Long-Term Outcome and Relative Risk in Women With Atypical Squamous Cells of Undetermined Significance

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1 Anatomic Pathology / LONG-TERM OUTCOME WITH ATYPICAL SQUAMOUS CELLS OF UNDETERMINED SIGNIFICANCE Long-Term Outcome and Relative Risk in Women With Atypical Squamous Cells of Undetermined Significance Stephen S. Raab, MD, N. Scott Bishop, EdS, and M. Sue Zaleski, CT(ASCP) Key Words: ASCUS; Cervical dysplasia; Cytology; Pap smear Few studies have compared long-term follow-up and risk for invasive cancer in women with atypical squamous cells of undetermined significance (ASCUS). We conducted a 6-year review of pathology files for 65 women in whom ASCUS had been diagnosed in 99. Data collected included patient demographics, followup diagnoses, time between follow-up examinations, and procedures performed. At follow-up, high-grade squamous intraepithelial lesions () had developed in 9.% of the women, and invasive cancer in none. Previous cervical history did not affect risk for an. Although the average time to first follow-up was 6.8 months, in.9% of the women the diagnosis of was not established until after. years. For individual pathologists, the percentage of s ranged from % to 8.8%. Thus women with ASCUS who are followed up regularly are at low risk for development of invasive cancer. Although the Papanicolaou smear diagnosis of atypical squamous cells of undetermined significance (ASCUS) is made annually in more than million women in the United States, there is no uniform practice for management in these patients. -5 Some practitioners advocate a conservative approach and simply perform a repeat Pap smear, because at follow-up most ASCUS lesions are benign. Others advocate aggressive follow-up and recommend colposcopy, because a small percentage of ASCUS lesions are at high risk to progress to invasive cancer. The annual cost of aggressively treating ASCUS lesions probably reaches billions of dollars., Follow-up should depend on the relative risk in a woman with ASCUS to have or develop invasive cervical cancer. This risk depends primarily on the number of squamous intraepithelial lesions (SIL), in particular high-grade SIL (), that lurk in or develop from an ASCUS lesion.- If the number of SIL is high and these SIL would progress to invasive cancer before the next Pap smear, aggressive followup is warranted. Short-term follow-up studies (less than years) demonstrate conflicting results, with follow-up SIL rates ranging from % to %._ Long-term populationbased follow-up studies measuring patient outcomes, not only including follow-up SIL rates but also per-patient costs and risk for, are lacking. We attempted to define the risks associated with an ASCUS diagnosis by measuring long-term follow-up (up to 6 years) in all women with Pap smears diagnosed as ASCUS at the University of Iowa during calender year 99. Materials and Methods In 99 at the University of Iowa, 9,9 cases were screened; the diagnoses" were.% unsatisfactory for diagnosis, 88.5% benign, 5.% atypical, % low-grade SIL Am J Clin Pathol 999;: Downloaded from by guest on September 8 Abstract

2 Raab et al / LONG-TERM OUTCOME WITH ATYPICAL SQUAMOUS CELLS OF UNDETERMINED SIGNIFICANCE The ASCUS diagnoses were made by of 7 pathologists. There was no consensus conference on how to use the ASCUS category. The authors used their experience and knowledge of the Bethesda system categories to make an ASCUS diagnosis. This reflects how the ASCUS diagnosis is used in most laboratories, with pathologists using the ASCUS category to a different extent. Pathologists and were most experienced, and had been interpreting smears for more than 5 years; pathologists and were new cytology faculty members, and had been interpreting smears for less than year; pathologists 5, 6, and 7 were cytopathology fellows who had passed the anatomic pathology boards or were board eligible. From January to June, there was cytopathology fellow who had completed half of the training program; from July to December, there were fellows who were beginning training. For the first months, these fellows were not granted independent sign-out privileges. In this study, the fellows' diagnoses were the final diagnoses and were not reviewed by an attending pathologist. In 99 the requirements limiting fellow sign-out were less stringent than currently. Pathology follow-up of women with an ASCUS diagnosis was obtained by review of the surgical pathology and cytology database (CoMed Utilities Version 6.5; Intersystems, Cambridge, MA). Data collected included the number of additional procedures after the ASCUS diagnosis, types of procedures, follow-up diagnoses, time to follow-up diagnosis, patient age, clinical history, and pathologist who made the interpretation. For women who underwent concurrent follow-up tests (Pap smear, and colposcopy with biopsy) or multiple follow-up procedures over time, only the worst diagnosis (based on either cytopathology or surgical pathology) was recorded. Thus only diagnosis per patient was recorded. Choosing the worst diagnosis was a bias toward the ASCUS category being of higher risk. Based on history, the women were classified into risk groups: the low-risk group included women with no history of cervical disease (ie, no history of SIL) other than ASCUS, and the high-risk group included women with a history of cervical disease (ie, history of SIL) other than ASCUS. This differentiation was made for several reasons. First, we 58 Am J Clin Pathol 999; :57-6 wanted to determine whether ASCUS diagnoses were made more frequently in either population; in other words, we wanted to determine if the ASCUS population was skewed toward women who had a history of cervical disease. Second, we wanted to determine whether the histologic and cytologic follow-up diagnoses were different for the groups; we wanted to determine if women who had an ASCUS diagnosis and a history of cervical disease had a higher, lower, or equal probability of having SIL at followup as did women with an ASCUS diagnosis and no history of cervical disease. If there were differences between groups, different follow-up protocols could be used. Results The number of women with a diagnosis of ASCUS was 97 (6.9%) in the low-risk group and 5 (9.%) in the high-risk group. The average number of follow-up specimens per patient and the average time between the first and last follow-up procedures are shown in ITable II. The percentage of women who underwent no follow-up procedure was.% and.%, respectively, in the low-risk and high-risk groups. In women who underwent a follow-up procedure, a Pap smear test was performed approximately every 7.6 and 7. months, respectively, in the low-risk and high-risk groups. Of all women who were followed up, developed in 9.%, and invasive cancer in %. The average time to first follow-up was 6.8 months. In women in the low-risk group, 66 had a first diagnosis of ASCUS and had either a second or third consecutive diagnosis of ASCUS. Follow-up data in women at low risk with a first diagnosis of ASCUS are shown in ITable. Of those with follow-up, 57 women (.%) had a diagnosis of SIL and (8.%) had a diagnosis of (cervical intraepithelial neoplasia II [CIN II] in 6, severe dysplasia or squamous carcinoma in situ [CIN III]) in ). Follow-up data in women at low risk with a second or third consecutive diagnosis of ASCUS are shown in ITable. Of those with follow-up, (7.%) had a diagnosis of SIL and (.%) had a diagnosis of (CIN II in, CIN III in ). Follow-up data in women at high risk are shown in ITable. Of those with follow-up, 6 (.%) had a diagnosis of SIL and (9.9%) had a diagnosis of (CIN II in 5, CIN III in 5). One patient with CIN III also had a focus of adenocarcinoma in situ (AIS). The diagnoses by pathologist and follow-up for each pathologist are shown in ITable 5. The high-risk and lowrisk groups were combined for this analysis. The pathologists used the ASCUS category to a different extent. Most ASCUS diagnoses were made by pathologists,, and 5, and at follow-up the number of women who had or developed was similar for each of these pathologists (range Downloaded from by guest on September 8 (),.% high-grade SIL (), and.% suspicious for carcinoma or carcinoma. Of the 959 atypical diagnoses, (.%) were associated with SIL on a -part smear test (separate endocervical and cervical components) or sameday surgical biopsy. These patients were excluded to leave a population of women with only a Pap smear diagnosis of ASCUS and no other confirmation of disease. Of the remaining 755 atypical diagnoses, 65 were ASCUS, atypical glandular cells of undetermined significance (AGUS), and ASCUS and AGUS. The 65 women with an ASCUS diagnosis served as the study set.

3 Anatomic Pathology / ORIGINAL ARTICLE Table I I Number of Follow-Up Procedures and Time to Follow-Up in Women With a Diagnosis of Atypical Squamous Cells of Undetermined Significance Patient Risk Low (n = 97) Variable High (n = 5) Mean No. of Women Mean Age(y) Follow-up procedures Follow-up Pap smear Follow-up biopsy Time to first follow-up (mo) Time to last follow-up (mo) liable Follow-Up in Women at Low Risk With First Diagnosis of Atypical Squamous Cells of Undetermined Significance (n = 6) Diagnosis Follow-Up Procedure Cytology alone Biopsy alone, or biopsy plus cytology ASCUS 9 9 AGUS = low-grade squamous intraepithelial lesion; = high-grade squamous intraepithelial lesion; ASCUS = atypical squamous cells of undetermined significance; AGUS = atypical glandular cells of undetermined significance. Table Follow-Up in Women at Low Risk With Second or Third Diagnosis of Atypical Squamous Cells of Undetermined Significance (n = 7) Diagnosis Follow-Up Procedure Cytology alone Biopsy alone, or biopsy plus cytology ASCUS AGUS 6 7 = low-grade squamous intraepithelial lesion; = high-grade squamous intraepithelial lesion; ASCUS = atypical squamous cells of undetermined significance; AGUS = atypical glandular cells of undetermined significance Table Follow-Up in Women at High Risk (n = ) Diagnosis Follow-Up Procedure Cytology alone Biopsy alone, or biopsy plus cytology ASCUS AGUS = low-grade squamous intraepithelial lesion; = high-grade squamous intraepithelial lesion; ASCUS = atypical squamous cells of undetermined significance; AGUS = atypical glandular cells of undetermined significance 9.7% to.8%). For pathologists who made fewer ASCUS diagnoses, and interpreted fewer cases, the number of women at follow-up who had or developed was much higher (range % to 8.8%). In general, these pathologists were least experienced. For those patients who had or developed, the time from initial ASCUS diagnosis to diagnosis is shown in Table 6 In approximately % of either the high-risk or lowrisk groups, the diagnosis of was not established until after. year. In the low-risk and high-risk groups combined, AmJCIinPathol 999;: Downloaded from by guest on September 8 No. of Women

4 Raab et al / LONG-TERM OUTCOME WITH ATYPICAL SQUAMOUS CELLS OF UNDETERMINED SIGNIFICANCE Table 5 Follow-Up by Pathologist Follow-Up Pathologist % ASCUS Atypical Cells % % ASCUS = atypical squamous cells of undetermined significance; = low-grade squamous intraepithelial lesion; = high-grade squamous intraepithelial lesion and adenocarcinoma in situ; % ASCUS = percentage of ASCUS diagnoses compared with total number of diagnoses made; atypical cells = atypical squamous cells of undetermined significance or atypical glandular cells of undetermined significance. Table 6 Follow-Up Time in Women at Low and High Risk With Atypical Squamous Cells of Undetermined Significance and High-tirade Squamous Intraepithelial Lesion at Follow-Up Women at Low Risk (i i = ) Time to Diagnosis (mo) Average <6 < < Women at High Risk (n = ) No. % No. % % did not have an diagnosis until. years after the original ASCUS diagnosis. For example, in the woman in the high-risk group who had an and an AIS, the diagnosis of was not made until 5.6 months after the original ASCUS diagnosis. Prior to this time, diagnoses of benign,, or ASCUS were made; the most recent diagnosis was, on a repeat smear 5 months after the ASCUS diagnosis. Discussion At the University of Iowa, women with a diagnosis of ASCUS receive more aggressive follow-up than simply a repeat smear test in year. The average time to follow-up (either repeat smear or biopsy or both) in our study was approximately 6 months. However, no invasive carcinomas developed, even in women with delayed follow-up (more than year) and women in whom SIL was detected up to 5 years after the original ASCUS diagnosis. A diagnosis of ASCUS is associated with low risk for development of invasive cervical cancer in women with routine follow-up. In a review of the literature, Ostor estimated that invasive cancer will develop in more than % (possibly up 6 Am J Clin Pathol 999;:57-6 to %) of women with untreated CIN III (a subcategory of ) and % of patients with untreated mild dysplasia (). The data from this study indicate that, irrespective of history of cervical disease, the probability that eventually will develop in a University of Iowa patient with ASCUS is 9%. It follows that, if untreated, invasive cancer eventually will develop in approximately % of University of Iowa patients with ASCUS (9% of women with ASCUS had or developed X % of women with may develop cancer = ~\%). Using the high end of the range of Ostor's data, if all women with ASCUS had CIN III, invasive cancer could develop in a higher percentage of women. In reality, however, the probability of invasive cancer developing should be less than %, because a large percentage of women with an ASCUS diagnosis have or will develop only CIN II (77% of patients with in this study), which, if untreated, has only a 5% probability of developing into invasive cancer. Another variable important in determining the optimal follow-up protocol for patients with ASCUS is the progression rate of SIL to invasive cancer.-5 It probably takes longer than 5. years for most untreated squamous carcinomas in situ to develop into invasive cancer, and for other subtypes the progression is considerably longer. With the assumption that rapidly progressing SIL is rare, in a woman who has had regular Pap smears and is diagnosed with ASCUS the probability is low that invasive cancer will develop if she has regular follow-up. Using a decision analytic model, our laboratory previously determined that -year repeat smear testing is the most cost-effective follow-up strategy in women with ASCUS. This is true even assuming higher rates of (more than %) and of rapid progression to cancer. Assuming an ASCUS diagnosis in million women annually, the annual cost savings to perform a repeat smear test in year, rather than immediate colposcopy, would be $5 million. Downloaded from by guest on September 8 Diagnoses

5 Anatomic Pathology / ORIGINAL ARTICLE In this study, the average time before a repeat smear test was 6.8 months, although in % of patients who had or developed the diagnosis was not established until after. year. In.9% of patients, the diagnosis of was not established until. or more years after the original ASCUS diagnosis. It is questionable that these women really had a lurking originally diagnosed as ASCUS, or an that progressed to in the intervening time. Women who had a history of atypical cells had a greater probability of ASCUS than did women with no such history. An ASCUS diagnosis was made in.% of the low-risk group, assuming that 88.5% of the University of Iowa screened population was at low risk. (This is a slight overestimation, because some of the women with benign smears had a history of atypical cells: 97 ASCUS diagnoses/[9,9 total smears X 88.5% benign diagnoses].) In comparison, an ASCUS diagnosis was made in.% of women in the high-risk group. With our data as a benchmark, an ASCUS diagnosis is relatively uncommon in women with no history of atypical cells. In addition, multiple consecutive ASCUS diagnoses are unusual (only.7% of the entire ASCUS population), indicating that repeat smears usually are definitive diagnostically. Allowing for the small sample size, or more ASCUS diagnoses denote increased risk for having or developing SIL but not for having or developing. Thus followup with repeat smear tests in women with consecutive ASCUS diagnoses appears to be justified. In a long-term follow-up study of a smaller number of patients, Stastny et al reported that women with ASCUS were at.6 times greater risk for development of SIL than women with a benign smear. In that study, in 7 women with ASCUS at high risk, SIL was diagnosed in 8 (.%) at follow-up, which is slightly lower than the % determined in our study. However, despite this increased risk for development of SIL, if followed up regularly, women with ASCUS still would be at low risk for development of invasive cancer. The ASCUS diagnosis is used differently by different pathologists, and is poorly reproducible among different pathologists and even for the same pathologist.^5 Although no attempt has been made to establish an "optimal" From the 'Department of Pathology and Laboratory Medicine, Allegheny General Hospital, Pittsburgh, PA, and the Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA. Address reprint requests to Dr Raab: Allegheny General Hospital, E North Ave, Pittsburgh, PA References. National Cancer Institute. ALTS: the ASCUS/ triage study. Alternatives in Women's Health Care Newsletter, :. Rockville, MD: National Cancer Institute, National Institutes of Health, Raab SS, Steiner AL, Hornberger J. The cost effectiveness of treating women with a cervical vaginal smear diagnosis of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 998;79:-.. Terry RR. Management of patients with atypical squamous cells of undetermined significance (ASCUS) on Papanicolaou smears. J Am Osteopath Assoc. 996;96: Kurman RJ, Henson DE, Herbst AL, et al. Interim guidelines for management of abnormal cervical cytology. JAMA. 99;7: Am J Clin Pathol 999;: Downloaded from by guest on September 8 In theory, if subgroups of women with ASCUS are at different risk for development of invasive cancer, these groups could be triaged for different follow-up, with more aggressive follow-up for women at higher risk. Stratification by history of cervical disease did not affect the probability of having or developing. Other factors that may prove more useful in differentiating women with ASCUS at high risk from those at low risk include ability to subclassify ASCUS on the basis of cytologic features,6 ancillary studies such as human papillomavirus testing,7 automation,8,9 and patient variables such as age and compliance. percentage of follow-up s, laboratory standardization of the ASCUS category may be critical before universal practice guidelines for ASCUS follow-up can be adopted.8 Currently the probability that a laboratory or pathologist underdiagnoses or overdiagnoses ASCUS may have a greater influence on follow-up data than any potential high-risk variables gleaned from patient demographics or ancillary studies. These data no not indicate that ASCUS is a useless category; ASCUS still denotes risk for having or developing a high-grade lesion (this risk is higher than for a benign diagnosis and lower than for an SIL diagnosis). This study did not investigate the necessity of the ASCUS category, but it could be argued that pathologists cannot always classify smears as SIL or benign, and therefore an intermediate category is needed. The reasons that pathologists use ASCUS and the extent to which ASCUS diagnoses are made because of fear of litigation needs further study. Depending on how women with ASCUS are treated, the ASCUS category may be viewed as expensive. The data from this study indicate that most women with ASCUS probably do not need to be followed up aggressively, and therefore ASCUS should not be a costly societal diagnosis. However, this issue is complex and depends on a number of factors, such as patient preference, which have not been extensively evaluated. In summary, the probability is low that a woman with an ASCUS diagnosis will have or develop, and the risk for development of invasive cancer before a routine -year follow-up smear test is extremely low. Further study is necessary to identify possible subpopulations in whom more aggressive follow-up may be warranted.

6 Raab e t al / LONG-TERM OUTCOME WITH ATYPICAL SQUAMOUS CELLS OF UNDETERMINED SIGNIFICANCE 5. Spitzer M, Krumholz BA, Chernys AE, et al. Comparative utility of repeat Papanicolaou smears, cervicography, and colposcopy in the evaluation of atypical Papanicolaou smears. Obstet Gynecol. 987;69: Jones DED, Creasman WT, Dombroski RA, et al. Evaluation of the atypical Pap smear. Am ] Obstet Gynecol. 987;57: DeMay RM. The Pap smear. In: The Art and Science of Cywpathology. Chicago, IL: ASCP Press; 996: Alanen KW, Elit LM, Molinaro PA, et al. Assessment of cytologic follow-up as the recommended management for patients with atypical squamous cells of undetermined significance or low grade squamous intraepithelial lesions. Cancer Cytopathol. 998;8:5-.. Howell LP, Davis RL. Follow-up of Papanicolaou smears diagnosed as atypical squamous cells of undetermined significance. Diagn Cytopathol. 99;:-.. The Bethesda Committee. The Bethesda System for Reporting Cervical/Vaginal Diagnoses. New York, NY: Springer-Verlag; 99.. Ostor A G. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 99;: Kiviat N. Natural history of cervical neoplasia: overview and update. Am] Obstet Gynecol. 996;75: Ryan MR, Stastny JF, Remmers R, et al. PAPNET-directed rescreening of cervicovaginal smears: a study of cases of atypical squamous cells of undetermined significance. A m i Clin Pathol. 996;5: Sherman ME, Schiffman MH, Mango LJ. Evaluation of PAPNET testing as an ancillary tool to clarify the status of the "atypical" cervical smear. Mod Pathol. 997;: Bowlin RB, Grillo D, Pittman KP, et al. Correlation of two A S C U S with cervical biopsy diagnoses: 9 cases from the Mississippi State Department of Health [abstract]. Acta CytoL 996;:A.. Stastny JF, Remmers RE, London WB, et al. Atypical squamous cells of undetermined significance: a comparative review of original and automated rescreen diagnosis of cervicovaginal smears with long term follow-up. Cancer Cytopathol. 997;8:8-5.. Renshaw H A, Lee KR, Granter SR. Use of statistical analysis of cytologic interpretation to determine the causes of interobserver disagreement and quality improvement. Cancer Cytopathol. 997;8:-9.. Sherman ME, Schiffman MH, Lorincz AT, et al. Toward objective quality assurance in cervical cytopathology: correlation of cytopathologic diagnoses with detection of high-risk human papillomavirus types. Am J Clin Pathol. 99;: Eddy DM. Screening for cervical cancer. Ann Intern Med. 99;:-6.. Soost H, Lange H, Lehmacher W, et al. The validation of cervical cytology: sensitivity, specificity and predictive values. Acta CytoL 99;5: Johnson N, Sutton J, Thornton JG, et al. Decision analysis for best management of mildly dyskaryotic smear. Lancet. 99;: Confortini M, Biggeri A, Cariaggi M, et al. Intralaboratory reproducibility in cervical cytology: results of the application of a slide set. Acta CytoL 99;7: Collins LC, Wang HH, Abu-Jawdeh GM. Qualifiers of atypical squamous cells of undetermined significance help in patient management. Mod Pathol. 996;9: AmJCIinPathol 999;:57-6 Downloaded from by guest on September 8 8. Davey DD, Naryshkin S, Nielsen ML, et al. Atypical squamous cells of undetermined significance: interlaboratory comparison and quality assurance monitors. Diagn Cytopathol. 99;: Cox JT, Lorincz AT, Schiffman MH, et al. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am] Obstet Gynecol. 995;7:96-95.