Although risk is measured on a continuous scale, risk thresholds are important for clinical management. Importantly, the perception of risk may differ in different situations and societies. Therefore, risk thresholds are not absolute, but they are tied to a certain societal perception of risk and are often reflective of established clinical practice.

Cervical cytology has played an important role in defining risk thresholds for cervical cancer screening and for management of abnormal screening results. Traditionally, women with LSIL and high-grade squamous intraepithelial lesion (HSIL) cytology results have been referred for colposcopic evaluation (Fig. 12.2) [2]. ASCUS cytology results have posed a challenge to clinical management, since the interpretation of ASCUS is an abnormal cytology result, but with a lower aggregate risk of cervical precancer compared to LSIL or HSIL. Thus, the PPV or posttest risk of ASCUS is not high enough to refer women to colposcopy. In the ASCUS-LSIL Triage Study (ALTS), three management strategies for women with ASCUS cytology results were evaluated: immediate referral to colposcopy, repeat cytology, and triage with high-risk HPV (hrHPV) testing [10]. The trial demonstrated that hrHPV-positive ASCUS has a very similar risk to LSIL and led to recommending HPV testing for triage of ASCUS (ASC-US after the 2001 Bethesda update) cytology results [11, 12]. This is an early example of a systematic application of the “similar risk-similar management” principle in cervical cancer screening and management guidelines.

The risk of cervical precancer associated with a LSIL cytology result or an HPV-positive ASC-US cytology result is used as a risk benchmark for colposcopy referral. Other benchmarks have been defined accordingly. In the 2012 US screening guideline update, 3-year screening intervals were recommended for women with a negative cytology result [13]. Thus, the risk benchmark for 3-year rescreening is a risk level equivalent to a negative Pap result [7]. Similarly, a 12-month repeat cytology is an accepted management for an ASC-US cytology result (with unknown HPV result). Consequently, the risk benchmark for a 6–12-month return is a risk level equivalent to an ASC-US Pap result (Fig. 12.2).

The same benchmarks can be used for primary screening and for management of abnormal screening results, since risk of cervical cancer is driving all clinical decisions. The risk benchmarks used for the 2012 American Society of Colposcopy and Cervical Pathology (ASCCP) updates to formulate the management guidelines for abnormal cervical cancer screening results were largely based on 5-year risk of histologic HSIL (CIN3) or greater observed in a cohort from the Kaiser Permanente Northern California, a large integrated health care organization with a population of over one million women screened with co-testing over 10 years [7].

While the absolute risk estimates for cervical cancer screening results may differ between populations, the relationship between the risk groups is very consistent, e.g., the aggregate risk for diagnosing histologic HSIL (CIN3+) in patients with cytologic LSIL is higher than that of those with cytologic ASC-US (HPV unknown) in most populations.

An important advantage of developing screening and management recommendations based on risk thresholds is that new assays can be integrated into current recommendations more easily based on risk equivalence studies. As noted above, the absolute risk thresholds among populations may vary; therefore, risks of precancer and cancer with new assays must either be specific to a population with established threshold-specific risks or risks at established benchmarks. For instance, the risk of precancer for a cytologic result of LSIL must be established for the population in which the new assay is validated.

Cytology has been the mainstay for cervical cancer screening for decades and has led to substantial reduction in cervical cancer incidence in countries with screening programs. Our now remarkable understanding of HPV and cervical cancer natural history has brought new tools for cervical cancer prevention, including HPV vaccines for primary prevention, HPV testing for screening, and various molecular assays for detection of cervical precancers [14, 15]. These new options have been progressively introduced in the United States over the last decade. The first major change from cervical cytology-only screening came in the early 2000s with the addition of HPV reflex testing in cases interpreted as ASCUS [10, 16]. Another major change then occurred in 2002 when HPV testing in combination with cytology was proposed for the first time as a primary screening option compared to cytology alone [17] and was designated as the preferred method of screening in the over 30 years of age population in 2012 [13]. In 2014, the FDA approved an indication for primary HPV testing alone for a previously approved HPV test [1].

It is very instructive to evaluate the different cervical cancer screening options in the context of risk-based management (Fig. 12.3):