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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