Human papillomavirus (HPV) is one of the most common sexually transmitted infections globally, encompassing a family of more than 200 viral strains. While many HPV genotypes are benign or cause self-limiting epithelial lesions, several can lead to anal, cervical, vaginal, throat, and neck HPV-related cancer. Approximately 15 high-risk HPV (HR-HPV) types that affect the anogenital region are associated with an increased risk of cancer.
The landscape of HPV diagnostics is currently undergoing an active shift in screening recommendations and advances aimed at improving the capture rate and efficiency of population screening.
Why is HPV a concern?
Though HPV is one of the most common STIs globally, most infections are cleared naturally by the immune system within two years. However, persistent HR-HPV infection in the basal cell layer of the epithelium can promote increased cell proliferation and dysplasia. These cellular changes can lead to basal cells differentiating into cancerous squamous epithelial cells, where high-grade cervical intraepithelial neoplasia (CIN) or invasive cervical cancer may occur. In fact, nearly all cases of cervical cancer are caused by an infection with a HR-HPV.
Reducing HPV-related cervical cancer hinges on prevention through vaccination, routine screening, patient surveillance, and surgical intervention.
Unfortunately, a significant and growing proportion of patients have never been previously screened for cervical cancer, contributing to an increase in late-stage diagnosis. Recent research published in JAMA Network Open found that the proportion of US women who had never undergone cervical cancer screening increased substantially from 2005 to 2023, particularly among women aged 21 to 29 years.
Detection
Cervical cancer screening predominantly relies on cytologic and molecular testing methods. Historically, exfoliative cytology-based methods, such as the Pap test, were the primary approach for detecting cellular changes like dysplasia.
Standard cytologic classifications ranged from NILM, ASC-US, LSIL, ASC-H, and HSIL. These cytologic classifications are correlated to the histologic findings of CIN.
NILM | Negative for intraepithelial lesion or malignancy |
ASC-US | Atypical squamous cells of undetermined significance |
LSIL | Low-grade squamous intraepithelial lesion |
ASC-H | Atypical squamous cells—cannot exclude HSIL |
HSIL | High-grade squamous intraepithelial lesion |
With the advent of molecular diagnostics for HPV, modern screening programs now utilize either co-testing algorithms, which pair cytology examination with molecular detection of HPV, or primary HPV testing without cytology. It’s important to note that the presence of HR-HPV is tied to histological findings for CIN rather than cytology results. In other words, detection of HR-HPV is a sensitive method for detecting cervical cellular dysplasia without performing tissue biopsy.
Among the primary commercial companies, only two have FDA approval for testing across all three screening modalities: cytology with reflex testing to HPV, cytology plus HPV testing, and primary HPV screening without cytology. As more testing options become available, screening modality may play an increasingly important role in helping healthcare systems reach more patients and improve cervical cancer screening.
Updated screening guidelines
Clinical guidelines for cervical cancer screening have undergone notable updates, reflecting growing evidence on the negative predictive value for cervical cancer and the accessibility of primary HPV testing.
In 2018, the United States Preventive Services Task Force (USPSTF) released guidance for cervical cancer screening to begin at age 21 using cytology alone. The guidelines allow primary HPV testing as an alternative to cytology alone or co-testing in individuals aged 30–65. By 2020, the American Cancer Society (ACS) released their guidelines of screening at age 25 with primary HPV every five years as its preferred screening strategy due to the high negative predictive value for cervical cancer.
As of 2025, the ACS recalibrated its guidelines to allow for self-collected vaginal specimens for HPV primary, however patients would be re-screened every three years (for now).
In similar fashion, the U.S. Department of Health and Human Services Health Resources and Services Administration released screening guidelines endorsing the use of self-collect samples and HPV primary as its preferred screening strategy for patients aged 30–65 of average risk. Importantly, it also requires most insurance plans to cover additional testing needed to complete cervical cancer screening.
It should be noted that the USPSTF initiated a draft statement in late 2024, signaling continued recalibration given much of the landscape has changed since 2018.
Surveillance vs screening
When it comes to cervical cancer, screening and surveillance serve different purposes and different patients. Screening is a broad tactic used on a large patient population where disease prevalence may be low (discussed above). By contrast, surveillance is used for individuals who have had an abnormal cytology or HPV result.
In 2019, the American Society for Colposcopy and Cervical Pathology (ASCCP) published Risk-Based Management Consensus Guidelines. These guidelines stratify risk to determine patient triage based on the individual’s immediate and five-year risk of developing CIN3+. Lower risk patients move into a more frequent screening interval whereas higher risk patients may be triaged into a colposcopy procedure.
HR-HPV genotypes
HPV genotypes are valuable in determining CIN3+ risk and medical management within the ASCCP guidelines.
Genotypes 16 and 18 are the most represented among current assays as they are major predictors of progression to CIN3+ and carry the highest cancer risk.
Genotypes 31, 45, 51, and 52 are not widely available but are notable as they possess varying risk of progression to CIN3+. An HR-HPV result that is not genotype 16 or 18 may result in providers choosing a higher risk management pathway.
As longitudinal data on HPV-related cancers continues to grow, changes to genotype menu offerings could shift. This may improve risk management and decrease unnecessary colposcopy procedures, allowing patients to be surveilled more frequently instead.
What’s new and what’s on the horizon?
Primary HPV screening was an important advancement in the field as a necessary first step toward future use of self-collected screening. Co-testing paradigms require an invasively collected cervical sample in a healthcare setting. By contrast, primary HPV allows for vaginal collection, a method considered by many as less discomforting or invasive. Several studies have supported the concept that self-collection is preferred by many patients. Additionally, self-collected samples are moving into home collection with some early entrants already offering this option. Keep an eye on urine as a future option for self-sampled HPV testing.
There is a lot of excitement regarding self-collected screening when you consider data from the CDC showing that half of all new cervical cancers are in women who have never been screened or have not been screened in the last five years. This is true even among women who see their doctors regularly and have health insurance.
At home self-collection can increase screening access for underserved populations, reduce travel costs, perform comparably to clinician-collected screening, and contribute to improved screening rates.
A threat to cytology?
Primary HPV screening should not be viewed as a threat to cytology labs. Rather, it presents an opportunity to relieve some of the volume burden being compounded by an aging workforce, expanding testing population, and dwindling cytology labor pool. Meanwhile, cytology needs are increasing for other invasive procedures like fine-needle aspirates and ultrasound-guided transbronchial procedures. As cytology education programs have shrunk nationwide, so too has the labor pool needed to support the growth in these non-gynecological areas. Primary HPV screening offers some small relief to reallocate this precious labor resource toward other clinical needs.
Closing the gap
As Leeya Pinder, MD, MPH, recently shared at ADLM, populations of patients are affected differently depending on factors largely outside of their control: race, ethnicity, disability, gender dysphoria, education, income, and locality. We must tailor our cervical cancer screening strategies to reach these underserved populations.
As the frontier of HPV diagnostics continues to evolve, labs should position themselves for leveraging self-collection and HPV primary to improve screening rates, reallocate technical resources, and contribute to population health initiatives. The conversation of where, when, and on whom to use these self-collect and HPV primary workflows has never been more relevant.
