Search

OBJECTIVE: To evaluate, in a preclinical feasibility study, the efficacy of NMP179, a monoclonal antibody recognizing a cervical tumor-associated nuclear matrix antigen, for the early detection of high and low grade cervical intraepithelial neoplasia. STUDY DESIGN: In a blind study involving two clinical sites, NMP179 immunocytochemical staining data from 261 cervicovaginal ThinPrep® specimens were evaluated. Assay sensitivity and specificity were calculated based upon a positive threshold of>10 immunostained cells per case, using cytologic diagnosis as an end point. RESULTS: Based upon the examination of squamous epithelial cells, NMP179 detected 96.7% of cases with cytologically diagnosed high grade squamous intraepithelial lesions (HSIL) and 70.5% of low grade squamous intraepithelial lesions. The antibody also reacted with 29.6% of normal (within normal limits or benign cellular changes) smears. CONCLUSION: The NMP179 assay detected HSIL with very high accuracy (96.7%). The assay was 79.3% sensitive for the detection of low and high grade cervical intraepithelial neoplasia (grades 1-3), with a specificity of 70.4%. NMP179 may be an effective marker for the early detection of preneoplastic squamous intraepithelial lesions of the cervix and may be useful as an adjunctive tool for better management of cervical intraepithelial neoplasia.

Issues Cell Preparation Methods Standardized fixation and optimal staining Sampling of cervix, sampling error, homogenization of sample, subsampling Assessment of liquid-based preparations: efficacy and economic impact Training and transitional procedures before full implementation of new technologies Criteria for Sample Adequacy Clinician responsibility for collecting and providing representative sample to laboratory Collection instruments, number of slides Cellular content of samples: evidence of transformation zone (TZ) sampling, number of squamous cells present, obscuring factors Screening issues CONSENSUS POSITION The conventional cervical smear remains the standard method of cervical cancer screening but has limitations in individual test sensitivity and specificity. Sample takers should: (1) receive appropriate training in sample collection, (2) be held responsible for providing the laboratory with appropriate samples, and (3) have their performance monitored. The instruments used for sampling should collect cells from both the ectocervix and endocervix; optimally, TZ sampling, represented by the presence of endocervical or squamous metaplastic cells, should be identifiable in samples other than atrophic specimens. The adequacy of a specimen (as judged microscopically) does not guarantee that it is representative of the cervix. Each cytology report should include a comment on cellular content/adequacy of the specimen. Liquid-based preparations may overcome many of the inherent problems with the conventional cervical smear. Ongoing issues We need further data on the cost-effectiveness of making two slides from cervical specimens and/or using two samplers rather than a single one. Do we have enough information to make recommendations as to the appropriate type of sampler to be used in particular situations, such as routine screening? What is the best method of screening for/detecting endocervical glandular neoplasia? How are such terms as unsatisfactory and inadequate defined in cervical cytology classifications other than the Bethesda System? What number and types of epithelial cells should be present (visualized) in a cervical smear or liquid-based preparation for it to be considered adequate? Do we need to have evidence of TZ sampling in specimens taken during the follow-up period after treatment of squamous intraepithelial lesion or after detection of endocervical glandular neoplasia? What criteria for obscuring factors, such as blood and inflammation, should be used in assessing adequacy? Cost-benefit analyses of utilizing liquid-based preparations are needed. Should we inform women about the technical details of the test methods available or chosen by the laboratory? Are women in a position to decide which method is the most appropriate to assess their cervical scrape sample? We need to obtain more information about the properties of proprietary liquid fixative/transport media with respect to inactivation of viral pathogens, tuberculosis and other bacterial pathogens and suitability for immunobiologic and molecular tests, etc. We need to obtain more information on the use of stoichiometric stains and the limitations of Papanicolaou stain for image analysis systems. The use of liquid-based preparations for nongynecologic cytopathology and ancillary tests must be considered, including criteria for adequacy. We need to obtain more information on the time required for and best methods of training experienced cytotechnologists to become competent at assessing liquid-based cervical preparations.

Issues Uterine cervical cytology smears are among the most cost-effective cancer prevention interventions available, but they are not infallible, and new or modified technologies have been and will be proposed to improve diagnostic accuracy. Before these new technologies are accepted, their performance attributes will be carefully studied and defined. Equally important in this era of fiscal constraints are cost/benefit analyses, for which we review certain guidelines. Consensus position In an effort to control rising costs in the health care sector, there has been a strong incentive to move toward a market system, and a variety of forces are acting to drive down expenditures. These same pressures will continue to be brought to bear on the providers of cervical cytology services. It must be emphasized that the technical knowledge required to define cost-effective medical practice lies within the medical profession itself, which must recognize the following: (a) Resources are finite; (b) Elimination of fraud, abuse and waste is not enough to bring health care expenditures down to levels considered acceptable to government and business; (c) The medical profession must take the responsibility to identify the health and economic consequences of the services it provides and make wise recommendations for allocation of resources to optimize health consequences. The analysis of costs and benefits must be viewed from a societal perspective and presented in terms of the marginal impact on current practice. This does not mean that new technologies must reduce cost; on the contrary, improvements in health can be expected to come at a price, but at a price commensurate with value gained in lives saved or in added quality adjusted life years. To be of value, a new technology for cervical cytology must be more effective in preventing cervical carcinoma. Dysplasia is considered a precursor of carcinoma, and detection of dysplasia has been a surrogate for prevention of cervical carcinoma, but dysplasia does not always lead to carcinoma, least of all mild dysplasia, and policy makers ultimately will insist that a favorable change in health outcome be effected by new technology before it is allocated resources. Alternatively, new technologies may lower cost, perhaps by modifying screening or rescreening procedures according to known risk; by improved cytopreparatory techniques that simplify, improve or speed screening; or by monitoring devices that minimize screening error. In each case the performance attributes of the instrument or human instrument process should be evaluated in the intended use environment. Ongoing issues While current cervical cytology methodology is one of the most effective means of cancer prevention, there continues to be development of new techniques to increase the sensitivity and specificity of this test. With present fiscal constraints, these will be subject to stringent cost/benefit analyses in which the medical profession must play a key role. Such analyses can be quite complicated, considering the additional costs or cost savings of clinical follow-up procedures and the reliability of dysplasias detected by cytology as a surrogate for cervical carcinoma in calculating quality of life years saved.

Issues The extension of automation to the diagnostic assessment of clinical materials raises issues of professional responsibility, on the part of both the medical professional and designer of the device. The International Academy of Cytology (IAC) and other professional cytology societies should develop a policy towards automation in the diagnostic assessment of clinical cytologic materials. Consensus position The following summarizes the discussion of the initial position statement at the International Expert Conference on Diagnostic Cytology Towards the 21st Century, Hawaii, June 1997. 1. The professional in charge of a clinical cytopathology laboratory continues to bear the ultimate medical responsibility for diagnostic decisions made at the facility, whether automated devices are involved or not. 2. The introduction of automated procedures into clinical cytology should under no circumstances lead to a lowering of standards of performance. A prime objective of any guidelines should be to ensure that an automated procedure, in principle, does not expose any patient to new risks, nor should it increase already-existing, inherent risks. 3. Automated devices should provide capabilities for the medical professional to conduct periodic tests of the appropriate performance of the device. 4. Supervisory personnel should continue visual quality control screening of a certain percentage of slides dismissed at primary screening as within normal limits (WNL), even when automated procedures are employed in the laboratory. 5. Specifications for the design of primary screening devices for the detection of cervical cancer issued by the IAC in 1984 were reaffirmed. 6. The setting of numeric performance criteria is the proper charge of regulatory agencies, which also have the power of enforcement. 7. Human expert verification of results represents the "gold standard" at this time. Performance characteristics of computerized cytology devices should be determined by adherence to defined and well-considered protocols. Manufacturers should not claim a new standard of care; this is the responsibility of the medical community and professional groups. 8. Cytology professionals should support the development of procedures that bring about an improvement in diagnostic decision making. Advances in technology should be adopted if they can help solve problems in clinical cytology. The introduction of automated procedures into diagnostic decision making should take place strictly under the supervision and with the active participation and critical evaluation by the professional cytology community. Ongoing issues Guidelines should be developed for the communication of technical information about the performance of automated screening devices by the IAC to governmental agencies and national societies. Also, guidelines are necessary for the official communication of IAC concerns to industry, medicolegal entities and the media. Procedures and guidelines for the evaluation of studies pertaining to the performance of automated devices, performance metrics and definitions for evaluation criteria should be established.

OBJECTIVE: To assess specimen adequacy of the ThinPrep slide preparation method in routine use. STUDY DESIGN: Two studies, a feasibility study of 299 women and a clinical study of 499 women, were conducted. A broom-type collection device was used and rinsed directly into PreservCyt vials. Slides were prepared with the ThinPrep 2000 device, screened and classified according to the Bethesda System. The proportion of ThinPrep slides described as Satisfactory But Limited By: No Endocervical Component (SBLB:No ECC) was then compared to the proportion of SBLB: No ECC slides found on conventional smears in a previously conducted clinical trial of over 7,000 patients. RESULTS: For the feasibility study the proportion of ThinPrep slides described as SBLB: No ECC was 9.36% as compared to the clinical trial combined rate of 9.4% for conventional smears. For the clinical study, 4.96% of ThinPrep slides were SBLB:No ECC as compared to the 4.4% SBLB:No ECC rate for conventional smears from the same clinical trial. The proportions were statistically equivalent for both studies. CONCLUSION: It is expected that the rate of representing endocervical component will be maintained when the ThinPrep preparation method is used routinely in place of the conventional cytologic smear method.