Obstetrics & Gynecology:
Potential Effects of Updated Pap Test Screening Guidelines and Adenocarcinoma In Situ of the Cervix
Barroilhet, Lisa MD; Van Hanegem, Lennie MD; Bernstein, Marilyn MHP; Feldman, Sarah MD, MPH
University of Wisconsin, Madison, Wisconsin; Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts; and Academisch Medisch Centrum, University of Amsterdam, Amsterdam, the Netherlands.
Corresponding author: Lisa Barroilhet, MD, UW Hospital, H4/658 CSC, 600 Highland Avenue, Madison,WI 53792; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To review cases of adenocarcinoma in situ (AIS) at our institution to examine how updated guidelines affect the timing of diagnosis.
METHODS: We identified patients with AIS diagnosed between 1998 and 2010 using the International Classification of Diseases, 9th Revision, Clinical Modification, code 233.1. Diagnosis was confirmed by pathology review. We abstracted demographic data, dysplasia history, and modalities utilized for diagnosis and treatment.
RESULTS: We identified 242 patients who met selection criteria. Two hundred eight (86%) had Pap test abnormalities at presentation. One hundred thirty-seven out of 208 (66%) patients with abnormal Pap test results had a squamous, rather than glandular, abnormality. The mean time from abnormal Pap test to diagnosis of AIS was 29 months in patients older than 30 years and was 21 months in patients 30 years or younger. In patients younger than 21 years, 16 out of 17 had abnormal screening Pap test results showing squamous lesions. Their subsequent treatment for squamous dysplasia ultimately led to the diagnosis of AIS.
CONCLUSION: Updated screening guidelines may prevent the expeditious diagnosis of AIS in females younger than 21 years and those aged 21–29 years, many of whom had normal Pap test results within 3 years of diagnosis.
LEVEL OF EVIDENCE: II
Adenocarcinoma of the cervix is an uncommon malignancy. However, its relative incidence when compared with squamous cell carcinoma of the cervix has increased in the past 60 years.1,2 Recent epidemiology studies indicate that adenocarcinoma now comprises more than 25% of all cervical malignancies diagnosed in the United States compared with 5% in the 1960s (Surveillance, Epidemiology, and End Results [SEER] database, 2011). In a large population-based study from the Netherlands, although the overall incidence rate of adenocarcinoma remained stable, it increased in women aged 15–29 (15.8% increase) and in women aged 30–44 (2.5% increase).2 This relative increase is widely attributed to an increase in high-risk human papillomavirus (HPV) infection (primarily HPV subtypes 16 and 18), oral contraceptive use, and implementation of an effective widespread screening for preinvasive squamous lesions.3,4
Adenocarcinoma in situ (AIS) of the cervix is considered a precursor lesion to its invasive counterpart.5–7 Adenocarcinoma in situ has increased in frequency in parallel to the increased frequency of adenocarcinoma of the cervix8,9 and may remain underdiagnosed. It is a disease of premenopausal women, with the median age of diagnosis reported as being between 35 and 40 years.10,11 Adenocarcinoma in situ is considered a curable condition. Although definitive treatment traditionally involves hysterectomy, a growing body of evidence supports the use of fertility-preserving interventions, such as loop excisional electrocautery procedure or cold-knife cone excisional procedures.12 Cure rates with appropriate excision are more than 90%8,13 but are dependent on the ability to effectively diagnose AIS and triage these patients to treatment efficiently.
Cytology alone often is ineffective in detecting AIS.14,15 The Pap test will detect between 38% and 50% of AIS cases before a definitive tissue diagnosis is made.16 Only 1.1--4.7% of Pap tests finding atypical glandular cells (formally of atypical glandular cells of undetermined significance) ultimately will result in a diagnosis of AIS.17,18 The use of liquid-based cytology has not improved our ability to accurately predict AIS using Pap tests.19 Even with the addition of endocervical curettage and colposcopy-directed biopsy, the sensitivity of detecting glandular abnormalities before conization has been described as approximately 60%.16,20 Data from Zappa et al21 in 2004 indicated that cytology screening was not effective in diagnosing AIS, particularly in young women.
Squamous abnormalities occur concurrently in many patients with AIS. A squamous intraepithelial lesion or invasive squamous carcinoma has been found in 25–71% of cone biopsy specimens containing AIS.22–24 Many patients with AIS diagnosed were being assessed and treated for squamous dysplasia. We hypothesized that in our patient population, many women with AIS ultimately diagnosed and treated were undergoing routing Pap tests that detected squamous, rather than glandular, abnormalities. Subsequent colposcopy and biopsy or excisional procedure led to the detection of AIS. New guidelines published by the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology25 (Table 1) recommend omitting Pap tests in patients younger than 21 years of age. Other changes include screening patients aged 21–29 years every 3 years with cytology alone and performing HPV and cytology “co-testing” in patients aged 30–65 years. This study examines how the updated guidelines may affect the timing of diagnosis and treatment of AIS.
MATERIALS AND METHODS
A Partners Healthcare Institutional Review Board–approved retrospective cohort study was conducted at Brigham and Women's hospital and the Dana Farber Cancer Institute. All cases of AIS in women were identified by searching the computerized hospital databases for the International Classification of Diseases, 9th Revision, Clinical Modification, code 233.1. Medical records were abstracted for clinical history, demographic information, procedures performed, and frequency or type of follow-up obtained. Pathology and cytology reports were reviewed for histology, margin status of the specimen, and HPV staining. The follow-up period was defined as the time of initial AIS diagnosis and the last known date of follow-up. Patients were excluded if no detailed pathology or Pap test data were available. We included patients with AIS diagnosed at time of Pap test or cervical biopsy, and patients who underwent loop excisional electrocautery procedure or cold knife cone for squamous abnormalities but who also were found to have AIS in the final pathology specimen.
Adenocarcinoma in situ was histologically defined by standard criteria. All pathology slides from patients referred from an outside hospital were reviewed by a gynecologic pathologist at Brigham and Women's hospital. Confidence intervals (CIs) for proportions were of the two-sided exact binomial 95% type. A one-way analysis of variance was used to compare means, with a one-way Kruskal-Wallis analysis of variance used to compare medians. Tests of counts were conducted using Fisher exact method and χ2 tests with continuity correction.
Two hundred forty-two patients were identified who met selection criteria (Table 2). One hundred twelve women with AIS aged 30 years or younger at the time of diagnosis were identified between 1998 and 2010. Of these, 96 patients (85.7%) had confirmed Pap test abnormalities documented at the time of presentation. The mean age in the group of 112 patients was 25 years (range 15–30 years), with 96 (85.7%) being nulliparous. The mean age of the first Pap test abnormality was 24 years. Seventy-nine of the 96 (82.3%, confidence interval 73.2–89.3) patients with abnormal Pap test results had pure squamous, rather than glandular, dysplasia. The mean duration of abnormal cytology before a diagnosis of AIS was 14 months (range 3–122 months).
In the study population older than 30 years, abnormal glandular Pap test results comprised almost 50% of all Pap tests performed before AIS diagnosis (Table 3). Also, the mean time from abnormal Pap test to AIS diagnosis was longer, averaging 29 months (range 0–283 months; Table 4). Five patients had normal Pap test results before their diagnosis of AIS. Three were triaged to colposcopy based on high-risk HPV status despite normal cytology. One had symptoms of abnormal bleeding that led to both cervical and endometrial biopsies.
There were 17 patients in our study younger than 21 at the time of diagnosis of AIS. In this subset, 17 of 17 had an abnormal screening Pap test result, 16 of which showed squamous intraepithelial lesions without glandular abnormalities (Table 3). For these young patients, their triage to colposcopic examination with appropriate biopsies led to excisional procedures for their high-grade squamous abnormalities. It was this subsequent procedure (loop excisional electrocautery procedure or cold knife cone) that led to the diagnosis of AIS. Cervical biopsies and endocervical curettage failed to identify glandular lesions in our patients younger than 21. In contrast, the majority of patients 21 and older had AIS diagnosed before an excisional procedure. One hundred ninety-eight out of 225 patients 21 years of age or older (88.0%, CI 83.0–91.9) had AIS diagnosed by Pap test, cervical biopsy, or endocervical curettage (Table 4).
Follow-up data were available for 186 of the 242 (76.9%, CI 71.0–82.0) patients included in our study. In our population of patients aged older than 30 years, 14 (10.8%) eventually had invasive adenocarcinoma of the cervix diagnosed. Follow-up data for more than 3 years were available for 11 of these patients, none of whom have recurrent or persistent disease. One patient had a positive pelvic lymph node at the time of hysterectomy and went on to receive chemotherapy and pelvic radiation postoperatively. She is disease-free 2 years after completion of adjuvant therapy. The remaining patients were cured with surgery (cold knife cone, simple hysterectomy, or radical hysterectomy) alone. In our subgroup of patients aged 30 or younger, three patients (2.7%) had invasive adenocarcinoma of the cervix diagnosed, two at the age of 30 years and one at the age of 29 years. They all underwent radical hysterectomy and have no evidence of disease after more than 3 years of follow-up.
There is substantial evidence that a well-organized prevention program of cervical carcinoma, including both early detection and appropriate treatment of preinvasive lesions, is an efficient means to reduce the incidence of invasive squamous cell carcinoma. No screening program exists that has high sensitivity for detecting preinvasive glandular lesions of the cervix. There are several reasons to explain why Pap testing for glandular lesions is relatively ineffective. Adenocarcinoma in situ is characteristically located in the glandular cells of the endocervical canal, which may be less readily sampled with Pap screening. Furthermore, the histologic appearance may resemble glandular atypia secondary to inflammation, tubal metaplasia, or endometriosis.
In the present series of 242 AIS cases, an abnormal Pap test result almost invariably was the reason for initiation of the work-up. This was especially true of the women younger than 21 with AIS ultimately diagnosed: 16 out of 17 patients in that cohort were being evaluated for a squamous abnormality that led to the diagnosis of AIS. No patients younger than 21 in our study were symptomatic at the time of presentation. Their AIS would not have been diagnosed without the implementation of routine Pap testing.
The rationale and data behind not screening women younger than 21 are that cervical cancer is rare in this population and may not be prevented by cytology screening.26 Based on the SEER database published in 2011, from 2004 to 2008 the median age at diagnosis for cancer of the cervix uteri was 48 years. Approximately 0.2% of patients in the United States had cervical cancer diagnosed at age younger than 20 years, including both squamous cell carcinoma and adenocarcinoma (SEER database 2011). Consistent with the national data, we did not detect any invasive adenocarcinomas in our patient population with AIS diagnosed at younger than 21 years of age.
For patients 21–30 years of age, the mean time between abnormal cytology and the diagnosis of AIS was 13 months. With the implementation of current screening guidelines, patients would not undergo Pap testing for 3 years if their last cytologic screen yielded normal results. Based on our data, the average patient in this age group with AIS may develop adenocarcinoma before the next scheduled Pap test. The clinical significance of this is less certain, because the natural history of untreated AIS and its progression to frank carcinoma is not well-known.
In our patients older than 30 years, HPV co-testing may be the key to detecting AIS. In a recent study by Katki et al,27 63% of adenocarcinomas diagnosed over a 5-year period followed an initial HPV-positive, cytology-negative co-test results. Five patients older than 30 years in our database had normal Pap test results before their diagnosis of AIS. Three had documented high-risk HPV and were appropriately triaged to colposcopy; two do not have HPV status documented in our electronic medical record. Human papillomavirus co-testing may help identify more patients with AIS who have normal cytologic screening.
Based on the retrospective data collected at our institution, recent revisions in national guidelines for cervical cancer screening may affect our ability to diagnosis AIS. The patient population younger than age 21 years appears to be particularly vulnerable. Sixteen out of 17 patients in our adolescent subgroup had squamous dysplasia diagnosed at the time of routine cytologic screening that eventually led to the diagnosis and appropriate treatment for AIS. It is not clear whether a delay in diagnosis would affect long-term survival, but it is reasonable to surmise that larger AIS lesions and invasive adenocarcinomas are more difficult to treat without compromising fertility or pregnancy outcomes, an area of particular importance to our younger patients. Further studies are needed to determine the clinical significance of updated Pap testing guidelines in patients between the ages of 21 and 30 years, but it does appear that screening every 3 years will result in AIS developing between routine cytologic screens in some patients. New guidelines in patients 30 years of age and older do not appear to negatively affect the detection of AIS and, in fact, HPV co-testing may aid in diagnosis, particularly because patients in this age group are more likely to have normal cytology.
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