The Cervical Cancer Incidence And Burden

Published Date: 02 Nov 2017

The role of HPV DNA testing in clinical practice

Clinical brief

Katherine Hung* BSc, MSc, BScPharm Candidate

*Corresponding author. Contact E-mail: [email protected]

Word Count:

This manuscript is original, is not under consideration by another journal, has not been previously published, and has been approved by all authors

Cervical cancer incidence and burden

Each year approximately 550 000 Canadians are affected by human papillomavirus (HPV) infection <1>. HPV is a sexually transmitted virus and its prevalence increases sharply after sexual debut <1>. Of the more than 100 types of HPV involved in human disease, approximately 30 different HPV genotypes preferentially infect the anogenital and oral mucosa <1>. HPV is categorized according to the propensity of the lesions that they cause to progress to malignancy. Low-risk viruses (e.g. types 6 and 11) cause benign mucosal warts that usually regress with time. In contrast, infection with high-risk HPVs (e.g. types 16, 18) can cause epithelial lesions that often progress to invasive cell carcinomas in the absence of early detection and treatment. Cervical cancer remains the second leading cause of cancer-deaths in women worldwide. Most HPV infections are cleared or suppressed by a healthy immune system within 1-2 years of exposure and the rate of carcinogenic progression is relatively low <2>. In a small fraction of cases however, persistent infection with the same high-risk HPV type can lead to epithelial abnormalities that progress to invasive carcinoma <3>. Progression from dysplasia to precancerous lesions and invasive carcinoma generally takes 10-20 years <4>. Over 99.7% of all cervical cancer biopsies contain HPV DNA <5>. It is now widely accepted that human papillomaviruses are the cause of nearly all cervical cancers, with HPV 16 and 18 accounting for 70% of all cases <2>.

Current strategies for cervical cancer prevention

Given the strong casual link between cervical cancer and infection with high-risk HPV genotype, early detection through organized screening programs has allowed detections of precancerous lesions early, allowing immediate treatment and minimizing progression of these lesions to invasive carcinomas. One of the most widely used screening methods is a cytology based test, the Papanicolaou test or "Pap smear" developed in 1943. Prior to its use to regularly screen for cancerous lesions, cervical cancer used to be the leading cause of death for women in North America <6>. Since its implementation into regular screening programs, it has proven to be a highly effective tool that has resulted in a dramatic decline in the number of deaths associated with cervical cancer.

Currently two prophylactic vaccines are available in Canada that offer protection against infection with HPV 6, 11, 16 and 18 –Gardasil and Cervarix <7>. Because these vaccines do not protect against all HPV types that can cause cancers, it becomes critical for women who have not been vaccinated or who are already infected with HPV should continue to be screened regularly.

There are however limitations with cytology-based screening. Clinical sensitivity of the Pap Smear is modestly 60-70% <8>, and its reliance on visual identification and subjective identification of morphologic changed induced by HPV results in high false-negative rates <8,9>. Consequently, 10-15% of women with equivocal (atypical squamous cell of undetermined significance [ASC-US] or mildly abnormal (low grade squamous intraepithelial lesions [LSIL] Pap results have underlying precancerous lesions (cervical intraepithelial neoplasia grade 3 or CIN3) <10,11>. As a result, the success of the Pap Smear is due, in part to frequent repeat testing. In an era of HPV-vaccinated populations, the reduction of CIN2+ will likely be much greater than the reduction of low-grade abnormalities, further decreasing the signal-to-noise ratio of cytology testing <12>. The increased economic burden on the healthcare system associated with excessive screening and complications of unnecessary treatment, warrants the use of more efficient approaches to cervical cancer prevention.

Introduction to HPV-DNA testing

Research and development in molecular technologies over the past two decades have led to the availability of novel screening tests that provide substitute primary or adjunctive methods to cytology. The development of HPV-DNA based screening assays provide a biologically salient approach to screening since virtually all cervical cancers contain the genes of high-risk HPVs. Current methods utilize signal amplification technology to report detect the aggregate presence or absence of oncgoenic HPV DNA, and are not genotype-specific. Both Health Canada and the FDA have approved use of Digene Hybrid Capture 2 (HC2) assay (by Qiagen) for HPV-DNA testing.

The primary benefits of this method is high sensitivity and high negative predictive value, as well as better reproducibility than cytology <6,13>. It is less likely to miss precancerous and cancerous lesions, and the absence of carcinogenic HPV types represent a low risk of CIN3 or ICC <13>. High sensitivity to infection not only improves detection resulting in early treatment, but also would allow for safe prolonging of screening intervals. In comparison to cytology, its lower specificity for disease, specifically CIN3+ and CIN2+ may lead to higher rates of false-positives. Since the majority of HPV infections are transient, there is potential for harm done through unnecessary treatment of lesions that have a high probability of regressing spontaneously, psychological burden, and invasive follow-up tests.

Implementation of HPV DNA testing in clinical practice: a staged approach

Several large randomized controlled studies over the past decade have evaluated the role of HPV DNA testing in comparison to cytology as an alternative to cytology in primary screening or as an adjunctive screening tool.

Canada vs. US

HPV infection and translating the connection to health practice and poliy