Understanding the association between persistent cervical infection with high-risk human papillomavirus (HPV) and the development of cervical cancer and its immediate precursor lesion, cervical intraepithelial neoplasia grade 3 (CIN3), is fundamental when underwriting cases where HPV is present. The addition of HPV testing to cytology-based cervical screening has significantly increased the detection of prevalent CIN3, with a concurrent decrease in CIN3+ or cancer detected in subsequent/follow-up screening. Across studies, a positive HPV test is the strongest independent predictor of recurrent disease or progression to invasive cancer. As such, underwriting guidelines that consider HPV test findings are critical for prudent underwriting decision-making when assessing cervical screening results. Current clinical cervical screening guidelines, however, should not be changed on the basis of HPV vaccination status due to a lack of empirical data concerning the age when screening is to be initiated or the screening interval for women who have been vaccinated.
Cervical cancer is the fourth most common cancer among women and second most common female-specific cancer, with human papillomavirus virus (HPV) genotypes 16 and 18 accounting for more than 70% of the world’s cervical cancer cases.1,2 Over the past 50 years, cytology-based screening (Papanicolaou or Pap test or smear) has been used routinely to screen women for precancerous or cancer cells in the cervix. Pap tests can detect cervical cancer and precancerous cells in the early stages, and the screening process has proven to be highly effective in reducing the number of deaths from squamous cell cervical cancer, which makes up 80% to 90% of cervical cancers3-5.
While the Pap test can detect abnormal cell changes, testing for HPV detects the viral infection that can cause the abnormal cell changes prior to the development of cancer. Importantly, numerous studies have shown that screening for HPV leads to earlier detection of cervical intraepithelial neoplasia (CIN) than cytology. Accordingly, the U.K., Australia and several countries in Europe have introduced HPV primary screening into their national screening programs6. This article discusses the important role HPV testing plays in cervical cancer screening, changes to the screening guidelines with HPV as a primary screening tool, and its direct impact on the way Pap smear results are currently underwritten in an insurance setting.
Studies have confirmed that persistent cervical infection with high-risk human papillomavirus (HPV) is necessary for the development of cervical cancers (both squamous and adenocarcinoma) and its immediate precursor lesion, cervical intraepithelial neoplasia grade 3 (CIN3)7,8.
Currently, more than 100 HPV genotypes have been identified9. The two high-risk HPV genotypes responsible for about 70% of all cases of cervical carcinomas are HPV 16 and HPV 1810,11,12,13, with one study observing 74% of squamous cell carcinomas and 78% of adenocarcinomas testing positive for either type14. HPV 16 accounts for approximately 55% to 60% of all cervical cancers while HPV 18 accounts for approximately 10% to 15%. Approximately 10 other HPV genotypes cause the remaining 25% to 35% of cervical cancers7,8,15.
The majority (~90%) of HPV infections are transient and become undetectable within one or two years16,17. Infections which are persistent have a high risk of developing into precancerous lesions. For example, a persistent two-year infection of HPV 16 strongly predicts CIN3 or a more severe diagnosis (CIN3+) in the following years (i.e., 20% to 30% risk of CIN3+ over five years for one-year or two-year persistent HPV 16). If left untreated, CIN3 has a 30% probability of becoming invasive cancer over a 30-year period. However, if treated, only approximately 1% will become invasive18.
There are multiple nomenclatures for reporting HPV-associated lesions. Starting in the mid-1960s, premalignant squamous changes of the cervix were classified as mild, moderate, or severe cervical dysplasia. Dysplasia is a lesion in which part of the thickness of the epithelium is replaced by cells showing varying degrees of atypia (i.e., structural abnormalities).
In 1988 the Bethesda system was introduced. In this system, which underwent revisions in 1991 and 2001, different terminology was used for cytologic (Pap test) and histologic (biopsy) findings. Cytologic findings were described with the term “squamous intraepithelial lesion (SIL)” whereas histologic findings were described with the term “cervical intraepithelial neoplasia (CIN)”19. The term “cervical intraepithelial neoplasia” (CIN) was originally introduced by Richart to present the concept of cervical neoplasia as a disease continuum20.
In 2012, the Lower Anogenital Squamous Terminology (LAST) consensus project
was convened to reassess and harmonize the biopsy and cytology terminology used
to report HPV-associated squamous lesions of the lower anogenital tract. The LAST nomenclature, which is now the global standard, relies on HPV 16 staining (though not routinely recommended) to triage CIN2. CIN2 with HPV 16-positive is classified as CIN3, representing a high-grade squamous intraepithelial lesion (HSIL), the immediate precursor to cervical cancer. In contrast, CIN2 with HPV 16-negative is classified as CIN1, representing a low-grade squamous intraepithelial lesion (LSIL), the histologic sign of HPV infection21,22.
Table 1: Histology and Cytology Terminology
* Per LAST nomenclature, CIN2 with HPV 16-negative test is considered as LSIL.
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