acts as a physical and immunological barrier preventing pathogens from ascending into the uterine cavity. However, co-infections that degrade this barrier or alter its composition (e.g., by increasing mucus viscosity or reducing antimicrobial peptide concentration) can allow HPV to bypass these defenses and establish infection in the endometrial lining [ 19 ]. Co-infections contribute to the delayed onset of HPV-associated endometrial malignancies by creating conditions that facilitate viral entry, persistence, and eventual oncogenic transformation. They may not initiate malignancy on their own but act as critical enablers, particularly when combined with hormonal imbalance, genetic susceptibility, and the immune tolerance of the endometrium.

The authors declare no conflict of interests.

hrHPV infection drives the histopathological (HP) signature of cervical and vulvar malignancies, typically manifesting as invasive squamous cell carcinoma (SCC) or keratinizing/non-keratinizing subtypes with koilocytosis and p16 block positivity. In vulvar SCC, for instance, HPV-associated tumors are frequently non-keratinizing, exhibit prominent koilocytes, and test strongly for p16, a surrogate marker of viral oncogenic activity [ 20 ]. HPV can also contribute to rare biphasic tumors such as sarcomatoid carcinomas, where both epithelial and mesenchymal differentiation coexist. One reported case featured an HPV-33-positive cervical tumor with both epithelioid and sarcomatous components confirmed by immunohistochemistry [both cytokeratin (CK) and vimentin positivity], underscoring HPV’s ability to transform cells beyond conventional squamous phenotypes [ 21 ]. Consider a clear case that aptly illustrates the extended latency and morphological transition potential of HPV-associated disease. Initial diagnosis showed a woman with HPV-related cervical SCC, Figure 1A , 1B , 1C . Treatment went well; the patient was considered healed. Ten years later the patient presented with a vulvar condyloma, Figure 1D , 1E , 1F , and an endometrial stromal sarcoma, Figure 1G , 1H , 1I , confirmed via microscopy showing a monotonous population of spindle/ovoid cells, tongue-like infiltration of the myometrium, and characteristic immunohistochemical markers as typically described in endometrial stromal sarcoma: ▪ CK AE1/AE3: negative in tumor cells (internal and external controls present); ▪ CK8/18: negative in tumor cells (internal and external controls present); ▪ Actin: negative in tumor cells (internal and external controls present); ▪ Desmin: uniformly positive in tumor cells (cytoplasmic staining) (internal and external controls present); ▪ CD10: uniformly positive in tumor cells (cytoplasmic staining) (external control present); ▪ Caldesmon: uniformly positive in tumor cells (cytoplasmic staining) (internal control present). This case emphasizes multiple HP dimensions: The initial HPV-driven lesion exhibited well-characterized morphological footprint. The subsequent sarcoma represents a non-squamous, mesenchymal phenotype occurring in the uterine endometrial stroma, arguably a separate neoplastic process rather than direct progression from the prior tumors. Published reports indicate that multiple primary malignancies in the female genital tract, especially combinations of cervical and vulvar carcinoma followed by a distinct endometrial sarcoma, though extremely rare, do occur [ 22 ]. Such occurrences may reflect a prolonged carcinogenic timeline, complex field effects, or even viral hit-and-run mechanisms leading to later de novo transformation. Microscopic findings. (A–C) SCC of the cervix: (A) Endocervical gland adjacent to infiltrating SCC, confirming the cervical origin of the lesion; (B) Higher magnification of the squamous tumor cell population showing areas of G2 and G3 differentiation; (C) Detail of marked nuclear pleomorphism. (D–F) Vulvar condyloma: (D) Low-power overview of the exophytic condylomatous lesion; (E and F) Higher magnifications highlighting the architecture and cytological features of the condyloma. (G–I) Uterine sarcoma: (G) Low-power overview of the uterine sarcoma; (H and I) Higher magnifications showing the cytological and architectural features of the sarcomatous proliferation. HE staining: (A) ×50; (B, E and H) ×100; (C, F and I) ×200; (D and G) ×10. HE: Hematoxylin–Eosin; SCC: Squamous cell carcinoma HPV-related carcinomas maintain distinct squamous morphology with koilocytosis and p16 positivity. Rare occurrences of sarcomatoid differentiation within cervical tumors highlight HPV’s broader oncogenic influence. A delayed onset mesenchymal malignancy, such as endometrial stromal sarcoma, underscores either a secondary, distinct neoplastic event or the eventual morphological divergence of HPV-induced neoplasia in the context of a permissive microenvironment. These findings reinforce the notion that HPV’s impact on gynecological tissues extends beyond rapid epithelial carcinogenesis and may culminate, decades later, in entirely different histological entities.