CANCER 202 CYTOPATHOLOGY The Promise and Risk of a New Technology The Lehigh Valley Hospital’s Experience with Liquid-Based Cervical Cytology William B. Dupree, M.D.1 Harry Z. Suprun, M.D., F.I.A.C.1 David G. Beckwith, Ph.D.1 John J. Shane, M.D.1 Vincent Lucente, M.D.2 1 Department of Pathology, Health Network Laboratories, Allentown, Pennsylvania. 2 Department of Obstetrics and Gynecology, Lehigh Valley Hospital, Allentown, Pennsylvania. The authors wish to thank: Eugene Alexandrin, M.D., Kelly Frankenfield, B.S., C.T., A.S.C.P., Stephen Klasko, M.D., M.B.A., Kimberly Kemp, B.S., M.T., A.S.C.P., Gazi Abdulhay, M.D., Cynthia Sagullo, M.D., and Elizabeth Dellers, M. D., for their part in the Health Network Laboratories Experience with liquid-based cervical cytology. Address for reprints: William B. Dupree, M.D., Health Network Laboratories, 2024 Lehigh Street, Allentown, PA 18103. Received September 2, 1997; revisions received December 15, 1997, and January 12, 1998; accepted January 22, 1998. © 1998 American Cancer Society ‘‘If you can look into the seeds of time and say which grain will grow and which will not, speak then to me. . .’’ Macbeth, Act 1, Scene 3 A nearly silent revolution in women’s health care began in May 1996 when the Federal Drug Administration (FDA) approved the 1 Thin Prep 2000t System for cervical carcinoma screening. The promise of this new technology is to provide a method by which cytopathologists can easily look into the ‘‘seeds’’ (cells) of time to predict which cervical lesions will grow (neoplasia) and which will not. This promise is coupled with a potential reduction in 1) atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells of undetermined significance (AGUS) diagnoses; 2) needless patient anxiety brought about by spurious ASCUS/AGUS; and 3) escalation of healthcare costs fueled by needless repeat Papanicolaou (Pap) tests, colposcopy, and cervical cone biopsies. This potential for improved quality of care and overall healthcare cost reduction has spawned a degree of optimism not experienced in cytology since the days of Papanicolaou. Mass population screening has proven to be effective in reducing 2– 6 the mortality from cervical carcinomas. Data from Fidler et al. imply that approximately 75,000 women have to be screened annually to 7 detect a single case of cervical carcinoma. Approximately 50 million Pap smears are performed annually in the U.S. Of these, approxi8 mately 8% are abnormal. These abnormal Pap smears result in an 8 annual cost approaching $6 billion to diagnose and treat. Many factors contribute to this inefficiency of scale (Table 1). However, one of the questions we have to face as a society is whether our system under managed care models will continue to pay for the relatively small percentage of malignancies that currently are detected by an inefficient screening and management program. The stage is ready for a new technology that will improve the efficiency of screening for cervical disease and provide for adjuvant testing that could help us to better separate those ‘‘which will grow’’ from those ‘‘which will not.’’ The allure of liquid-based cervical cytology is potent (Table 2). Trends in preliminary data reported from Lehigh Valley Hospital, which was among the first wave of laboratories in the nation to adopt Thin Prep technology, suggest that the promise may be a reality of practice. Although other liquid-based cytology methodologies are evolving (Autocyte Prept, Elon College, NC) the focus of this discussion is limited to our experience with the Thin Prept method developed by Cytyc Corporation (Boxboro, MA). Liquid-Based Cervical Cytology/Dupree et al. TABLE 1 Factors Contributing to the Inefficiency of Scale of Cervical Vaginal Cytology Screening9 –15 I II III IV V VI Inherent inefficiency due to the screening nature of the test Technical shortcomings of the test A Sampling B ASCUS/AGUS Variable intervals for repeat Pap A Normal setting B Abnormal setting The borderline Pap dilemma13,19–36,50,54 A ASCUS B AGUS A lack of consensus as to management of borderline cervical lesions Malpractice climate in U.S. ASCUS: atypical squamous cells of undetermined significance; AGUS: atypical glandular cells of undetermined significance; Pap: Papanicolaou smear. The New Technology With Thin Prept methods the clinician obtains the gynecologic specimen from the patient in the usual manner either by the FDA-approved cervical broom, plastic spatula, or cytobrush. The clinician then rinses the collection device in a vial containing an alcoholbased preservative solution (Preserv-cyt [Cytyc Corp.]) for transport to the cytology laboratory. The vial and matching slide are placed into the Thin Prep processor along with a disposable filter cylinder. The Thin Prep processor automatically prepares the slide in three steps: dispersion, filtration, and transfer of the cells to 48 the slide. Because cellular material on Thin Prept slides has been collected in a solution and then filtered, its microscopic presentation results in a somewhat different appearance than on conventional Pap smears. Of distinct advantage for cytotechnologists is the decreased need to switch between low and high power objectives for screening information. As a result of immediate wet fixation, the nuclear hyperchromatic staining appearance, typically associated with squamous lesions on conventional Pap smears, is reduced. On Thin Prep slides, cell nuclei often take on a more delicate vesicular appearance and cytoplasmic differentiation becomes an increasingly important indicator of cell origin. Some cytologic characteristics of the liquid-based method are slightly different from those of the conventional Pap smears; however, the similarities greatly outweigh the differences. Health Network Laboratories’ Experience with Thin Prep Technology Health Network Laboratories (HNL), the clinical laboratory service of Lehigh Valley Hospital, first employed the Thin Prept method in January 1997. When Thin 203 Prept results from the initial period of January through September 1997 were compared with the same 1996 9-month interval of conventional Pap smears taken from the same patient pool, certain positive trends were noted. Although more time is required to accrue numbers that will support rigorous statistical analysis, preliminary trends tend to support the promise of Thin Prep technology (Table 3). Results of conventional cervical smears prepared by the standard Pap technique after alcohol fixation reported from January through September 1996 were compared with the liquid-based cervical cytology preparations (Thin Prept) results that were reported from January through September 1997 (Table 3). The general patient sample space for both periods of time was identical, comprised of cervical cytology specimens taken from the same private, group, and clinic practices. The six cytotechnologists and three cytopathologists handling the cases were the same for both time periods. The interobserver variability between the cytotechnologists was approximately 2%. Data regarding interobservor variability between the three cytopathologists were not available. Although the plastic spatula and cytobrush now have been approved by the FDA for use with the Thin Prept system, during the initial phase of HNL experience, clinicians were limited to the ‘‘broom’’ sampling device, the only appliance earlier approved by the FDA for Thin Prept. This fact, coupled with the learning curve inherent in any new technology, may have contributed to the 284 additional cases deemed ‘‘unsatisfactory due to lack of endocervical elements,’’ garnered by the liquid-based method. The costs incurred by repeating many of these Pap tests was assumed by HNL as part of the developmental expense of instituting a new test. The 1997 liquid-based Pap test results reflected 159 fewer cases of AGUS and 218 fewer cases of ASCUS than the equivalent 1996 conventional Pap smear interval. This trend in part may be due to a more effective presentation of cells. Although the reduction in needless patient anxiety is indisputable, it is more difficult to calculate the magnitude of the healthcare cost savings. It is the general consensus among gynecologists that ASCUS/AGUS findings warrant increased patient monitoring. However, experts are divided as to which algorithm represents optimal 49 management. A balance must be reached between overtreatment of cytologic changes (which in the majority of cases would regress) and underdiagnosis of a 34,35,36 minority of women at risk for a high grade lesion. In addition, ASCUS management guidelines may not necessarily be applied uniformly from locale to locale or even by members of the same clinical practice 204 CANCER (CANCER CYTOPATHOLOGY) August 25, 1998 / Volume 84 / Number 4 TABLE 2 The ‘‘Promise’’ of Liquid-Based Cervical Cytology Specimens (Thin Prept, CYTYC Corporation) The ‘‘promise’’ The problem (Thin Prep) (Conventional Pap smear) I Enhanced recovery of cells38,39,40 Eighty percent of cervical cells lost with discarded cervical collection device37 Up to 40% comprised by artifact41 II Reduction obscurring artifacts A Preservative solution lyses RBCs B Obscuring clumps of mucus dispersed C Aggregates of ‘‘polys’’ homogenized D Cellular overlap reduction E Air-dried artifact eliminated III Advantage for cytotechnologist A Improved cell presentation IV Ancillary tests Liquid-based specimen container serves as ready source of cells for ancillary studies such as HPV typing17–19,46,47 V Cost Cost benefit studies and outcome studies will justify use of liquidbased cervical cytology screening The ‘‘hope’’ Significant reduction in false-negative rate38–40 (increased sensitivity) Reduction in diagnosis ASCUS/AGUS due to specimen compromise A Fewer repeat Pap tests B Fewer colposcopies C Fewer biopsies (Increased sensitivity)42,54 Up to 40% compromised by artifact41 Reduction in screening-related stress15 Greater productivity45 Elimination of added cost and inconvenience of a repeat specimen The majority of ancillary studies require repeat specimen The conventional Pap test is undervalued Minimal added cost will be justified by cost benefit and outcome studies Pap: Papanicolaou smear; RBCs: red blood cells; ASCUS: atypical squamous cells of undetermined significance; AGUS: atypical glandular cells of undetermined significance; HPV: human papillomavirus. TABLE 3 Preliminary HNL Liquid-Based Cytology Results Compared with Conventional Cervical Smear Results–1996 Total preparations Unsatisfactory ASCUS AGUS LSIL HSIL Turnaround time Conventional cervical smears (January–September 1996) Liquid-based cytology preparations (January–September 1997) 22,323 cases 447 1102 202 218 47 12 days 19,351 cases 731 884 43 270 54 6 days Comparison 2972 fewer liquid-based cases 284-case increase in liquid-based method 218-case decrease in liquid-based method 159-case decrease in liquid-based method 52-case increase in liquid-based method 7-case increase in liquid-based method Turnaround time decrease of 6 days for liquid-based method ASCUS: atypical squamous cells of undetermined significance; AGUS: atypical glandular cells of undetermined significance; LSIL: low grade squamous intraepithelial lesion; HSIL: high grade squamous intraepithelial lesion. group. In areas in which sensitivity of detection of squamous intraepithelial lesions (SIL) is of paramount importance, colposcopy and biopsy make sense. However, in areas in which a more cost-effective approach is preferred, cytologic follow-up may be utilized. In a similar fashion, management options for AGUS include: 1) repeat cytologies at more frequent intervals; 2) colposcopy with biopsy as indicated and endocervical curettage/cytobrush specimens; or 3) cone biopsy. Regardless of differences in philosophies and attendant management strategies, the potential reduction of spurious ASCUS and AGUS cases will spell significant savings in needless patient anxiety and healthcare costs. Preliminary numbers indicate that the liquid-based Pap tests potentially identified 52 additional cases of low grade SIL (LSIL) and 7 additional cases of high grade SIL (HSIL). This potential enrichment of significant diagnoses may in part be due to a reduction in ASCUS/AGUS cases due to a compromise in the conventional smear or actually may reflect a greater sensitivity linked to superior sampling by the clinician and Thin Prept method. An added positive feature of Thin Prept technology was a unanimous vote of increased job satisfaction among Liquid-Based Cervical Cytology/Dupree et al. HNL cytotechnologists. This finding was coupled with a 20% increase in productivity and a reduction of turnaround time from 12 to 6 days. The Risk of New Technology Many uncertainties face cytology laboratories that will be processing Pap smears in the late 1990s. In an age of managed care and at best marginal reimbursement, some cytology laboratories have found it difficult to even recoup the cost of performing the test. Medical malpractice suits against pathologists and cytotechnologists who allegedly miss abnormal cells may now charge homicide. Will there be tort reforms? Will the promise of liquid-based cytology and automated screening be realized? Will the new technology be cost-effective? Will society and payers of healthcare put their money where the value is? Faced with these uncertainties, many prominent cytology laboratories are wondering whether the risk/benefit ratio warrants the continuation of even conventional Pap services and are reluctant to explore new technologies because of increased cost and potential medicolegal risks. The clinical and scientific allure of liquid-based technology is potent. Early experience at HNL suggests that the scientific and clinical promise of Thin Prept are real. However, the early acquisition of any new technology forces the sponsoring institution to assess risk centering around operational issues such as test performance, test quality, cost, reimbursement, customer acceptance, customer satisfaction, improved clinical outcomes, and obsolescence. The opposite perspective from risk is organizational advantage, which for a new technology includes market recognition, competitive edge, better patient outcomes, new sources of profit, and more satisfied employees. A risk/benefit analysis was conducted as part of Lehigh Valley Hospital’s decision to adopt Thin Prept methods as an alternative to conventional methods of Pap smear processing. In keeping with Lehigh Valley Hospital’s commitment to offering the most up-to-date and cost-effective technologies to improve community health outcomes, assessment of liquid-based Pap smear technology became a high priority. To evaluate the potential risk of failed performance and suboptimal quality one must ignore marketing propaganda coupled with testimonials and rely heavily on the critical review of pilot studies employing the new technology in question. A careful review of preliminary studies in conjunction with FDA analysis quickly demonstrated the clinical and scientific validity of the method. Meetings with gynecologists and gynecologic oncologists revealed a similar level of confidence enjoined with conservative optimism. A program to acquaint gyne- 205 cologists, residents, and office support teams with the technical aspects of the new liquid-based process was instituted and met with guarded enthusiasm. This initial introductory program is critical to create a relatively problem free transition from conventional to liquid-based Pap smears and promote customer acceptance. In addition, to ensure patient satisfaction a short educational program was crafted explaining the advantages of Thin Prep, which warrant the relatively small increase in cost. Programs were devised to inform patients that depending on the policies of their health care payer, some of this additional cost might represent an out-of-pocket expense. With the final decision to implement liquid-based Pap smears, a cytotechnologist-cytopathologist team attended training sessions at Cytyc Corporation headquarters and after certification became instructors to certify the remaining cytotechnologists and pathologists at HNL. Split sample testing including conventional Pap smears and liquid-based preparations was instituted to validate the in-house procedure. Our recommendation is that all users of the liquid-based method allow time and resources for adequate training with split sample trials to mitigate risks occurring during familiarization of technologists and pathologists with a new method. The risk associated with adding increased costs to an already underreimbursed test was of concern. Today laboratories are scrutinizing their costs closely and realizing that previously established reimbursement rates do not even come close to covering the true cost of conventional Pap smears.50 An April 1996 article in the Dark Report, a business intelligence service for clinical laboratory executives, reported that even large commercial laboratories are subjecting their laboratory services to rigorous cost analyses and finding that the Pap smear is a major money loser. Whether laboratories will be able to move prices upward to recover full costs, the author speculated, could vary regionally according to competition.51,52 With these problems keenly in mind, it was our contention that, when legally possible, the consumer would be willing to shoulder the minimal added financial burden once educated as to the advantages of the test. Although work remains to be done, in general women are beginning to understand better the importance of screening tests for cervical carcinoma. Women want a test that is reliable, accurate, and predictive and that ideally leads to as few questionable results and repeat testing as possible. HNL market research indicated that women in the Lehigh Valley would be willing to pay for this test even if the payment is above and beyond that covered by their insurance. Our first belief, now supported by the preliminary trends reported here, was that the promise of the new technology to 206 CANCER (CANCER CYTOPATHOLOGY) August 25, 1998 / Volume 84 / Number 4 reduce both patient anxiety and the overall outlay of community expenses in detecting and managing cervical disease would be realized. We chose to assume the risk related to reimbursement. To date several insurers have agreed to reimburse all or in some instances at least a part of the minimally increased charge. As predicted, women whose insurance plans will not cover the expense are choosing to pay out-ofpocket. Our customer acceptance data indicate women appreciate the option to have their Pap smears prepared using liquid-based technology and in some instances insist on the method. Another risk in adopting any new technologic advance is the risk of obsolescence. Monolayer technology finds its origin in the quest for the perfect automated screening device. It is our opinion that liquidbased technology will play a key role in more efficient and accurate automated screening in the future. In addition, this new technology lends itself more effectively to the triage of LSIL as well as ASCUS/AGUS on the basis of human papillomavirus viral typing. We believe that liquid-based Pap technology will prepare our laboratory for the day when these additional technologies become a central part of the diagnosis and management of cervical disease. The liquid-based Pap technology is one of several technologies we have chosen to invest in as part of an automation initiative. It is viewed as an investment that will in the future ‘‘pay off’’ by enhancing methods for Pap screening that should improve clinical outcomes and productivity, and reduce overall cost of care. As an additional immediate advantage, our implementation of the liquid-based method has greatly improved our cytotechnologist job satisfaction rating, increased our market share, and provided HNL with the opportunity to support our Women’s Health Program. calating costs and the plethora of new medical alternatives, the federal government, insurers, physicians, hospital administrators, and nurses have initiated critical reviews with a single goal: to determine which of our medical technologies truly are effective. One approach to such a review is embodied in the rapidly growing field of outcomes research.53 It is hoped that with more liquid-based Pap tests and their outcome studies, our ability to evaluate whether liquid-based systems will truly allow us to better ‘‘look into the seeds’’ (cells) ‘‘of time’’ and predict ‘‘which will grow and which will not.’’ REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Conclusions Comparison of conventional Pap smears and fluidbased thin layer systems are beginning to show a statistically significant increase in the sensitivity of liquid-based systems over conventional Pap tests.55 Preliminary experience of HNL suggests that the promise of liquid-based cervical cytology preparations not only improves the sensitivity of the cytology test but also greatly enhances the overall quality of the cervicovaginal cytology service. Although the promise of liquid-based cervicovaginal cytology appears to be real, cautious optimism is indicated. 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