Human papillomavirus vaccination history and diagnosis of cervical intraepithelial neoplasia grade ≥2 severe lesions among a cohort of women who underwent colposcopy in Kaiser Permanente Southern California.

BACKGROUND: The risk of a high-grade lesion in women undergoing colposcopy following an abnormal screening result may be different by human papillomavirus vaccination status, because women who are vaccinated are presumably less likely to harbor human papillomavirus types 16 and 18. OBJECTIVE: This study aimed to evaluate whether the risk of high-grade cervical lesion diagnosed through colposcopy is lower in women with human papillomavirus vaccination than in women without vaccination referred to colposcopy based on equal abnormal screening findings. STUDY DESIGN: Kaiser Permanente Orange County female patients between ages 21 and 38 years were included following an abnormal screening if they had ≥1 colposcopies between July 2017 and August 2018 and had at least 1 pathology diagnosis from the colposcopy visits. Data on demographic characteristics, clinical and sexual histories, and human papillomavirus vaccination were collected using a colposcopy registry smart form and from electronic medical records. Human papillomavirus genotyping was performed for tissues from confirmed cervical intraepithelial neoplasm grade 2+ diagnoses. A multilevel generalized linear model with a logic function was used to evaluate the association between human papillomavirus vaccination history and the outcome of a cervical intraepithelial neoplasm grade 2+ diagnosis and for human papillomavirus type 16- or 18-positive cervical intraepithelial neoplasm grade 2+ as an alternative outcome, adjusting for screening results and potential confounders. RESULTS: Of 730 women included in the study, 170 had a histologic diagnosis of cervical intraepithelial neoplasm grade 2+ (23.2%). Moreover, 68 cases (40.0%) were histologically human papillomavirus type 16 and/or 18 positive. Of the 730 women, 311 (43%) were vaccinated for the human papillomavirus before colposcopy. Most women (206 [66.2%]) with human papillomavirus vaccination received the vaccine between the ages 18 and 26 years. A history of human papillomavirus vaccination overall, before sexual debut, before the age of 18 years, or with complete dosing was not associated with lower odds of a cervical intraepithelial neoplasm grade 2+ diagnosis (odds ratio, 1.07 [95% confidence interval, 0.70-1.64]; odds ratio, 1.11 [95% confidence interval, 0.55-2.24]; odds ratio, 0.96 [95% confidence interval, 0.49-1.91]; and odds ratio, 0.84 [95% confidence interval, 0.53-1.35], respectively, in reference to no vaccination). Human papillomavirus vaccination history was not significantly associated with the odds of a human papillomavirus type 16- or 18-positive cervical intraepithelial neoplasm grade 2+ diagnosis (P=.45). Notably, 8 cases (4.8% of all cervical intraepithelial neoplasm grade 2+ cases) showed a human papillomavirus type 16 on a cervical intraepithelial neoplasm grade 2+ histologic polymerase chain reaction analysis despite reported or documented human papillomavirus vaccination before sexual debut, including 2 cases who started vaccination before the age of 13 years. CONCLUSION: Our study did not support modifying the colposcopy management guidelines for abnormal screening results for women with human papillomavirus vaccination, especially those vaccinated in the catch-up age range. Our findings on the 8 cases of human papillomavirus 16-positive cervical intraepithelial neoplasm grade 2+ vaccination before sexual debut suggested that lowering the recommended age for human papillomavirus vaccination may have additional benefits for preventing human papillomavirus infection that could occur early in life in some women.

Patterns and correlates of cervical cancer screening initiation in a large integrated health care system.

BACKGROUND: The latest 2012 US Preventive Services Task Force cervical cancer screening guidelines recommended screening initiation at age 21 years. Little is known about the cervical cancer screening initiation practices in the community and whether there are critical gaps with respect to adherence to current clinical guidelines. Despite an overall decline in cervical cancer incidence across women of all ages, the incidence rate has not declined among 24-25 year olds between 2000 (2.79 per 100,000) and 2013 (2.93 per 100,000). Thus, it is important to understand cervical cancer screening initiation in young women and how woman- and provider-level factors affect the timing of screening initiation to identify areas for improving cervical cancer prevention. OBJECTIVE: We examined patterns and correlates of cervical cancer screening initiation among women turning age 21 years in a large community-based practice. STUDY DESIGN: Female members of Kaiser Permanente Southern California who turned age 21 years (baseline) during 2013-2015 and had not previously received a Papanicolaou test were included. Cervical cancer screening initiation through October 2016 was captured using electronic health records. Incidence rate and cumulative incidence of screening initiation was calculated. Associations between patient and provider characteristics and screening initiation were evaluated using multivariable Cox models. RESULTS: A total of 38,257 women were included and the Papanicolaou screening initiation rate was 44 per 100 person-years during the study period. Approximately 40% initiated screening within 1 year after turning age 21 years. In multivariable analyses, Asian/Pacific Islanders (hazard ratio, 0.91; confidence interval, 0.86-0.96 compared with non-Hispanic whites); Medicaid enrollees (hazard ratio, 0.90; confidence interval, 0.83, 0.97); those whose primary language is not English (hazard ratio, 0.71; confidence interval, 0.67, 0.75); those who have a historical inpatient visit, primary care physician in pediatrics, internal medicine, or another specialty compared with family practice; and have a male rather than female primary care physician (hazard ratio, 0.46; confidence interval, 0.36, 0.57) less often initiated screening. On the other hand, those who used other preventive services such as getting a human papilloma virus and influenza vaccination and those with a history of pregnancy, contraception use, and sexually transmitted infections more often had timely screening initiation. CONCLUSION: Less than half of the women insured for preventative services initiated screening at age 21 years. Strategies to improve adherence to screening initiation guidelines should consider a tailored approach for at-risk subgroups and addressing initiation challenges associated with male physicians.

Prevalence of hair shedding among women.

Hair shedding in female patients is a frequent complaint in dermatological, endocrinological, and gynecological consults. Previously, the Sinclair Hair Shedding Scale was developed to assess normal versus excessive hair shedding in female pattern hair loss (FPHL) subjects. However, the prevalence of hair shedding in females not suffering from FPHL is unknown. To gain better understanding of hair shedding in the general population, we recruited 300 subjects visiting a public hospital for conditions other than alopecia. Of the 300 subjects recruited, 263 did not suffer from FPHL. Among those subjects, approximately 40% reported experiencing excessive hair shedding (as defined by the Sinclair Hair Shedding Scale) on hair washing days. In comparison, in our subject population, approximately 60% of subjects with FPHL reported excessive hair shedding on hair washing days. To best of our knowledge, this is the first study to quantify the prevalence of hair shedding in women. While, no treatment currently exists for this condition, we hope that this study would encourage physicians and researchers to address this frequent concern.

Contribution of Exocervical Biopsy, Endocervical Curettage, and Colposcopic Grading in Diagnosing High-Grade Cervical Intraepithelial Neoplasia.

OBJECTIVE: To determine the utility of random biopsy and endocervical curettage (ECC) during colposcopy among women who ultimately underwent cervical excisional biopsy. MATERIALS AND METHODS: In a retrospective observational study, the charts were reviewed of every patient who underwent cervical excisional procedure performed between June 2010 and August 2011, including the antecedent colposcopic examination and any pathological specimens. A random sample of 15% all pathologic specimens was reviewed. Practice of biopsy, use of ECC, demographic factors, referral cytology results, lesion distribution, and size were assessed for correlation with high-grade cervical intraepithelial neoplasia 2 or worse (CIN 2+). RESULTS: A total of 555 patients were included in our analysis. Of them, 333 (60%) had CIN 2+ on colposcopy or excision. CIN 2+ was most likely in younger women and those referred for high-grade cytology. Among 111 women with no visual lesion seen at colposcopy, 66 underwent ECC alone, 33 had ECC and random biopsy, 9 were referred straight to excision, and 3 underwent random biopsy alone. Of the 99 who underwent ECC, this was consistent with the highest-grade lesion in 68% of cases. Among the 36 with random biopsy, this was consistent with the highest-grade lesion in 72% of cases.At the time of colposcopy, there were 326 who had CIN 2+ diagnosed with satisfactory colposcopy. Biopsy and ECC were performed in 278 cases. In 235 cases, biopsy alone showed CIN 2+; in 43, the biopsy and ECC both showed CIN 2+. In the remaining 48 cases, CIN 2+ was diagnosed with ECC alone. CONCLUSIONS: In those ultimately treated with excision, younger women and those whose referral cytology was high-grade both were at higher risk of high-grade histology. Random biopsy and ECC (even among satisfactory colposcopy) were significantly associated with disclosure of high-grade pathology.

Current aims and challenges associated with cervical cancer prevention.

This chapter will review the current modalities available to the clinician to screen for premalignant and malignant cervical lesions, which cast a broad net. The majority who test positive are not destined to suffer from or die from cervical cancer. Many who undergo screening and are triaged are young and subsequently face a number of aggressive and destructive therapies. This calls into question whether higher-risk patients should be managed more aggressively than an average-risk patient represented in the study population used to craft the guidelines.

Secondary prevention of cervical cancer part 3: evidence-based management of women with cervical intraepithelial neoplasia.

The management of cervical intraepithelial neoplasia has evolved over the last 20 years. Observation has replaced aggressive therapy in many cases. Evidence based guidelines now guide therapy. This chapter presents an overview of various treatment options, as well as the most recent guidelines of therapy.

Secondary prevention of cervical cancer part 1: screening for cervical cancer and its precursors.

Discussion of screening for cervical cancer and it precursors, management of abnormal cervical cancer screening test, and evidence-based management of women with cervical intraepithelial neoplasia.

Do colposcopically directed biopsy and endocervical curettage serve to induce regression of cervical intraepithelial neoplasia?

OBJECTIVE: We investigated the clinical and demographic characteristics that could influence regression of cervical intraepithelial neoplasia (CIN) from colposcopy to excision, and evaluated the association of the performance of multiple biopsies and endocervical curettage (ECC) with regression of high-grade (CIN2+) by the time of excisional therapy. MATERIALS AND METHODS: This was an institutional review board-approved retrospective analysis of 555 patients who had abnormal screening and who underwent colposcopy followed by cervical excision procedures for CIN2+ or high-risk status. We assessed demographic variables, referral reason, colposcopic findings, and the latency between colposcopic biopsy and excision to which we correlated the likelihood of regression of disease on the excisional specimen. RESULTS: Mean age was 39 years, and median interval from colposcopy to excision was 48 days. Neither demographics nor colposcopic findings influenced the probability of regression. Patients with shorter intervals between colposcopy biopsy and excision exhibited a higher rate of regression (p=.04). The addition of ECC to colposcopy was associated with regression (p=.002). CONCLUSIONS: During routine colposcopic practice using punch biopsy and ECC when indicated, regression was less likely with longer latency from colposcopy to excision. This was possibly owing to emergence and documentation of persistent occult neoplasia. The effect of intentional complete biopsy excision with conventional tools as a potential therapeutic intervention was not evaluated.

Adenomyosis in women undergoing hysterectomy for abnormal uterine bleeding associated with uterine leiomyomas.

BACKGROUND: Uterine leiomyomas and adenomyosis are both common and often associated with abnormal uterine bleeding (AUB), including the symptom of heavy menstrual bleeding (HMB). Understanding the prevalence of adenomyosis in women with uterine leiomyomas could inform clinicians and patients in a way that may improve therapeutic approaches. OBJECTIVE: To explore the prevalence of adenomyosis in a group of women who underwent hysterectomy for AUB-L, to determine the prevalence of submucous leiomyomas, and to examine the utility of preoperative ultrasound to detect the presence of adenomyosis. METHODS: The Kaiser Permanente Hysterectomy Database (KPHD) was searched for women aged 18-52 undergoing hysterectomy for leiomyoma-associated chronic AUB (AUB-L) in 2018 and 2019. A target sample of 400 comprised those with at least 3 years in the Health System. Radiologists evaluated preoperative pelvic ultrasound images to determine leiomyoma size and level 2 FIGO type (submucous or other), and the linked electronic medical record abstracted for clinical features, including histopathological evidence of adenomyosis. RESULTS: Of the 370 subjects that met the study criteria, adenomyosis was identified via histopathology in 170 (45.9%). There was no difference in the adenomyosis prevalence with (47.1%) and without (43.0%) at least one submucous leiomyoma. Subgroup analysis of ultrasound images by an expert radiologist for the presence of adenomyosis demonstrated a positive predictive value of 54.0% and a negative predictive value of 43.4%. CONCLUSIONS: Adenomyosis was present in almost half of this AUB-L cohort undergoing hysterectomy and was equally prevalent in those with and without submucous leiomyomas as determined by sonographic evaluation. The imaging findings are in accord with prior investigators and demonstrate that 2-D ultrasound is insensitive to the presence of adenomyosis when the uterus is affected by leiomyomas. Further research is necessary to determine the impact of various adenomyosis phenotypes on the presence and severity of the symptom of HMB.

Evaluation of the clinical performance of high-risk human papillomavirus testing for primary screening: a retrospective review of the Southern California Permanente Medical Group experience.

OBJECTIVE: We investigated the potential impact of using the high-risk human papillomavirus (HPV) test as a primary screening tool for the detection of cervical cancer and its precursor lesions. MATERIALS AND METHODS: From October 2005 to March 2006, conventional cervical cytological samples and Hybrid Capture II HPV tests were cocollected from all patients. Human papillomavirus tests were processed in all women aged 30 years and older and women younger than 30 years with a cytological finding of atypical squamous cells of undetermined significance. Patients with biopsy-proven cervical intraepithelial neoplasia (CIN) served as the study population. RESULTS: We identified 263 women with CIN of whom 194 (73.8%) (95% confidence interval [CI] = 68.2%-78.8%) had HPV results. Human papillomavirus tests were negative in 4 (6.1%) of 66 CIN 3 cases (95% CI = 2.1%-14.5%), in 8 (16%) of 50 CIN 2 cases (95% CI = 7.3%-28.2%), and in 22 (22.8%) of 78 CIN 1 cases (95% CI = 18.6%-38.9%) distributed across all referral cytology categories. Negative HPV test rates were most significant for CIN 1 cases anteceded by a cytological finding of atypical squamous cells of undetermined significance (p =.0016). The mean age of women with HPV-negative CIN was 10 years older than that for women with HPV-positive CIN. CONCLUSIONS: Human papillomavirus testing may miss more CIN than previously reported, especially in older women. Prospective trials of HPV testing as a primary screen for cervical cancer should incorporate additional tests to minimize missed lesions.

Adherence to Cervical Cancer Screening Guidelines Among Women Aged 66-68 Years in a Large Community-Based Practice.

INTRODUCTION: The 2012 national cervical cancer screening guidelines recommended cessation of screening after age 65 years in women with adequate prior screening. In this retrospective cohort study, adherence to these screening exit guidelines was examined. METHODS: Women who turned age 66 years in 2012-2013 at Kaiser Permanente Southern California were followed through age 68 years for cervical cancer screening uptake. Adequacy of prior screening was assessed between age 56 and 65 years using electronic medical records. Guideline adherence was determined based on screening pattern between age 66 and 68 years. Patient- and physician-level correlates for guideline adherence were examined using multivariable logistic regression. Data collection and analyses were conducted in 2018. RESULTS: A total of 14,778 women were included; 24% did not have adequate prior screening by age 65 years. Among those without adequate prior screening, the proportion screened after age 65 years ranged from 71% (177 of 249) in those whose most recent test was abnormal to 3% (34 of 1,330) in those who did not have any testing in 10 years. Prior screening pattern was the only factor associated with screening after age 65 years. Of those with adequate prior screening, 10% (1,135 of 11,295) continued to receive screening after age 65 years. Frequent office visits and having a male primary care physician were associated with continuing screening after age 65 years. CONCLUSIONS: A considerable proportion of women did not have adequate prior screening by age 65 years. Of these, a large proportion did not receive screening after age 65 years, except those who had a recent abnormal screening result. Further research is needed to understand barriers for guideline adherence and rationales for clinical decision making.

Hysterectomy for benign conditions: Complications relative to surgical approach and other variables that lead to post-operative readmission within 90 days of surgery.

OBJECTIVE: To examine variables associated with hysterectomy-related complications, relative to surgical approach and other variables, that lead to readmission within 90 days of surgery. METHODS: We conducted an observational cohort study for which data were extracted from electronic health records. Data were extracted of all patients (n = 3106) who underwent hysterectomies at 10 Kaiser Permanente Southern California medical centers between June 2010 and September 2011. Patients who were pregnant or had a cancer diagnosis were excluded from the study. To identify univariate associations between examined variables and procedure type, chi-square tests for categorical variables and t-tests or analysis of variance for continuous variables were used. Generalized estimating equations methods were used to test associations between independent variables and primary outcomes of interest. Statistical significance was determined using a p-value <.05. RESULTS: Of 3106 patients, 109 experienced 168 post-operative complications. The most common post-operative complications were related to pelvic abscesses, bowel obstruction, or severe ileus, and the vaginal cuff. Pelvic abscesses were most frequent among total laparoscopic hysterectomy and total abdominal hysterectomy cases (p = .002), and vaginal cuff complications were most frequent among total laparoscopic hysterectomy cases (p = .015). Patients who underwent total vaginal hysterectomy (odds ratio = 2.13, confidence interval = 1.15-3.92), laparoscopic supracervical hysterectomy (odds ratio = 3.11, confidence interval = 1.13-8.57), and total laparoscopic hysterectomy (odds ratio = 5.60, confidence interval = 2.90-10.79) experienced increased occurrence of post-operative complications resulting in readmission. Other variables associated with an increased risk for readmission included high estimated blood loss (201-300 mL and 301+ mL, relative to 0-50 mL; odds ratio = 2.28, confidence interval = 1.24-4.18 and odds ratio = 2.63, confidence interval = 1.67-4.14) and long length of stay of 3 days or more (relative to 0 days; odds ratio = 2.93, confidence interval = 1.28-6.69). Pelvic specimen weight in the 151-300 g and 501+ g ranges appeared protective (odds ratio = 0.40, confidence interval = 0.25-0.64 and odds ratio = 0.54, confidence interval = 0.33-0.90). In a sub-analysis of 1294 patients, 74 hospital operative complications directly related to hysterectomy were identified among 59 patients. The most common hospital operative complications were excessive bleeding associated with surgery or injury to nearby structures. Among the sub-sample of 1294 patients, those with hospital operative complications were more likely to experience post-operative complications that lead to readmission (odds ratio = 3.82, confidence interval = 1.55-9.43, p = .004). CONCLUSION: The observed increased risk of complications among patients of Black race, who underwent laparoscopic supracervical hysterectomy or total laparoscopic hysterectomy, who experienced more than 300 mL surgical blood loss, who suffered hospital operative complications, and those whose hospitalization was 3 days or greater, offers an opportunity for higher scrutiny and preventive measures during usual hysterectomy care to prevent later readmission.

Size matters in planning hysterectomy approach.

Hysterectomy is the second most common gynecologic surgery; approximately 600,000 women undergo hysterectomies each year in the United States. Estimated uterine size, either by bimanual examination, ultrasonography, or both, is one of the major factors in evaluating the need for hysterectomy and in selecting the surgical approach. In this article, we review how physician-estimated uterine size can be confidently used in providing optimal hysterectomy care, as data indicate estimation is closely correlated with actual post-surgical pelvic specimen weight.

Triage of atypical squamous cells of undetermined significance with hybrid capture II: colposcopy and histologic human papillomavirus correlation.

OBJECTIVE: To estimate the effectiveness of Hybrid Capture II to predict high-grade cervical intraepithelial neoplasia (CIN) from a cytological cervical sample. Evidence of high-risk human papillomavirus (HPV) was also determined from biopsy samples using the polymerase chain reaction (PCR) for women referred with atypical squamous cells of undetermined significance (ASCUS) Papanicolaou smears. METHODS: We screened 8170 women with Papanicolaou smears, of whom 278 (3.4%) returned ASCUS. All ASCUS cases underwent colposcopy and Hybrid Capture II testing. High-grade CIN biopsy specimens were tested for high-risk HPV by PCR. RESULTS: Nearly 30% of ASCUS cases had CIN biopsy results (11.9% showing CIN II or CIN III and 17.6% showing CIN I). Hybrid Capture II positive rates were 93.3% for cases with CIN III, 72.2% for CIN II, and 51.0% for CIN I (P <.001). ASCUS-Premalignant Process Favored cases showed a 28.1% high-grade biopsy rate and a 100% Hybrid Capture II positive rate. For ASCUS-Undefined and ASCUS-Reactive Process Favored cases, Hybrid Capture II returned positive in 90.9% of CIN III and 61.5% of CIN II cases (P <.001). Sixty-nine of 178 (38.8%) patients with no evidence of CIN tested positive for Hybrid Capture II. Human papillomavirus deoxyribonucleic acid (DNA) high-risk subtypes were detected by PCR in the tissue of all high-grade CIN cases with negative Hybrid Capture II results. CONCLUSION: Hybrid Capture II returned negative in 25% of cases with biopsy-proven high-grade CIN with associated high-risk HPV DNA by PCR (non-Premalignant ASCUS subset), and positive in 39.3% of cases with normal results; this limits its clinical utility.

A stiff bristled, spiral-shaped ectocervical brush: a device for transepithelial tissue biopsy.

OBJECTIVE: To compare a new spiral-shaped tissue-sampling brush with a standard cervical punch biopsy. METHODS: Before large loop excision of the transformation zone, women with cervical intraepithelial neoplasia underwent a transepithelial brush biopsy of a portion of a colposcopically identified lesion, followed by a punch biopsy of the remaining portion. Brush biopsy samples were processed using liquid-based cytology and cell block techniques. Diagnoses were made using a consensus of three pathologists. Brush biopsy samples without basal cells were considered inadequate. The histological diagnosis was compared with the brush biopsy and punch biopsy samples. Patient-reported pain and physician-reported bleeding for punch and brush biopsies were compared. RESULTS: Fifty-two women were enrolled in the study; 47 successfully completed the study protocol. Eight brush biopsy specimens were inadequate. Thirty-nine women showed abnormal pathology (human papillomavirus/cervical intraepithelial neoplasia I or worse) on large loop excision of the transformation zone, and 32 women had high-grade (or worse) lesions. The punch biopsy correlated with high-grade disease in 53.1% of these women. The brush biopsy result correlated with high-grade disease in 79.3% of these women using a cell block technique and 76.7% using liquid cytology. There was significantly less pain (P <.001) and significantly less bleeding (P <.001) with the brush biopsy. CONCLUSION: When an adequate sample is collected, spiral brush biopsy is as good as a standard punch biopsy for detecting cervical pathology, with substantially less pain and bleeding. User training and guidelines for sampling are needed to assure that an adequate sample is collected.

Reducing death from cervical cancer examining the prevention paradigms.

The prevention of morbidity and mortality from cervical cancer will hinge upon our understanding of the epidemiology, the molecular basis, and natural history of the disease and its associated precursors. This article serves as an introduction and presents our current challenge to prevent or find all women at risk, and alter the course of disease to effect a regression or a cure.

Risk factors related to the development and mortality from invasive cervical cancer clinical utility and impact on prevention.

The focus of this article is to explore the various risk factors related to cervical cancer and the practical context in which they can be applied. The ability to link dinical outcomes (disease presence, persistence, progression, and recurrence) with antecedent risk factors is strengthened by a new understanding of the molecular mechanisms that are responsible for malignant transformation.

Cost-effectiveness of adding human papilloma virus testing to a managed care cervical cancer screening program.

OBJECTIVE: The purpose of this study was to demonstrate a methodology for auditing the impact of HCII testing on the direct cost of cervical cancer cytological screening, where the test is collected in all women screened and processed routinely in women age 30 years and older. MATERIALS AND METHODS: After a policy change to screen all patients 30 years or older with both Pap smears and high-risk human papillomavirus (HR-HPV), as well as cocollection of HR-HPV in women younger than 30 years, all cytological, HPV, and histological data pertaining to cervical screening was collected retrospectively during a 2-month period. We documented the direct costs of performing these tests and estimated the necessary compliance rate for balanced cost-effectiveness. RESULTS: During the 2-month period, 8,300 women were screened with both Pap smear and HPV cocollection. Of the 'nonnormal' cytological findings, 5% of patients showed either atypical squamous cells (3.5%) or squamous intraepithelial abnormalities (1.5%). An additional 427 (5%) patients had the finding of positive HR-HPV with normal cytology. Six of these patients opted for immediate colposcopy, 2 of which were found to have cervical intraepithelial neoplasia 2. In women age 30 years and older, 900 patients per 1,000 screened would be eligible for a 2-year screening interval based on negative cytology and negative HR-HPV. Based on the direct costs associated with this cohort, no more than 164 women could request screening at an interval shorter than 3 years for the total costs of such a program to equal that of one without HR-HPV cocollection. CONCLUSIONS: By adding HCII collection to the Pap smear for our entire screening cohort, we intended to reduce the number of tests performed, which was impacted by its age distribution. Our findings indicate that at least 736 of the 900 double-negative patients (82%) would have to be screened at no less than 3 years for such a screening paradigm to be cost-effective in managing women 30 years and older.