Human Papillomavirus (HPV) is a common group of viruses, with over 200 known types, that infect skin and mucosal surfaces. High-risk HPV types have the potential to cause cellular changes leading to cancer. These types are divided into a primary group (HPV-16 and HPV-18) and a secondary group composed of the remaining oncogenic types. Understanding the nature of the high-risk types outside of the two most common ones is important for anyone navigating a positive screening result. This secondary classification is often grouped in diagnostic testing, leading to questions about its specific cancer risk and appropriate follow-up care.
Characteristics of Non-16/18 High-Risk Types
The high-risk classification includes approximately 12 to 14 oncogenic types. This group includes the following types:
- HPV-31
- HPV-33
- HPV-35
- HPV-39
- HPV-45
- HPV-51
- HPV-52
- HPV-56
- HPV-58
- HPV-59
- HPV-66
- HPV-68
These types are collectively referred to as the “pooled group” in clinical laboratory reports, which test for the presence of any high-risk type other than 16 and 18.
This pooling occurs because clinical guidelines manage these non-16/18 results similarly, even though individual genotyping is possible. The five most prevalent non-16/18 types—HPV-31, 33, 45, 52, and 58—account for an estimated 20% of cervical cancers globally. A positive result for the pooled group indicates infection with one or more of these high-risk types, requiring a specific management strategy.
Comparative Cancer Risk
The risk of developing high-grade cervical lesions (CIN2 or CIN3) or cancer is not uniform across all high-risk HPV types. HPV-16 and HPV-18 are responsible for approximately 70% of all cervical cancer cases. In comparison, the non-16/18 high-risk types, while still classified as oncogenic, carry a lower absolute risk of progression to cancer.
In one study, the cumulative 36-month progression rate to high-grade lesions (CIN2/3) was highest for HPV-16 at 16.5%, followed by HPV-18 at 8.2%. The remaining high-risk types demonstrate a lower cumulative incidence of these severe lesions over the same timeframe. Cancer development is a long process, generally requiring 25 to 30 years from the initial infection, which supports surveillance as an effective strategy.
The main driver of risk for the non-16/18 group is viral persistence, meaning the infection is not cleared by the immune system. Infections persisting for six months or longer significantly increase the risk of progression to precancerous lesions. The mean time for low-grade lesions associated with these types to regress is often longer than for non-oncogenic types, indicating a slower clearance rate.
Even within the non-16/18 group, certain types, such as HPV-31 and HPV-33, present a higher individual risk than others. Because of the pooled group’s lower overall risk profile, management protocols allow more time for the infection to clear naturally before considering invasive procedures. For instance, the risk of CIN3+ in a person with normal cytology but a positive non-16/18 result is typically low, often less than 4%.
Detection and Follow-Up Protocols
Detection of non-16/18 high-risk HPV occurs through routine cervical cancer screening, via primary HPV testing or co-testing (HPV test with a Pap smear). Modern testing systems identify any high-risk HPV, specifically check for HPV-16 and HPV-18, and then report the remaining positive result as the pooled non-16/18 group. This genotyping allows clinicians to tailor the next steps based on the specific virus type found.
When a patient tests positive for the non-16/18 group, management is guided by risk-based consensus guidelines, such as those from the American Society for Colposcopy and Cervical Pathology (ASCCP). For patients with a positive non-16/18 result but normal or low-grade cytology, immediate colposcopy is often not necessary due to the low immediate cancer risk. Instead, the preferred approach is surveillance, involving a follow-up test, typically in one year.
This surveillance period checks for viral persistence or progression of cellular changes. If the initial test was primary HPV screening, the sample may undergo “reflex cytology” to analyze for abnormal cellular changes before determining the follow-up plan.
If the one-year follow-up shows persistent non-16/18 HPV positivity or new cellular abnormalities, the cumulative risk may cross the threshold requiring a referral for colposcopy. This strategic delay minimizes unnecessary procedures for infections that would otherwise clear naturally.
Prevention Through Vaccination and Screening
Prevention against high-risk HPV is achieved through two main strategies: primary prevention via vaccination and secondary prevention through routine screening. The current 9-valent HPV vaccine (Gardasil 9) offers protection against the most common high-risk types. Importantly, the vaccine covers five of the most oncogenic types within the non-16/18 group: HPV-31, 33, 45, 52, and 58.
By targeting these types, the vaccine significantly reduces the overall risk of developing cervical and other HPV-related cancers caused by this pooled group. Since not all high-risk types are covered, continued secondary prevention through regular screening remains necessary. Screening protocols, including Pap tests and HPV testing, act as a safety net to detect persistent infections and precancerous lesions early.
This secondary prevention is crucial for monitoring the natural history of any detected non-16/18 infection. Routine screening ensures that any new or persistent infection is caught before it progresses to a higher-grade lesion, even if a previous positive result cleared or the individual was vaccinated. The combination of vaccination and consistent screening offers the most effective, long-term defense against cancer caused by all high-risk HPV types.