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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cooper, A. L. Articles by Modesitt, S. C. Search for Related Content PubMed PubMed Citation Articles by Cooper, A. L. Articles by Modesitt, S. C. Related Collections Cytology/colposcopy Gynecologic oncology Cost effective analysis Pathology

Is Cytologic Screening an Effective Surveillance Method for Detection of Vaginal Recurrence of Uterine Cancer?

From the ¹Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and the ²Department of Pathology and Laboratory Medicine, University of Kentucky Chandler Medical Center, Lexington, Kentucky.

	ABSTRACT

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OBJECTIVE: Cytologic screening is commonly used in follow-up of women with uterine cancer to detect vaginal recurrence. The study objective was to assess the efficacy and costs associated with Pap tests in routine surveillance of women with uterine cancer.

METHODS: Medical records and pathology databases identified patients with uterine cancer at one institution from 1990 to 2002. Patients with their cytologic follow-up at our institution were selected for a subset analysis of Pap tests to estimate the number of Paps and associated charges and costs during follow-up.

RESULTS: Seven hundred seventeen women were diagnosed with uterine cancer; the mean age was 60.9 years and the median follow-up was 46 months. A total of 36 women had a recurrence in the vagina; 31 (86%) were apparent clinically, and only 5 (14%) were asymptomatic and identified by Pap test. Women with grade 1 tumors had decreased risk of vaginal recurrence, with an odds ratio of 0.186 (95% confidence interval 0.49–0.712) on multivariate analysis (stage and histology were not significant factors for vaginal recurrence). A subset of 435 patients received cytologic follow-up at our institution, with a median 3 Pap tests/patient (mean 4.25, range 1–24). Estimates based on our data demonstrate that 430 Pap tests are required to detect one asymptomatic vaginal recurrence, and the addition of the Pap test increases the cost of surveillance by $15,142 per asymptomatic recurrence detected (but a charge to insurance of $23,487). Pap tests identified an asymptomatic vaginal recurrence in only 0.7% of this uterine cancer population.

CONCLUSION: Pap tests after diagnosis and treatment of uterine cancer infrequently detect asymptomatic vaginal recurrences and may not be cost-effective.

LEVEL OF EVIDENCE: III

Subsequently, several studies have examined the effectiveness of routine use of the Pap test for posttreatment surveillance. Each of these studies followed approximately 300–400 endometrial cancer patients and evaluated the ability of the Pap test to diagnose vaginal recurrences; these results demonstrated that the Pap test infrequently (0–25%) identifies asymptomatic vaginal recurrences. These studies raise important questions regarding the routine use of cytologic screening for posttreatment surveillance. The objective of this study was to assess the efficacy and costs associated with Pap test use in clinical follow-up for women with uterine cancers.

	MATERIALS AND METHODS

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Institutional review board approval was obtained for this retrospective analysis. The Department of Medical Records used International Classification of Diseases, 9th Revision (ICD-9) codes (179–182) to initially identify patients with diagnoses of endometrial or uterine cancer treated during 1990–2002. Patients were subsequently included in the study group if they had histologically confirmed endometrial or uterine cancer on hysterectomy specimen at the University of Kentucky. Patient data were then collected regarding age, diagnosis, tumor characteristics, number and results of Pap tests performed in follow-up at our institution, and follow-up data regarding recurrence, location of recurrence, and patient health status at last contact. Pathology databases were also searched for all vaginal biopsy results demonstrating cancer, and these were correlated with our patient list. To facilitate complete data collection, outpatient charts, as well as computer databases, were abstracted. Additionally, the University of Kentucky Cancer Registry database was used to confirm patient health status and date of last known contact.

Pap test charges were calculated based on 2004 charges at the University of Kentucky Chandler Medical Center for a liquid-based Pap test. Excluding the physician visit charges, the maximum charge incurred for a Pap test would be $93.00 (based on a $45.00 technical and $48.00 professional Pap charge) and a minimum of $45.00 per patient (technical charges only). At our institution, approximately 20% of the Pap tests are referred for professional review in this population. Pap test costs estimates were based on low cost ($28.00 for a technical cost only) and a high cost ($64.00 for both a technical cost and physician review) as previously reported in the cervical cancer screening literature.⁶ Abnormal Pap tests were defined as any epithelial abnormality.

Data were analyzed using the SPSS 13.0 (SPSS Inc, Chicago, IL) program for statistical analysis. Chi-square tests were used to test the association between categorical variables. Survival analysis was performed using the Kaplan-Meier method and the log-rank statistic. Multivariate analyses were performed using a multinomial logistic regression model with a vaginal recurrence as the variable of interest. The precision in estimating the prevalence of uncommon events such as vaginal recurrence in a sample of size 717 is adequate because the half-width of an approximate 95% confidence interval for a proportion P = .05 is roughly 1.6%. For all tests, a P value < .05 was deemed statistically significant.

	RESULTS

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Seven hundred and seventeen patients with uterine cancer who met the inclusion criteria for this retrospective study were identified from the University of Kentucky databases. The mean age of the cohort was 60.9 years (standard deviation 12.8), and the median follow-up was 46 months (mean 52.5 months). The rest of the characteristics for the entire cohort are provided in Table 1, but the majority of the patients were stage I (72%) and had endometrioid histology (81%).

Of the original 717 patients, 435 (61%) had cytologic follow-up at the University of Kentucky, and these women did not differ from the entire cohort with regard to grade or histologic type but did differ significantly with regard to stage (P = .003) and cancer recurrence (P < .001). There was an equal percentage of women with stage I disease followed cytologically at University of Kentucky compared with the women followed outside, but a higher percentage of stages II and III (University of Kentucky with 67% compared with 33% on the outside), a lower percentage of stage IV (University of Kentucky with 36% stage IV versus 64% on the outside). With regard to recurrence status, the proportion of women with a recurrence was slightly lower in the women followed at University of Kentucky. Additionally, 95% of the 20 women where the recurrence status was unknown were not followed at University of Kentucky. Overall survival, however, did not differ between the 2 groups on Kaplan-Meier survival curves (log-rank test = 0.099).

A total of 1,848 Pap tests were performed on the 435 women followed at the University of Kentucky (Table 2). The mean number of Pap tests performed was 4.25 (median 3, range 1–24), and 82 Pap tests (4.4%) were abnormal in 52 patients, but the vast majority of patients (87.8%, 382/435) never had an abnormality on a Pap test. The most common abnormality was atypical squamous cells of undetermined significance (ASC-US) followed by cancer and low-grade squamous intraepithelial lesions (LSIL) (Table 2). Of note, the majority of the Pap tests that demonstrated cancer were performed simultaneously with a biopsy of a suspicious lesion as delineated below.

During the course of the study, 132 women were documented to have recurrence of their disease (Table 1), and of those, 36 women suffered a vaginal recurrence (Table 3). Women with vaginal recurrences differed from women without vaginal recurrences with regard to grade (P = .012); only 3 (8.3%) vaginal recurrences occurred in women with grade 1 disease even though 33.3% of the study population had grade 1 disease. Otherwise, women with vaginal recurrences did not differ from the women without vaginal recurrences with regard to either stage (P = .087) or histology (P = .314). Looking more closely at the pathologic subsets, we compared the 43 sarcoma patients with the 674 adenocarcinoma patients and found significant differences with regard to stage (P < .001) and recurrence (P < .001), but not with regard to vaginal recurrence (P = .403). Specifically, the sarcoma patients were less likely to be stage I at diagnosis (53% versus 73%) and more likely to recur (42% versus 17%). A multivariate regression analysis was performed using stage, grade, and histology; this confirmed that grade was the only significant factor that influenced vaginal recurrence. Specifically, women with grade 1 tumors had a markedly decreased risk of vaginal recurrence, with an odds ratio of 0.186 (95% confidence interval 0.49–0.712), compared with those with more advanced grade tumors. A post hoc power analysis did reveal a limited power to detect differences across stage (power = 56%).

The majority of the vaginal recurrences (86%, 31/36) was symptomatic and identified on pelvic examination, and only 5 (14%) were identified on a routine Pap test. Seventy-five percent (27/36) of the vaginal recurrences were isolated, and 89% (24/27) of these were identified on examination with a confirmatory biopsy performed. Women with an isolated vaginal recurrence had markedly improved overall Kaplan-Meier survival compared with women with additional pelvic or distant disease (Fig. 1, log-rank P = .003). In these women diagnosed with a vaginal recurrence, 3/20 (15%) had a simultaneous false-negative Pap at the time of their biopsy of a visible lesion (Table 3). These Pap tests were all reported as satisfactory, although one was noted to be limited by partially obscuring blood. These false-negative Pap tests were all re-reviewed for this study by one of the authors (D.D.) and were not found to have any significant abnormalities.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Kaplan Meier Survival curve comparing overall survival in women with a vaginal recurrence. Illustration: John Yanson. Cooper. Pap Tests for Follow-up in Uterine Cancer. Obstet Gynecol 2006.

Of 717 patients, only 5 (0.7%) developed an asymptomatic vaginal recurrence that was detected on a routine Pap test. All 5 had reportedly normal pelvic exams at the time of the Pap test that demonstrated cancer. Following the Pap abnormality, in 4 of 5 women, a follow-up examination diagnosed a vaginal lesion, and biopsy was performed. The remaining patient had liver lesions identified at the time of the abnormal Pap, and further vaginal evaluation was not performed. The women who were asymptomatic at the time of their vaginal recurrence did not differ with regard to overall survival compared with the women diagnosed on examination based on Kaplan-Meier survival curves (log-rank P = .574).

We estimated the charges and costs of routine surveillance Pap tests in our patient population. By extrapolating from the data on the women who received all their cytologic follow-up at our institution, we estimated that 2,151 Pap tests were performed on 717 patients (based on a median of 3 per patient) to find 5 asymptomatic vaginal recurrences. Stated another way, this was 430 Pap tests to detect each asymptomatic vaginal recurrence. Excluding the physician visit charges, the maximum charges incurred in Pap surveillance alone would be $93 per Pap test (based on a $45.00 technical and $48.00 professional Pap charge) and a minimum of $45 per Pap (technical charges only) during the follow-up period. At our institution, approximately 20% of the Pap tests are referred for professional review in this population; this translates into 430 of the total estimated 2,151 Pap tests. Thus, for the entire patient population of 717 patients, the charge incurred to detect 5 asymptomatic vaginal recurrences was $23,487 per recurrence. We also estimated Pap test costs. We based our cost estimates on a low cost ($28.00 for a technical cost only) and a high cost ($64.00 for both a technical cost and physician review) previously reported in the cervical cancer screening literature.⁶ Again, assuming that 20% of the Pap tests would be referred for professional review, the actual additional costs of detecting an asymptomatic vaginal recurrence was $15,142 in our population.

	DISCUSSION

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Cancer of the uterine corpus is the fourth most common malignancy diagnosed in U.S. women in 2005. Although the prognosis is generally favorable, it is still estimated to account for 7,310 deaths in the United States in 2005.¹ At the time of surgical treatment, 70–80% of endometrial carcinomas are confined to the uterus. In these patients, the rate of recurrence is low at 10–20%.⁷ Despite the favorable prognosis and relatively low risk of recurrence, these women usually undergo concerted postsurgical surveillance regimens for 3–5 years. This type of routine postsurgical surveillance has been increasingly scrutinized as health care costs continue to increase.

The follow-up regimen for women with endometrial cancer typically involves a physical examination and Pap test, with or without chest radiograph. The goal of this surveillance is to detect recurrence early and to potentially improve survival. Rosenberg et al⁸ found that 90% of isolated vaginal recurrences in endometrial adenocarcinoma patients were diagnosed at a scheduled outpatient evaluation but did not specify how the diagnosis was made. Similarly, Reddoch et al⁹ at M. D. Anderson Cancer Center reviewed their series of endometrial cancer patients and concluded that a surveillance scheme using physical examination, vaginal cytology, and serum CA 125, in addition to prompt evaluation of any symptoms, at 6–12 month intervals for 3 years would identify 95% of recurrent endometrial cancer patients. They did note, however, that the prompt detection of recurrence might not convey a survival advantage, given the lack of success of salvage therapy.

Most women with a vaginal recurrence of cancer will have signs or symptoms of disease, and the additive effect of the Pap test in surveillance remains unclear. Prior studies demonstrated that the Pap test infrequently (0–25%) identifies vaginal recurrences in asymptomatic patients, and this is consistent with our data from one of the largest patient series that demonstrated a 14% rate in identifying asymptomatic vaginal recurrences (Table 4). ^3–5,9,10 For example, Berchuck et al⁵ found that 84% of recurrent endometrial cancer patients manifested either signs or symptoms of recurrent disease and that 3/12 (25%) isolated vaginal recurrences were picked up solely on a Pap test. In contrast, another study from Canada of 435 patients found that vaginal cytology did not diagnose any cancer recurrences,¹⁰ and the M. D. Anderson series detected only one asymptomatic patient on vaginal cytology.⁹ Likewise, Agboola et al³ in 1997 evaluated 432 patients diagnosed with endometrial cancer and demonstrated 19 local recurrences, and only 2 were detected by Pap test at routine screening intervals. More recently, Morice et al⁴ found that, in 390 patients diagnosed with clinical stage I/II endometrioid carcinoma, 5 developed vaginal recurrences, and none were detected on Pap tests. In all of these series, a total of 2,736 patients were evaluated, and only 11 patients (0.4%) had an asymptomatic vaginal recurrence identified on a Pap test.

Even in the face of a visible lesion, the Pap test may lack sensitivity in detecting a vaginal recurrence. This is probably generally related to sampling problems because some vaginal recurrences may not shed cells on the surface epithelium or be located in the area sampled. Additionally, some recurrences may in fact be subepithelial in location and not detectable on a vaginal cytology specimen. In our series there were 3 instances with a vaginal abnormality where a Pap test was normal, even when the biopsy confirmed cancer. Similarly, in Morice et al’s study,⁴ 3 vaginal recurrences were diagnosed on clinical examination and biopsy, yet their Pap smears done at the same time were negative. These documented false-negative Pap events raise concerns regarding a lack of sensitivity, even in women with confirmed recurrence, and serve to foster further doubt about the test’s utility in picking up asymptomatic vaginal recurrences before clinical detection.

In times of increasing concern over rising health care costs, one must weigh monetary issues as one factor that influences the use of diagnostic tests. Our data, along with the other series listed above, confirm that most women with vaginal recurrences are symptomatic and, conversely, infrequently picked up on a routine Pap test. Estimates based on our data demonstrate that 430 Pap tests are required to detect one asymptomatic vaginal recurrence, and the addition of the Pap test increases the cost of surveillance by $15,142 per asymptomatic recurrence detected (but a charge to insurance of $23,487). Costs and charges of Pap tests vary among different institutions, and this could affect the results. The assumption in this paper was that 20% of the cytology specimens would require pathologist review and that a liquid-based preparation was used. This cost does not begin to address the cost of physician visits and any other tests that occur during routine follow-up. Given the fact that the majority of vaginal recurrences can be diagnosed on examination alone, as well as the potential lack of sensitivity of the Pap, it indicates that the addition of the Pap test to the routine surveillance routine does not add to optimal clinical care. A potential rational surveillance regimen for women with endometrial cancer should include a clinical examination (with a thorough vaginal examination) at periodic intervals; intervals should be every 3–6 months for the first 5 years, depending on other clinical factors that influence the risk of recurrence. Any symptoms should be promptly evaluated with the appropriate examination and testing procedures, and Pap tests should not be routinely performed, especially in women with grade 1 tumors.

	Footnotes

 
Dr. Modesitt was supported in part by a Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) scholarship.

Partially presented in poster form at the 36th Annual Meeting of the Society for Gynecologic Oncologists, Miami, Florida, March 19–23, 2005.

Corresponding author: Susan C. Modesitt, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0298; e-mail: smode2{at}uky.edu.

doi:10.1097/01.AOG.0000194206.38105.c8

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
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2. Barnhill D, O’Connor D, Farley J, Teneriello M, Armstrong D, Park R. Clinical surveillance of gynecologic cancer patients. Gynecol Oncol 1992;46:275–80.[Medline]

3. Agboola OO, Grunfeld E, Coyle D, Perry GA. Costs and benefits of routine follow-up after curative treatment for endometrial cancer [published erratum appears in CMAJ 1998;158:26]. CMAJ 1997;157:879–86.[Abstract]

4. Morice P, Levy-Piedbois C, Ajaj S, Pautier P, Haie-Meder C, Lhomme C, et al. Value and cost evaluation of routine follow-up for patients with clinical stage I/II endometrial cancer. Eur J Cancer 2001;37:985–90.[Medline]

5. Berchuck A, Anspach C, Evans AC, Soper JT, Rodriguez GC, Dodge R, et al. Postsurgical surveillance of patients with FIGO stage I/II endometrial adenocarcinoma. Gynecol Oncol 1995;59:20–4.[Medline]

6. Kim JJ, Wright TC, Goldie SJ. Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance. JAMA 2002;287:2382–90.[Abstract/Free Full Text]

7. Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55–65.[Medline]

8. Rosenberg P, Blom R, Hogberg T, Simonsen E. Death rate and recurrence pattern among 841 clinical stage I endometrial cancer patients with special reference to uterine papillary serous carcinoma. Gynecol Oncol 1993;51:311–5.[Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cooper, A. L. Articles by Modesitt, S. C. Search for Related Content PubMed PubMed Citation Articles by Cooper, A. L. Articles by Modesitt, S. C. Related Collections Cytology/colposcopy Gynecologic oncology Cost effective analysis Pathology