Advanced laboratory services

INTRODUCTION

Cervical cancer screening guidelines advise HPV testing in women ages 30 to 64 years as co-testing with cervical cytology or as a reflex test when the Pap test result is atypical squamous cells of undetermined significance (ASC-US). HPV testing is generally not recommended in women ages 21 to 29 years. Reflex testing may be performed with an ASC-US Pap, although repeat cytology in 12 months is the preferred next step (Algorithm 1). New HPV infections often occur soon after the onset of sexual activity. As such, HPV infection is very common in sexually active women under age 25. However, clinically relevant disease related to women in this age group is exceedingly rare. If an HPV test is performed in young women and is positive, we use conservative approaches for management. These include more frequent follow-up cytology and/or HPV testing rather than colposcopy. HPV testing alone as a screening test has also been introduced, but opinions vary regarding the role of primary HPV testing.

First HPV-positive result

This is a common result and if there is no prior HPV-positive testing, this most likely represents a new infection. Most new infections will revert to a negative result within 6 to 12 months. Women with a new HPV-positive result may be counseled about the high likelihood of the test results reverting to negative. These patients are managed based on the combination of HPV and cytology results.

HPV-positive, cytology negative

A patient ≥30 years with a positive HPV and negative cytology is at an increased risk of cervical disease. The management of this may include repeat HPV and cytology co-testing at 12 months or HPV genotyping (algorithm 2). If the patient is positive for HPV 16 or 18, colposcopy should be performed immediately.

Recurrent HPV-positive

A common clinical scenario is positive HPV testing followed by testing that is HPV negative. This happens in most women with a positive test, likely due to the appropriate immune response being generated to make the HPV infection latent. Keep in mind, it is likely that the HPV has not cleared, but is merely in a latent subclinical state below the threshold of the testing for being "positive."

In some patients who have had HPV-positive and then HPV-negative testing, the positive HPV testing may recur. Often, it is the same HPV type as a past infection, suggesting a "reactivation" from a latent infection. However, it is impossible to prove or disprove if a current HPV infection is a new infection or reactivation of an old, latent infection. Many patients will ask about the timing of infection, but it is not possible to know this since an infection may be new or reactivated. Patients should be counseled that most infections detected over the years of screening are reactivations of latent infections that are acquired at or near sexual debut.  

Persistent HPV-positive

Persistent HPV infection (defined as consecutively positive HPV results at least 12 months apart) is a necessary pathogenetic step for progression to clinically relevant disease (cervical intraepithelial neoplasia 2 or more severe [CIN 2+]). In patients who have persistent HPV infection, most, if not all, will eventually be diagnosed with CIN 2+. Because of this high-risk clinical scenario, women with persistent high-risk HPV infection should be managed with active surveillance and treatment, as indicated.

HPV and cervical cytology cotesting allows a clinician to better individualize management and determine if there is progression to CIN 2+ or likely regression. Some clinical examples include:

● If a patient had normal cytology in the past and now has persistent HPV positivity and cytology with low-grade squamous intraepithelial lesion (LSIL), a clinician should be suspicious that this patient is going to have CIN 2+ disease at some time in the future. This patient has three likely outcomes: progression, continued equivocal results, or regression. There are no good surrogate testing markers to predict the direction the infection and disease will take. The patient should be evaluated with colposcopy, and if the results are negative or CIN, should be followed with active surveillance.

● Conversely, if a patient had HPV-positive testing and LSIL in the past and her last set of testing is HPV negative and negative cytology, then she is likely going to improve and her chances of CIN 2+ in the near future are very small.

Persistent HPV-positive, low-risk cytology, negative colposcopy

This clinical scenario is common and frustrating (to both patient and clinician). It is important that a vaginal colposcopy be performed in these women. However, if that is negative, patients may still be at risk of disease progression and active surveillance remains prudent. Only a small percentage of these patients will progress, but there are no clinical markers to predict progression.

HPV GENOTYPING

HPV 16- or 18-positive

HPV genotyping positive for strains 16 and/or 18 signals a high risk of current or future high-grade cervical neoplasia. This result is an indication for immediate referral to colposcopy and should supersede other testing, even if the patient's cytology is negative or atypical squamous cells of undetermined significance (ASC-US). In fact, the risk of clinically relevant disease in the setting of HPV 16 is higher than most risks associated with severely immunocompromised patients without HPV 16.

Other relevant high-risk HPV types

There are a number of non-16/18 HPV types that are associated with cervical cancer. HPV 16 and 18 have the highest risk, and the remainder carry risk, but not as high as 16/18. As such, continued active surveillance is recommended, unless the cytology warrants immediate colposcopy. Some labs use a test that has a combined HPV 18/45 endpoint instead of just HPV 18. HPV 45 is associated with approximately 3.7 percent of cervical cancers and has nearly, but not equal to, the risk with HPV 16 or 18.

HPV-NEGATIVE CYTOLOGY UNSATISFACTORY 

Cervical cytology reported as unsatisfactory must be repeated even if the result is also HPV negative. An unsatisfactory cervical cytology specimen is considered unreliable for the evaluation of epithelial abnormalities. Scant cellularity may result in a false-negative HPV test. Management of this result is shown in the algorithm 3. 

Source: Mark H Einstein, MD; UpToDate: Human papillomavirus testing of the cervix: Management of abnormal results; last updated: Jun 17, 2019