Incredibly low false-negative proportion: watch out!
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Biomedical subjects
Publications and source records attributed to S Naryshkin.
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BACKGROUND: The question of the minimum number of Papanicolaou (Pap) smear slides that must be rescreened to draw statistically valid conclusions regarding the accuracy of screening often is raised. No method for generating answers in varying laboratory circumstances has achieved widespread application; standard statistical sample size calculations may represent such a resource. METHODS: A series of tables was constructed to display minimum required numbers of rescreens, with each table representing differing hypothetical laboratory circumstances. To use each table, assumptions must be specified in advance as to prevalence of abnormality, definition of error, baseline false-negative proportions (FNPs) of performance, and a degree of increase in FNPs that is considered a departure from baseline warranting concern, among others. RESULTS: The authors constructed four sample tables displaying minimum numbers of slides that must be rescreened in differing specified laboratory scenarios. Depending on assumed conditions and predetermined levels of satisfactory and unsatisfactory accuracy, the range of numbers is very broad (38-10,000). One example representing likely conditions indicates that 1040 slides must be reexamined; in another scenario, a sample size of 300 is sufficient. CONCLUSIONS: The minimum number of rescreened slides needed to draw statistically valid conclusions regarding Pap smear screening accuracy can be calculated using standard statistical methods. However, a number of assumptions must be detailed in advance. The authors offer this as a practical guide and a continuation of a general inquiry regarding Pap smear error rate measurement and display. The use of these tables raises at least as many questions as it answers, but still may represent a significant advance. Future efforts at further numeric characterization of aspects of Pap smear screening performance are warranted to enable rational decision making when performance is examined in the course of quality assurance, and during quality control and regulatory activities. [See editorial on pages 127-9, this issue.]
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Screening error rates have been measured in various ways. The false-negative fraction is advantageous because it is valid for comparisons between laboratories, which is crucial if standards for error rates are to be developed. False-negative fractions reported or calculated from data in the literature range from approximately 2% to 28%. Some of the highest published rates have come from prestigious academic laboratories. The lowest rates are from studies that covered terms of a year or less and in which only small parts of each slide were rescreened or the rescreeners were relatively inexperienced. Before standards for false-negative fractions can be set, we must collect more data and encourage more laboratories to measure the false-negative fraction.
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OBJECTIVE: To evaluate current laboratory practices and rates for atypical squamous cells of undetermined significance (ASCUS), a category of epithelial cell abnormality in the Bethesda System. DESIGN: Questionnaire surveys were mailed in December 1993 and March 1994. SETTING: Cytopathology laboratory participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology (PAP). RESULTS: Most responding laboratories (82.5%) limited the use of "atypia" terminology to abnormalities of undetermined significance. Nearly half of the laboratories employed only the term ASCUS for squamous epithelial changes in this category. The median rate of ASCUS in 1993 was 2.8%, with 10% of laboratories reporting rates greater than 9.0%. The median squamous intraepithelial lesion rate was 2.0%, with a median ASCUS-squamous intraepithelial lesion ratio of 1.3. The majority of laboratories qualified a portion of ASCUS cases and issued recommendations for follow-up when appropriate. Fifty-six percent of laboratories surveyed included patients diagnosed with ASCUS in follow-up programs. Laboratories estimated that about 20% (median response) of patients with ASCUS smears had a squamous intraepithelial lesion or equivalent diagnosis made within a year's follow-up. CONCLUSIONS: The ASCUS category is used by the majority of laboratories as recommended by the Bethesda System, but reporting rates vary. The results of this survey and associated surveys provide laboratories with useful benchmark figures for interlaboratory comparison of ASCUS practices.
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The reproducibility of reporting squamous lesions by the Bethesda System (TBS) was evaluated by distributing 20 slides to be classified among 5 panelists considered experts in the field of cytopathology. Four cases were chosen for their classic morphology and the remainder were foreseen to produce possible discrepancies within one diagnostic category. For 7/20 (35%) cases there was unanimous agreement. Participants disagreed within one category of magnitude for seven (35%) cases. In six (30%) cases there was a range of more than one category disagreement. However, additional written comments modifying TBS diagnoses often diminished the clinical significance of these discrepancies. We conclude that despite the important role of TBS in standardization of Pap smear reports, a great degree of subjectivity exists in classifying squamous abnormalities without "classic" morphology. The lack of reproducibility should be taken into account in cytology proficiency testing.
The Bethesda System recognizes "Atypical Squamous Cells of Undetermined Significance" (ASCUS) as a category of epithelial cell abnormality. Neither the acceptable rate of ASCUS nor the clinical follow-up are well defined. This study focused on interlaboratory comparison and quality assurance methods for evaluating the rate and outcome of ASCUS. Data was collected from questionnaire surveys from the College of American Pathologists Interlaboratory PAP Program and the four authors' laboratories. Most PAP laboratories (82.5%) limit the use of "atypia" terminology to abnormalities of undetermined significance. According to PAP data, the median rate of ASCUS in 1992 was 2.9%, with 10% of laboratories reporting rates greater than 9.0%. The median squamous intraepithelial lesion (SIL) rate was 2.2%, with a median ASCUS/SIL ration of 1.3. The authors' laboratories (university, independent, and hospital) revealed ASCUS rates of 1.6-9.0%, while SIL rates were 2.1-9.0%. The ASCUS/SIL ratio was less variable, 0.8-2.7. Follow-up of ASCUS patients in the authors' laboratories showed 10.3-43% with SIL, but less than 6% with high grade SIL. The ratio ASCUS/SIL may serve as a useful laboratory monitor. Peer review and follow-up studies of ASCUS serve to validate laboratory criteria and consequent clinical follow-up. Communication with clinicians is vital in ensuring optimal patient care.
Respiratory cytology has its share of pitfalls. Some, such as vegetable cell contaminants, pose problems for only inexperienced observers, while others, such as reactive bronchoalveolar cells from pneumonia, can lead even experienced cytopathologists to make a misdiagnosis of malignancy. This review illustrates and analyzes those benign conditions or entities known to mimic malignancy in exfoliative respiratory cytology and fine-needle aspiration biopsy of the lung. Entities are grouped by the type of malignancy they mimic, and guidelines are presented for avoiding specific pitfalls.
Transmission electron microscopy (TEM) is an important adjuvant to light microscopy, but is underutilized in cytopathology because of technical obstacles. One should attempt to obtain properly fixed material for TEM whenever possible. If that is not available, TEM on the cell block requires no preplanning or additional needle passes, and avoids problems of inadequate tissue for diagnosis. However, cell blocks are often not examined because of the perception that their poor ultrastructural preservation precludes their utility. We describe our experience in performing TEM on cell blocks from 15 cytologic specimens. In 13 of 15 cases, the cell block material was adequate for ultrastructural evaluation, and it clarified or extended the diagnosis in seven of these cases. TEM is a useful adjuvant technique to cytodiagnosis and can be successfully performed on cell blocks when gluteraldehyde-fixed material is not available.
At our institution, gynecologists perform Pap smears not only as an initial screening procedure but also at the time of colposcopy and biopsy. We compared the results of initial Papanicolaou (Pap) smears with those taken at colposcopic biopsy to determine if repeating the Pap smear at the time of colposcopy contributed to patient management. We found that repeat colposcopic smears often agreed with the referral smears and biopsies. When there was disagreement, the colposcopic smear was more often a lower grade than the referral smear and correlated best with the biopsy. Both referral and colposcopic smears underestimated the severity of cervical lesions with the same frequency. We could document only 5/414 (1.2%) colposcopic smears that contributed to patient care.
The few guidelines that exist for performing autopsy quality assurance are vague. Much has been written about the use of the autopsy to monitor clinical services, but not how to monitor the quality of the autopsy and autopsy reports. We present the comprehensive quality assurance program that has been developed and implemented at Hahnemann University Hospital, Philadelphia, Pa, for the past 2 years; this program has encompassed quality control of our diagnostic work. Key features have included in-depth peer review of completed reports, documentation of review at conferences, and careful monitoring of turnaround time. We have found that integrating quality assurance into departmental conferences is a useful supplement to in-depth peer review of randomly chosen autopsies. Our approach to quality assurance may serve as a model for other pathology departments, particularly those with pathology residency training programs.
The reliability of bronchoscopic cytology relative to biopsy is controversial. Some still consider biopsy the definitive procedure. Comparative studies are few and limited in scope. Therefore, we compared simultaneously obtained biopsies and cytologies for 224 cases. One hundred and sixty-six cases (74.6%) correlated completely. Forty-four cases (19.6%) did not correlate and cytology was diagnostic in 24 of these. Biopsy was diagnostic in sarcoidosis and vasculitis, whereas cytology only excluded the presence of neoplasm or infection. In 14 cases (5.8%), biopsy and cytology showed pathologic changes, but one or the other was more definitive. Rarely, the 2 techniques provided complementary information. A specific diagnosis was obtained more often from the combination of cytology and biopsy than from either alone. However, when biopsy is contraindicated it is reassuring that cytology usually yields the same information as biopsy, and can detect neoplastic and infectious diseases when the biopsy is non-diagnostic.
The objective of this investigation was to test the hypothesis that blood glutathione levels are lower in aging human subjects as previously found in blood and tissues of standard rodent models of aging. Thus a study was conducted with 39 men and 130 women, 20 to 94 years old, who were selected by the criteria of being ambulatory, healthy, and free from diabetes mellitus, thyroid disease, anemias, and cancer. The reference group was comprised of the 20- to 39-year-old subjects, whose blood glutathione levels were 547 +/- 53.5 micrograms/10(10) erythrocytes (mean +/- SD) for 40 individuals and defined the reference range (95% confidence limits) of 440 to 654. Based on the 440 micrograms/10(10) erythrocyte cutoff, the incidence of low blood glutathione content in the older subjects increased significantly, particularly in the 60- to 79-year-old group. Their glutathione levels were 452 +/- 86.8 micrograms/10(10) erythrocytes, 17% lower than the reference group (p < 0.001). These findings demonstrate an increased incidence of low glutathione levels in apparently healthy elderly subjects, who thus may be at risk because of a decreased capacity to maintain many metabolic and detoxification reactions mediated by glutathione.
To clarify the role of foamy alveolar casts (FACs) in the diagnosis of Pneumocystis carinii pneumonia (PCP), we retrospectively reviewed Papanicolaou (Pap)- and Grocott methenamine silver (GMS)-stained slides from 205 bronchial specimens submitted for suspected opportunistic lung infection. FACs containing sporozoites were seen in 86 cases, all with positive GMS. FACs were absent in 119 cases with negative GMS. In patients previously treated for PCP, Pap showed FAC-like material which lacked sporozoites. GMS demonstrated clumped degenerated Pneumocystis carinii (PC) cysts. In 17 GMS-positive cases there were no FACs on Pap due to sampling error and low burden of organisms. Morphologic features of macrophages in these cases can suggest the presence of PC. When FACs are lacking, a special stain is required. When GMS is used, the control must contain PC to avoid a false negative GMS. The inconsistent uptake of GMS by PC is a pitfall which is distinct from sampling error and which to our knowledge has not been previously reported.
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