Management Strategies for Patients with Atypical Squamous Cells of Undetermine Significance
abstract & commentary
The alts trial was funded by the national cancer institute for the purpose of determining the most appropriate method of evaluating women with atypical squamous cell of undetermined significance (ASCUS) and low-grade squamous lesions (LGSIL) of the cervix. The details of this study design have been published previously.1 The present study reports the results of entry data only. The project is designed as a randomized prospective study; the longitudinal results will be reported later.
Women were initially admitted to this study if they had a community performed and read cytology specimen that was interpreted as showing ASCUS or LGSIL changes. If they agreed to participate in the study, they were randomly assigned to 1 of 3 triage arms: 1) immediate colposcopy; 2) human papillomavirus (HPV) testing and referral for colposcopy if high-risk HPV positive; or 3) "conservative management" using cytology follow-up with referral for colposcopy if any specimen was reported with high-grade (HGSIL) changes. The current publication reports only those women who were entered with
ASCUS cytology. (Of interest, and published previously, the LGSIL arm of the study was terminated early as it was shown there was no benefit to HPV testing of women with LGSIL reports.)
At the initial visit all women had a ThinPrep cytology specimen prepared. The residual liquid in the vial after preparation of the cytology sample was used for HPV testing using the Hybrid Capture 2 (HC 2) technique. Only the high-risk probe was used. If the sample was positive for a high-risk HPV type, or it was not possible to prepare a sample for HPV testing due to a shortage of residual fluid, the patient was referred for colposcopy. Based on this scheme, slightly more than half (55.3%) of the women were referred for colposcopy.
If the cytology specimen obtained at entry was interpreted as showing HGSIL changes, the patient was referred for colposcopy. Only 7% of the cytology samples were interpreted as showing HGSIL.
Solomon and colleagues went to great lengths to assure appropriate randomization. Because there were 4 study centers, and because it was expected (and found) that there would be differences among the centers in age of participants, race, ethnicity, risk factors, number of sexual partners, age at first intercourse, parity, years of education, and previous number of Pap smears, the randomization was stratified by center. In addition, both the community acquired Pap smear and the entry Pap smear was subject to a quality control review group. Biopsies obtained at colposcopy were reviewed by a pathology quality control group.
In order to estimate the prevalence of high-grade disease in this population of women with ASCUS, the results of the women randomly assigned to the colposcopy arm were used to estimate the prevalence of disease. In the immediate colposcopy arm, 14.5% of the women had cervical intraepithelial neoplasia (CIN) 1, 6.3% had CIN 2, and 5.1% had CIN 3 or greater.
HPV DNA testing resulted in referral of virtually all expected cases of CIN 3 disease. The test sensitivity was estimated to be 96.3%. Cytology was less sensitive, but was based only on the initial. Cytology was consid-
erably more sensitive if the threshold for referral for colposcopy was decreased to any SIL report or an ASCUS report.
In the discussion section of the paper, Solomon et al point out that the ultimate sensitivity of the conservative management arm (cytology follow-up) will not be known until the longitudinal data are available and reported. Although cytology appeared not to perform as well as Hybrid Capture 2 in this cross-sectional review of the data, its performance would be expected to increase with the availability of prospective data. (Solomon D, et al. J Natl Cancer Inst. 2001;93:293-299).
Comment by Kenneth L. Noller, MD
All of us who are interested in colposcopy and cytology screening have been waiting patiently for the ALTS trial to report its data. The initial report showing that HPV testing was not useful in the triage of patients with low-grade cytologic changes has previously been reviewed in OB/GYN Clinical Alert. This new report now focuses on women with ASCUS reports—the group with which we have the most difficulty in clinical settings.
Based on 1 sample only, HPV DNA testing performs better than cytology. However, we do not know whether cytology will be shown to be as sensitive as HPV DNA testing when the prospective data are available. Addi- tionally, this study does not prove that HPV DNA testing is cost-effective.
For just a moment let’s completely forget about this study and think about our options as clinicians. If we have a woman who has a Pap smear which is reported as showing ASCUS changes there are now 3 potential options, all of which are able to separate those women who have "real" (high-grade) neoplasia which can theoretically progress to invasive cancer from those who have no such disease. We can: 1) perform immediate colposcopy; 2) obtain a sample for high-risk HPV DNA and colposcope those who are high-risk probe positive; or 3) follow with serial Pap smears. How will we decide which choice is preferable? At the present time, we do not have the data from the ALTS trial on the sensitivity of cytology follow-up. We do know that HPV DNA testing appropriately refers to colposcopy most women have high-grade disease. It may very well be that repeat cytology is just as good.
For a moment let’s assume that all 3 management schemes are equal. How then will we make a determina-tion of which arm to follow? It seems to me that the choice will be based on 1 of 2 factors: cost-effectiveness or patient preference. It is too early to know which of the 3 schemes is most cost-effective. I strongly suspect that there will be little difference in the cost-effectiveness of the 3 methods as the cost of the "high technology" (col- poscopy) alternative may well be offset by the high cost of HPV DNA testing or repeat office visits and cytology. Therefore, I predict that we will (as we currently do) continue to base our patient management to a large degree on patient and physician preference. The woman who is very anxious about a slightly abnormal Pap smear may very well be best evaluated by immediate colposcopy. On the other hand, the woman who is not much concerned about a minimally abnormal Pap smear may feel comfortable with cytology follow-up.
While I applaud Solomon et al (and the National Cancer Institute and ALTS trial investigators in general) for their work, this article should not change our clinical practice. Until the ALTS trial publishes the longitudinal data, it is not possible to make a decision concerning the best method to manage women with ASCUS Pap smear reports. Indeed, though beautifully written, the only important conclusion of this paper is that HPV DNA testing is an acceptable triage method for women with ASCUS smears. However, it may be no better than sequential cytology and was shown to be no better than immediate colposcopy. The cost effectiveness of HPV testing is not yet known.
Reference
1. Schiffman M, et al. Acta Cytologica. 2000;44:726-742.
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