The use of digital images to evaluate the interobserver agreement on cervical smear readings in Italian cervical cancer screening.

OBJECTIVE: The aim of this study was to measure interobserver agreement among cytologists on using a set of digital images. METHODS: A set of 90 selected Papanicolaou-stained cervical smears were digitalized and the digital images circulated among 117 readers, from laboratories spread across almost all Italian regions. Three representative fields of each smear were displayed at 20× and 40× magnification (overall six images for each case). The diagnoses made by the cytologists who provided the images were taken as target diagnoses. RESULTS: The κ values were: very low for the categories atypical squamous cells of undetermined significance (ASC-US), and atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion (ASC-H); poor for the categories atypical glandular cells (AGC), high-grade squamous intraepithelial lesion (HSIL) and invasive cancer; and fair to good for the categories negative and low-grade squamous intraepithelial lesion (LSIL). However, we found a cluster of 42 best concordant readers. The overall κ value and overall weighted κ with the target diagnosis for these 42 readers were 0.45 and 0.66, respectively. This finding is in contrast with the overall κ value and overall weighted κ for the other readers of 0.39 and 0.59, respectively. CONCLUSIONS: As this finding is an estimate of the accuracy of the readers, we can infer that it will be very important to reach this level of concordance for all the participating readers. Future effort will facilitate common experiences in order to improve the reproducibility of diagnostic criteria. Digital images could be the key to reach this aim.

Interlaboratory reproducibility of liquid-based equivocal cervical cytology within a randomized controlled trial framework.

Within a multicentre controlled trial framework, an external quality control (EQC) was scheduled to evaluate the interlaboratory reproducibility of liquid-based cytology. In particular, this EQC intended to evaluate the reproducibility of the ASCUS diagnosis.A selected set of 30 slides (4 within normal limit cases, 16 atypical squamous cells of undetermined significance; 4 low-grade squamous intraepithelial lesions and 6 high-grade squamous intraepithelial lesions) circulated among the 13 laboratories involved in the trial.Kappa values were obtained from the comparison between individual laboratory diagnoses and majority diagnoses with target diagnoses. Specific kappa values resulted moderate to high for HSIL and low to moderate for LSIL and WNL. Meanwhile, the specific kappa for ASCUS was below 0.4 in 12 of 13 participating laboratories. The lack of reproducibility for ASCUS was not a result of the introduction of this new technology but rather to the low reproducibility of the ASCUS category itself stemming from intrinsic uncertainties in the reporting criteria.

Clinical impact (cost-effectiveness) of qualifying atypical squamous cells of undeterminate significance (ASCUS) in cases favoring a reactive or dysplastic process.

The cost-effectiveness of qualifying ASCUS cases into two different subcategories, favoring a reactive (ASCUS-R) or dysplastic process (ASCUS-S), was evaluated at the Centro per lo Studio e la Prevenzione Oncologica of Florence in a prospective study. The study determined the positive predictive value (PPV) for histologically confirmed cervical intraepithelial neoplasia grade 2 (CIN2) or more (CIN>) severe lesion of the two ASCUS subgroups. ASCUS-S had a PPV (10.78%) comparable to low-grade squamous intraepithelial lesions (LSIL) (11.40%). For ASCUS-R cases, the recommendation of 6-mo repeat cytology prompting colposcopy in cases of persistent ASCUS or more severe cytology was also effective, as it selected a subgroup with a relatively high PPV (10.34%). The cost-effectiveness of a protocol based on ASCUS qualification was compared with two other possible options for nonqualified ASCUS cases: immediate colposcopy and colposcopy in persistent ASCUS at 6-mo repeat cytology. The detection rate of CIN2> was substantially higher using ASCUS qualification (35.9 vs 14.8 or 17.1). The cost per ASCUS subject was euro 24.99, 27.11, or 25.14 and that per CIN2> detected was euro 697, 1,831 or 1,470 for the three options, respectively. The evidence that ASCUS detection option implies a higher detection rate of CIN2> and subsequently a lower cost per CIN2> detection must be considered with caution and deserves confirmation by other comparative studies.

Detection of false-negative Pap smears using the PAPNET system.

AIMS AND BACKGROUND: False-negative cytological diagnoses represent the critical point of a screening program for early detection of cervical cancer. Computer-assisted reading using neural network technology has been suggested as a possible approach to manage the problem. The study assessed the performance and the cost-outcome ratio of computer-assisted versus conventional manual Pap smear reading. METHODS: One thousand routine smears, seeded with 81 false-negative smears, were independently interpreted by two readers by conventional and PAPNET-assisted reading. Results of both readings were compared in terms of: a)sensitivity for false-negative smears, b)specificity, and c) cost-outcome (cost per CIN2+ lesion detected). RESULTS: PAPNET-assisted reading showed a small increase in sensitivity only for one reader. Including the cost of PAPNET, the cost per detected lesion would be $7,543 and the cost per additional detected lesion would be $25,748. CONCLUSIONS: The present study provides further evidence that PAPNET-assisted screening may allow the detection of a few extra cases of CIN2+ lesions with respect to conventional reading, though at a very high cost.

Solid nonpalpable breast lesions. Success and failure of guided fine-needle aspiration cytology in a consecutive series of 2444 cases.

PURPOSE: To evaluate the contribution of guided fine-needle aspiration cytology in reducing unnecessary biopsies of benign solid nonpalpable breast lesions with low suspicion of malignancy at mammography. MATERIAL AND METHODS: An evaluation was made of a consecutive series of 2444 solid nonpalpable breast lesions detected by mammography and undergoing guided (sonography or stereotaxy) fine-needle aspiration cytology. Surgical biopsy was made in the presence of strong suspicion of malignancy at mammography and/or of abnormal cytology. RESULTS: The sensitivity was 96.7% and the specificity 77.7% (average follow-up 2.77 years). False-negative/inadequate cytology associated with low suspicion of malignancy at mammography resulted in a diagnostic delay in 27 cancer cases (invasive 20, intraductal 7). On the other hand, cytology led to surgical biopsy in 53 cancer cases which might not otherwise have been biopsied because of low radiological suspicion of cancer. Surgical biopsy of all cases, to avoid diagnostic delays, would have increased the benign biopsy rate by a factor of 4.5, with a rise in the benign: malignant biopsy ratio from 0.44:1 to 1.93:1. CONCLUSION: Stereotaxy- or ultrasound-guided fine-needle aspiration cytology of nonpalpable mammographic abnormalities can achieve a sharp reduction in unnecessary benign biopsies in cases of low suspicion of malignancy at mammography.

Analysis of false-negative and underreported smears in the Florence district screening program for cervical carcinoma.

AIMS AND BACKGROUND: To review false-negative or underreported (reactive changes, squamous or glandular atypia) smears performed in women developing histologically proven CIN2 or more severe lesions within 24 months and evaluate error causes. The study setting was the Florence District cervical cancer population-based screening: about 60,000 women age 25-60 years screened per year. METHODS: 118 false-negative or underreported cases were identified at screening files-cancer Registry matching, and the original smears were reviewed by six independent readers to judge smear adequacy and error type. RESULTS: Sampling errors (reported as inadequate, negative or less severe than CIN1 at review) accounted for 74% and screening/interpretation errors (reported as CIN1 or more severe at review) accounted for 26% of studied cases. Screening/interpretation errors were more likely ascribed to misinterpretation and underreporting than to misperception of cellular abnormalities. CONCLUSIONS: Quality control should above all address the problem of sampling adequacy. Due to the rarity of misperceived abnormalities (true screening errors), manual or automated rescreening of negative smears would not be an effective procedure for quality control.

Interlaboratory reproducibility in reporting inadequate cervical smears--a multicentre multinational study.

A set of 300 vaginal smears was interpreted by 13 cytologists from six European laboratories, who were requested to report inadequate and suboptimal smears. The set had been appropriately seeded to reach approximately 10% inadequate and 20% suboptimal smear frequency. According to the majority report, 230 smears were classified as adequate (76.7%), 43 as inadequate (14.3%), and 27 as suboptimal (9.0%). Agreement with the majority report ranged from 52% to 91% (average 78%). Kappa statistics for reporting inadequate smears showed a high level of agreement for five cytologists, and fair to good agreement for eight. In contrast, kappa statistics for reporting suboptimal smears showed fair to good agreement with the majority report only in five instances, whereas agreement was poor for eight cytologists. 'Inadequate smear' rates may be used to compare the quality of smears received in different laboratories, as there is a high level of agreement among cytologists as to what constitutes an inadequate smear. However, this is not true for "suboptimal smear" rates, and more precise reporting criteria must be defined and tested if an intermediate category is to be retained to report poor quality smears: more precise reporting criteria must be defined and tested if an intermediate category is to be retained to report poor quality smears.

Analysis of the causes of false negative cytology reports on breast cancer fine needle aspirates.

Forty-six (2.9%) false negative reports were recorded among adequate fine needle aspirates from 1609 consecutive histologically proven carcinomas, observed from 1991 to 1993. False negatives were more frequent among younger women (< 40 years = 7.1; 40-49 years = 4.0; 50-59 years = 3.6; 60-69 years = 1.7; > 69 years = 1.5%), lobular invasive subtypes (5.4%), and smaller tumours (pT1a = 4.2; pT1b = 7.6; pT1c = 1.9; pT2 = 2.1; pT3-4 = 1.5%). The latter findings is probably ascribable to better differentiation and less precise sampling of small non-palpable tumours. No significant association was found between the false negative rate and the sampler's or reader's skill and experience. The former finding may be ascribed to the wide use of sonography guided aspiration, even for palpable masses, and the latter to the fact that readers were highly experienced and undergo periodic quality control of individual performance. False negatives were reclassified at reviews as true false negatives, reading errors or inadequates in 27, 11, and eight cases, respectively. The observed findings suggest that in most cases cytological faults were due to the absence of cytological atypia in cells sampled from well differentiated tumours, rather than to misinterpretation or sampling from adjacent normal tissues.

Performance of fine-needle aspiration cytology of the breast-multicenter study of 23,063 aspirates in ten Italian laboratories.

AIMS AND BACKGROUND: The aim of this study was to assess the performance of routine breast cytology in a group of Italian laboratories, as a basis for interlaboratory quality control. METHODS: A multicenter retrospective consecutive series of 23,063 aspirates from breast lesions (5,130 invasive carcinoma, 247 intraductal carcinoma, 2,386 benign lesions [histological], 13,144 benign lesions [follow-up], 2,156 other [no follow-up]) was reviewed. Standard accuracy measurements (inadequacy rate, sensitivity, specificity, predictive value) were determined, as well as the contribution of diagnostic tests such as physical examination and instrumental diagnostic procedures (mammography, sonography). RESULTS: Overall, inadequacy rate was 6.5% for malignant and 23.2% for benign lesions. Sensitivity was 92.2%, specificity was 95.3%, and the positive predictive value of an equivocal or malignant report was 53.4% or 96.9%, respectively. Sensitivity was associated with histological type (intraductal vs invasive: 77.0% vs 92.9%, p < 0.000001; lobular vs other invasive: 85.5% vs 94%, p = 0.0025) as well as with tumor size (pT1 = 91.6%, pT2 = 94.3%, pT3-4 = 96.0%, p < 0.000001). Observed differences in performance indicators between centers may be explained by variability in sampling or reading accuracy, and warrant the need for some adjustment in single centers, especially, as far as the criteria to report an equivocal smear are concerned. Cytology contributed to detect otherwise unsuspected carcinomas, although in some centers this benefit was poor and not cost-effective because a large number of unnecessary biopsies were caused by false equivocal/positive reports. CONCLUSIONS: Although centers scored, on average, well within standards recommended by national authorities, this study suggests the opportunity of interlaboratory quality control to achieve more homogeneous criteria.

Intralaboratory reproducibility in cervical cytology. Results of the application of a 100-slide set.

In order to evaluate the agreement and accuracy of cervical (vaginal) cytologic diagnoses, 16 cytologists from a large laboratory in Florence, Italy, with experience ranging from 2 to 25 years, independently examined a set of 100 slides. A common reporting form based on a seven-category classification system was used. Concordance was calculated for each pairwise comparison between the 16 cytologists and between each cytologist and the target diagnosis. The values of the kappa statistic for the whole laboratory were .49 for the multiple raters comparison and .59 for the target diagnosis comparison, showing a relatively good degree of agreement.

Positive predictive value of fine needle aspiration cytology of breast lesions.

The predictive value of fine needle aspiration (FNA) was assessed in 1,181 consecutive cases of breast lesions in which cytologic abnormalities were reported. The positive predictive value (PPV) of an FNA cytologic report of atypia, suspicious or positive was 0.49, 0.95 or 0.996, respectively. In the presence of a suspicious/positive report by both physical examination and mammography, the PPV of a cytologic report of suspicious was 0.99. The PPV was directly correlated with age, partly due to the incidence of fibroadenomas among younger patients; fibroadenomas were present in 53 of 146 cases with a false FNA report of atypia, in 10 of 19 cases with a false FNA report of suspicious and in 2 of 2 cases with a false FNA report of positive. Overall, 93 cases reported as benign by physical examination and mammography were biopsied on the basis of the FNA cytologic report; cancers were diagnosed in 33 of these 93 cases (6 cancers among 42 women less than 40 years old and 27 cancers among 51 women greater than 39 years old). The widespread use of FNA cytology to study breast lesions is thus recommended, without regard to patient age and even in the presence of clinically benign findings, since the increase in the rate of cancer detection is worth the excess of unnecessary biopsies. The predictive value of a positive report of FNA cytology, or even of a suspicious report in the presence of clinical suspicion, is so high that an intraoperative frozen section biopsy might be spared in such cases.