American Society for Colposcopy and Cervical Pathology

Cervical cancer is one of the most common gynecological malignancies. Upregulation of programmed death ligand-1 (PD-L1), an immunoregulatory protein, is associated with an adverse outcomes in several malignancies. Most studies evaluating PD-L1 expression in cervical squamous cell carcinoma (CSCC) lack data on outcomes. In this study, we correlate PD-L1 expression with clinicopathologic factors and clinical outcomes in invasive CSCC. Seventy-three cases of CSCC from 2010 to 2018 were immunostained for PD-L1. A combined positive score (CPS) of ≥1 and ≥10 was correlated with age, stage, and survival outcomes. Kaplan-Meier curves for progression-free survival and overall survival were plotted and compared using the log-rank test. Cox regression analysis was performed to identify significant prognostic factors (2-tailed P <0.05 was considered statistically significant). With CPS ≥1 or ≥10 as the cut-off, PD-L1 was positive in 52/73 (71.2%) and 23/73 (31.5%) of cases, respectively. PD-L1 positive patients present at a higher stage of disease, especially those with CPS ≥10. With CPS of ≥10 as the cut-off, the 5-yr progression-free survival and 5-yr overall survival were significantly lower ( P = 0.034 and 0.012, respectively). Only stage was statistically significant for worse overall survival on multivariate analysis. PD-L1 positive patients present at a higher stage of disease, and stage is an independent prognostic indicator for adverse outcomes in CSCC. This study highlights the potential of PD-L1 targeted therapy in patients with CSCC.

In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology or cotesting (cytology in combination with high-risk HPV (hrHPV) testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective US-based registration study. Thirteen experts including representatives from the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the FDA for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for health care providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation.

“The code is more what you’d call ‘guidelines’ than actual rules” [Captain Hector Barbossa to Miss Elizabeth Swann, in Pirates of the Caribbean, 2003] Interim consensus guidance for cervical cancer screening using primary high-risk human papillomavirus (hrHPV) testing has now been copublished ahead of print by the Journal of Lower Genital Tract Disease, Obstetrics & Gynecology, and Gynecologic Oncology.1 The guidance states that using primary hrHPV screening is now acceptable, by a test that uses polymerase chain reaction and nucleic acid hybridization for the detection of 14 high-risk HPV types in a single analysis. The test result is either negative or positive for HPV-16 and HPV-18 (16/18), or the 12 other high-risk types in a pooled analysis. The US Food and Drug Administration approved the test in April 2014 for primary cervical cancer screening in women aged 25 years or older. The change in guidance acknowledges age-based alternative primary screening paradigms: cervical cytologic test alone, cotesting, and hrHPV test alone. Frontline clinicians and women may find themselves adrift in a sea of change. Many women and providers have not yet adapted to the prior guidance that recommended 3-year and 5-year intervals for screening after negative cytologic test results alone and cotesting results, respectively.2–5 Many patients still cling to the notion of an annual Papanicolaou test. With alternative screening regimens, there could be confusion. Since the patients’ experience is the same whether they have a cytologic test, hrHPV test, a cytologic/hrHPV cotest, or a speculum examination without screening, it will be important to explain to patients what tests were done and the future plan of care, in case the patient moves to another provider in the interim. Beyond the provision of essential information, education, informed consent, and greater patient empowerment will be critical for a flourishing system in support of universal cervical cancer screening. The specimen used for the hrHPV screening test must be collected in the usual way, with a speculum, spatula, and brush, with the obtained adequate amount to be placed in liquid medium. In this way, if the hrHPV is positive but genotyping is 16/18 negative, the specimen would contain the cells needed for a reflex cytologic examination. As of this writing, the thousands of providers use a variety of collection techniques and specimen solutions.6 Moreover, the myriad of laboratories have a variety of hrHPV tests and have not created the ordering test names and codes for the stepped testing algorithm of hrHPV screening that would include reflex cytology if the hrHPV was positive for the 12 other high-risk types in pooled analysis. Providers would receive 1 of 4 possible laboratory reports after ordering a primary hrHPV screen with reflex cytology: (1) negative hrHPV, (2) positive hrHPV, negative 16/18, and negative for intraepithelial lesion or malignancy cytology, (3) positive hrHPV, positive 16/18, or (4) positive hrHPV, negative 16/18, and abnormal cytologic result. The new interim guidance for primary hrHPV testing states that women can wait at least 3 years before retesting after a negative hrHPV screen. According to prior consensus management guidance and algorithms,3 patients older than 30 years with negative for intraepithelial lesion or malignancy cytologic result, who are hrHPV positive but HPV-16/18 negative should have cotesting in 12 months. Patients in aforementioned categories 3 and 4 should have a colposcopy examination.3 Some questions remain unanswered. There is a possibility of hrHPV-negative result and existing cervical intraepithelial neoplasia 3+ in the patient; large prospective trials are needed to define this risk and provide more evidence for the appropriate screening intervals. The colposcopy rate associated with primary hrHPV screening has not been established, and colposcopy was defined as harm in the most recent national screening guideline.2 Whether the “real-life routine practice conditions” cost of testing and follow-up might be higher or lower with primary hrHPV testing is not known. Among populations with different prevalence, it is not known how the positive and negative predictive values might change. Are there additional benefits or harms with cotest screening versus primary hrHPV screening? The reported improved detection rates for atypical glandular cells and adenocarcinoma in situ need to be verified. Future research includes the current HPV FOCAL Trial, designed to establish the efficiency of testing for hrHPV as primary screening and as triage in 3 arms. In all 3 arms, cervical intraepithelial neoplasia 3+ is the outcome of interest.7 What is clear is the objective to screen and prevent cervical cancer. Better primary prevention will be achieved by more widespread uptake of HPV vaccination. Secondary prevention involves screening and management of selected patients with abnormal screening results. Current unmet needs include universal access to screening services and identifying and screening eligible women either never or rarely (less than every 5 years) screened who bear the greatest burden of cervical cancer morbidity and mortality. Jeff Andrews, MD, FRCSC American Society for Colposcopy and Cervical Pathology Bethesda, MD Editor-in-Chief

It has been barely 5 years since medicine and public health gained an extraordinary new weapon for preventing cervical cancer, one of the most important neoplastic diseases of women worldwide and a major cause of premature female death in developing countries. The two commercially available vaccines against human papillomavirus (HPV) infection are very effective in preventing infections with the two major cancer-causing genotypes, HPV-16 and HPV-18, and the cervical precancerous lesions that originate from such infections. The clinical trial data are among the strongest of any new vaccines, their safety meets today's standards of low tolerance to risk of adverse events, and protection seems to extend at least to 10 years and probably well beyond. One of the approved vaccines adds protection against two other HPV genotypes (HPV-6 and HPV-11) that cause genital warts and respiratory papillomatosis, diseases that bring substantial suffering and stigmatization to those affected. Both vaccines seem to protect also against other HPV genotypes that are closely related phylogenetically to HPV-16 and -18, although the duration of that protection remains to be established. Clinical trials of men and mid-adult women have also shown promising results. At least one country, Australia (an early adopter of publicly funded HPV vaccination), has already begun to reap the benefits of HPV vaccination via reductions in rates of cervical abnormalities and genital warts.

: Editor's Note: This guideline was first published in The Colposcopist in January 1996 and reflected the peer-reviewed literature available on the management of ASCUS at that time. The decision to republish this guideline in The Journal of Lower Genital Tract Disease, to accompany guidelines on the management of low-grade squamous intraepithelial lesion (LGSIL) and benign cellular changes (BCC) was made to complete the set of guidelines in the Journal pertaining to management of the cytology screening system. (See also previous guidelines on Management Issues Related to the Quality of the Smear, Management of Atypical Glandular Cells of Undetermined Significance (AGUS), and the Abnormal Pap Follow-up System.) Our original intention was to update the ASCUS guideline for this publication in the expectation that the data from the enrollment phase of the National Cancer Institute's ASCUS LGSIL Triage Study (ALTS) would be available to provide relevant evidence-based recommendations. The unavailability of this data at this time has ensured a later update of the ASCUS guideline. However, an accumulating body of new literature, particularly on the clinical utility of HPV testing with Hybrid Capture II (Digene Corp., Gaithersburg, MD), will be incorporated within the next year with the enrollment ALTS data in a new ASCUS guideline. Until that time, the guideline presented here remains the recommendation of the ASCCP, based on the review of the literature at that time, and on the collective experience and knowledge of the ASCCP Practice Committee and the Board of Directors.The cost analysis in this guideline is based upon a set of cost assumptions which will vary from setting to setting. This analysis is intended to serve as a reference for average costs in a fee-for-service setting. The individual practitioner will need to analyze cost differentials for his/her own setting.This guideline reflects emerging clinical and scientific advances as of February 1996, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed.

President, American Society for Colposcopy and Cervical Pathology, and Department of Obstetrics and Gynecology, University of Arizona, Tucson, AZ Reprint requests to: Dr. Kenneth D. Hatch, Department of Obstetrics and Gynecology, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724.