By Mitchell Linder, MD
Assistant Professor, Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Strong Memorial Hospital, Rochester, NY
Dr. Linder reports no financial relationships relevant to this field of study.
According to the World Health Organization’s most recent reporting, cervical cancer is the fourth most common malignancy in the world. In 2018, there were 12,831 new cases in the United States and 4,207 patients who died of cervical cancer. This amounts to eight new cervical cancer cases per 100,000 women per year. Looking more broadly, an estimated 579,000 women were diagnosed worldwide, and there were 311,000 deaths.1 Nine-tenths of the worldwide deaths attributed to cervical cancer come from developing countries.1
Despite its current prevalence in the care of patients, the Pap smear has been used for less than 100 years. The Pap smear test was first developed and reported by Dr. Georgios Papanicolaou in the 1940s.2 Despite initial enthusiasm in the medical community, it was not until 1957 that annual cytologic screening was advocated by the American Cancer Society (ACS) and then by the American College of Obstetricians and Gynecologists (ACOG) in 1975. The next major advancement in the field of screening came in the late 1970s and early 1980s with the identification that the human papilloma virus (HPV) and, eventually, more specifically that HPV 16 and 18 were responsible for the large majority of squamous cell carcinomas of the cervix.3
Over time, efforts were undertaken to consolidate disparate terminologies and provide a common language in reference to cytologic and pathologic specimens. This included the introduction of the Bethesda naming system in 1988, which has been updated over time, most recently in 2014.4
Since the year 2000, there have been multiple progressive cycles of updates to both screening and management guidelines as the result of our rapidly evolving understanding of HPV regarding its prevalence, mechanism of action, and its time course for carcinogenic transformation. This new understanding, coupled with the introduction of the initial quadrivalent HPV vaccine series (2006) and then the expansion to a 9-valent vaccine (2014), has worked to refine those guidelines to strike the right balance for testing frequency in regard to benefits and harms.
The most recognized and implemented screening guidelines were published most recently in 2012 as a joint effort by the American Society for Colposcopy and Cervical Pathology (ASCCP) in conjunction with the ACS and the American Society for Clinical Pathology.5 This strategy relied on cervical cytology testing, with and without HPV testing, based on patient age. In 2015, these received a needed update to incorporate new testing technologies, such as primary HPV testing. Since that time, the United States Preventive Services Task Force and the ACS each has released its own recommendations that increasingly are inclusive of primary HPV testing.6,7 Each of these provides slight variations on testing strategies, depending on what is available to the individual practitioner.
Although there are a variety of similar but not exactly overlapping screening recommendations, when it comes to management, ASCCP has produced the definitive guidelines. The seminal publication of strategies for how to handle abnormal test results was in 2012. Earlier in 2020, ASCCP, in conjunction with the National Cancer Institute, published their updated management guidelines.8
This new management update brought a paradigm shift regarding how abnormal results are treated. Previously, management of results was based on a generic algorithm dictated by the patient’s age, pregnancy status, and, most importantly, the cytology/HPV screening results themselves. Although this was a very straightforward and accessible way to provide management direction, it failed to take into account prior patient history and to provide a customized recommendation based on that particular scenario. In addition, as new testing technologies emerge, including primary HPV testing, these need to be able to be added to allow for appropriate management recommendations. The newly published management guidelines attempt to improve those prior algorithms by incorporating the patients’ prior results in an effort to create individualized risk estimates.9
The generalized principle for the new guidelines takes the current patient results in conjunction with prior results to determine the immediate risk of cervical intraepithelial neoplasia (CIN) 3+ being present and/or the five-year risk of CIN 3+ (if the immediate risk is low). Then, it uses that risk as the marker on which to base recommendations for management strategies. Simply put, using large-scale data models, the guideline authors created clinical action thresholds where, after a patient is estimated to have an X% immediate or five-year risk for CIN 3+, the recommendation always would hold true. Having these clinical action thresholds will allow for future integration of new testing options as they become available. The clinical thresholds themselves will not change, just the means by which the specimen was collected/tested.10
The important clinical action threshold to understand for this is 4%. If a 4% or greater immediate risk of CIN 3+ is calculated, then the recommendation will be to proceed for further evaluation (and possible treatment.) On the other hand, if the risk is < 1% for CIN 3+ in a five-year timeframe, then the recommendation will be to perform some type of retesting surveillance. What combination of factors came together to create that calculation (a long history of abnormal results vs. a particularly high result on one test vs. some other sequence of events) is immaterial regarding this risk-based management strategy. The simple fact is that the calculated risk (immediate risk of CIN 3+ is ≥ 4% or < 1% in the next five years) is the driving factor. There may be some situations where the risk is in between 1% and 4%. In these circumstances, clinical judgment may be indicated.
Outside of the large shift in the basis of how recommendations are crafted, there were other changes of note in this new set of management guidelines. One of these is related to management of certain first-time abnormal results (low-grade changes after prior negative screens) that previously would have been recommended for immediate colposcopy that can now be followed with repeat testing in one year instead (because of the low risk of CIN 3+ over time). This more conservative approach extends to the preferred treatment for CIN 1 results on colposcopic-directed biopsies as well.
Another change involves increasing the amount of time surveillance is recommended following treatment of high-grade lesions from 20 years post-treatment to 25 years post-treatment. In addition, the guidelines outline that excisional treatments are preferred over ablative treatments for high-grade lesions. The new recommendations also provide increased clarity regarding who should receive expedited treatment (i.e., skipping colposcopy and going directly to an excisional procedure). Each of these refinements helps to create a more standard approach to the care of the patient with abnormal cervical results.
A major issue with having a risk-based algorithm is the complexity of the data tables required to assess any patient’s specific risk because of the need for comparison to similar cases in a large database. As such, gone are the beloved PDF flow diagrams that had been the mainstay of the 2012 guidance. In their place, ASCCP has developed an app that allows providers to input patient information about current and prior results and then calculates risk based on the input. Recently, they also made a web-based tool available as well.
As our collective knowledge regarding HPV and cervical cancer continues to evolve at a rapid pace, it is comforting to know that efforts in refining the guidance about screening and management of results also are working to keep up. Future directions may include starting to develop a clearer picture on whether patients who received the HPV vaccine series need the same guidelines for screening and management as patients who did not, and further incorporation/adoption of primary HPV testing as the standard of care.
REFERENCES
- Arbyn M, Weiderpas E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018: A worldwide analysis. Lancet Glob Health 2020;8:e191-e203.
- Shaw PA. The history of cervical screening I: The Pap. test. J Soc Obstet Gynaecol Can 2000;22:110-114.
- Kauffman RP, Griffin SJ, Lund JD, Tullar PE. Current recommendations for cervical cancer screening: Do they render the annual pelvic examination obsolete? Med Princ Pract 2013;22:313-322.
- Nayar R, Wilbur DC. The Pap test and Bethesda 2014. Cancer Cytopathol 2015;123:271-281.
- Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013;17(5 Suppl 1):S1-S27.
- US Preventive Services Task Force; Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2018;320:674-686.
- Fontham ET, Wolf AM, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J Clin 2020; Jul 30. doi: 10.3322/caac.21628. [Online ahead of print].
- Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2020;24:102-131.
- Egemen D, Cheung LC, Chen X, et al. Risk estimates supporting the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis 2020;24:132-143.
- Cheung LC, Egemen D, Chen X, et al. 2019 ASCCP risk-based management consensus guidelines: Methods for risk estimation, recommended management, and validation. J Low Genit Tract Dis 2020;24:90-101.
