The impact of mammography screening programmes on incidence of advanced breast cancer in Europe: a literature review.

BACKGROUND: Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. METHODS: The PubMed database was searched for English language studies published between 01-01-2000 and 01-06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. RESULTS: Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. CONCLUSIONS: We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology.

Strategies for delivery of faecal occult blood test kits and participation to colorectal cancer screening in the Emilia-Romagna Region of Italy.

There is a lack of agreement about which routine invitation strategy should be adopted in colorectal cancer screening. We conducted an observational study to assess the impact of three invitation strategies on participation. Invitation records for the years 2005-2009 were evaluated. There were 2,234,276 invitations from 1,230,683 individuals. Among first invitations, participation associated with direct mailing of the faecal occult blood test kits was slightly lower (relative risk, RR 0.985; 95% confidence interval 0.979-0.990) than that of the reference invitation strategy, that is, the distribution of the test kits by pharmacies. In repeated invitations/previous non-responders, the participation associated with the direct mailing of the test kits was even lower (RR 0.914; 95% confidence interval 0.895-0.933) and this was also the case for the distribution of the test kits by primary care centres (RR 0.983; 95% confidence interval 0.971-0.995). In contrast, in repeated invitations/previous responders, the impact of primary care centres and direct mailing of the test kits was greater than the use of pharmacies, showing only modest RRs: 1.021 (95% confidence interval 1.019-1.023) and 1.029 (95% confidence interval 1.025-1.033) respectively. The faecal occult blood test mailing strategy modestly increased participation in previous responders.

Combining cytology, TRAP assay, and FISH analysis for the detection of bladder cancer in symptomatic patients.

BACKGROUND: There is a need to improve the performance of urine cytology in bladder cancer diagnosis. We assessed the diagnostic performance of (i) telomerase activity detected by telomeric repeat amplification protocol (TRAP) assay, (ii) cytology and TRAP assay in parallel, (iii) cytology in parallel with the in-series combination of TRAP assay and FISH analysis, and (iv) the in-series combination of TRAP assay and FISH analysis. PATIENTS AND METHODS: Cross-sectional study of 289 consecutive patients who presented with urinary symptoms at a north Italian hospital between 2007 and 2008. All underwent cystoscopy and cytology evaluation, and conclusive results were available for TRAP assay and FISH analysis. RESULTS: Sensitivity and specificity were 0.39 and 0.83, respectively, for cytology; 0.66 and 0.72 for TRAP; 0.78 and 0.60 for the combination of cytology and TRAP; 0.78 and 0.78 for the combination of cytology, TRAP, and FISH; and 0.65 and 0.93 for the combination of TRAP and FISH. All differences versus cytology alone were significant (P ≤ 0.011). CONCLUSION: Compared with cytology alone, the combination of cytology, TRAP, and FISH provided the best trade-off between increase in sensitivity and loss in specificity, especially among non-bleeding patients, low-grade cancers, and early-stage cancers.

The influence of endoscopic biliary stents on the accuracy of endoscopic ultrasound for pancreatic head cancer staging.

BACKGROUND AND STUDY AIMS: Biliary stents have been found to interfere with endoscopic ultrasound (EUS) tumor (T) and nodal (N) staging in patients with periampullary cancer. Our aim was to determine whether this also occurs in patients with pancreatic head cancer. PATIENTS AND METHODS: We studied a consecutive series of patients who were undergoing preoperative EUS for diagnosis and staging of suspected pancreatic cancer, some of whom had biliary stents in situ and some of whom did not. The main end point was the uni- and multivariate association of biliary stenting with T and N mis-staging by EUS. The surgical T and N stages were used as gold standards. RESULTS: A total of 65 patients were identified (19 with biliary stents in situ and 46 without). Surgical stage T4 was found more frequently in patients with stents (53% vs. 22%, P = 0.014). The T stage by EUS was correct in 85% of the patients without biliary stents and in 47% of the patients with stents. The frequency of mis-staging by EUS was significant only among patients with a biliary stent. The distribution by EUS N stage did not differ significantly from the surgical N-stage distribution in the two groups of patients. According to the multivariate analysis, patients with stents were 6.55 times more likely to be incorrectly T staged (95% confidence interval [CI] 1.69-25.49) and 3.71 times more likely to be incorrectly N staged (95% CI 1.11-12.45) than patients without stents. CONCLUSIONS: The results add support to the recommendation that EUS staging of pancreatic head neoplasms should be performed prior to stent placement.

Association of cyst type with risk factors for breast cancer and relapse rate in women with gross cystic disease of the breast.

The concentration of potassium (K+) and sodium (Na+) was measured in breast cyst fluid (BCF) from 611 cysts greater than 3 ml aspirated in 520 women with gross cystic disease of the breast. These women were enrolled, from 1983 on, in a cohort study aimed at assessing the relationship between cyst type, as defined by the K+/Na+ ratio in BCF, and the risk of breast cancer. The inverse relationship between K+ and Na+ and the bimodal distribution of the K+/Na+ ratio in BCF were confirmed. Type I cysts were defined as cysts with a K+/Na+ greater than 1.5 in BCF. Among women with type I cysts, a higher proportion of women with one or no births, of women with a history of apocrine cysts, of current smokers, and of women who do not drink coffee was found, as compared to women with other types of cysts. The risk of cyst relapse was significantly higher among women with type I cysts than among women with other types of cysts and among women with multiple cysts at presentation. These findings indicate that type I BCF is a marker of "active" gross cystic disease of the breast and suggest that it may be associated with increased breast cancer risk.

Relative and absolute cancer mortality of women in agriculture in northern Italy.

Most studies of cancer risk related to agricultural exposures have focused on male operators. Cancer mortality in a cohort of 38 962 women engaged in agriculture (Province of Forlì, 1969-1993) was compared with that of the rest of the female residents using the ratio of age-standardized (Europe) mortality rates (ASR) with 95% confidence interval (CI). Moreover, mortality time trends in both subsets of the population were evaluated. The cohort yielded 798 439 person-years with 2397 cancer deaths. Total ASR ratio was 0.86 (95% CI 0.80-0.92). Only gastric cancer was associated with a significant but declining excess mortality (ASR ratio 1.26; 95% CI 1.11-1.43). Total ASR ratio decreased from 1.07 (95% CI 0.95-1.20) in 1969-1976 to 0.74 (95% CI 0.66-0.82) in 1985-1993. This resulted from a downward mortality trend restricted to the cohort. In particular, mortality from cancers of the oesophagus, stomach and colon/rectum decreased more steeply in the cohort. Mortality from liver cancer decreased only in the cohort. Mortality from cancers of the pancreas, lung, breast, bladder and skin melanoma remained stable in the cohort whilst increasing in the rest of the population. In conclusion, risk excesses previously reported were not confirmed. Agricultural workers qualified as a subset of the female population with atypical, favourable epidemiologic characteristics.

The impact of organised screening programmes on the stage-specific incidence of breast cancer in some Italian areas.

The aim of this study was to examine the effects of mammographic screening programmes on stage-specific incidence of breast cancer. The study compared prescreening and screening periods in seven areas in Italy, primarily evaluating the first screening round. All 17617 breast cancers (16554 invasive, 1063 in situ) registered in women aged 40-79 years between 1988 and 1999 were analysed through age-standardised rates and Poisson regression models. For all areas, independent of the baseline rates, the introduction of screening increased incidence for invasive cancers overall and, more markedly, for early cancers (screening/prescreening ratio: range 1.07-1.47 and 1.23-1.82, respectively), modifying the pattern of age-specific rates. The multiple regression analysis showed that the percentage of cases diagnosed at screening explained most of the increase; a residual effect of diagnosis period (screening versus prescreening) suggested a role for 'spontaneous' early detection in ages outside of the screening programme. Advanced cases did not show consistent variations across the registries for those aged 40-79 years (range: 0.91-1.21), whereas a more coherent picture was observed for those aged 50-69 years. In one area, a moderate reduction in the number of 'advanced' cases in the second screening period was observed. For all stages, the age-specific incidence rates of cases diagnosed outside of the screening programme for the age groups 50-69 years were lower than the corresponding rates in the prescreening period, suggesting a shift from the usual clinical services to the screening programme. Our results confirmed the increase in early-stage cancers occurring at the start of screening, and substantially explained the rise in breast cancer incidence. In addition, our study confirms the importance of cancer registries in monitoring the effect of breast cancer screening and the validity, for this purpose, of the linkage between cancer registries and screening programme databases.

Wolfe's mammographic patterns in women with gross cystic disease of the breast.

The epidemiologic determinants of the mammographic pattern were studied in 710 patients with aspirated gross (> 1 ml) cysts of the breast. The prevalence of the mammograms classified as P2-DY, that are considered to be associated with an increased breast cancer risk, was 636/710 or 89.6%. No relationship between mammographic patterns and characteristics of breast cyst fluid such as K+/Na+ ratio, apocrine changes and dehydroepiandrosterone sulfate concentration was observed. A significant decrease in the proportion of these patterns with increasing age (p = 0.006), Quetelet Index (p < 0.001), parity (p = 0.001), and in postmenopausal women (p = 0.026) was found. Conversely, P2-DY patterns were significantly associated with a later age at menarche (p = 0.023) and alcohol consumption (p = 0.001). In multivariate analysis, an independent association with age was not observed whereas the associations with age at menarche, parity, and relative weight were confirmed. In conclusion, the epidemiologic determinants of mammographic patterns are the same in Gross Cystic Disease patients as in unaffected women, and the lack of correlation between mammographic pattern and cyst type suggests that the latter may represent an independent predictor of breast cancer risk.

Diagnosis and treatment of cervical intraepithelial neoplasia grade 3: a registry-based study in the Romagna region of Italy (1986-1993).

BACKGROUND: Treatment of cervical intraepithelial neoplasia grade 3 (CIN3) is one of the most unexplored issues of the monitoring of cervical cancer screening. We evaluated (1) the frequency of major patterns of diagnosis and treatment of CIN3 (ICD-O code 8070.2), (2) the determinants of hysterectomy as a first choice treatment, and (3) the determinants of invasive cervical squamous carcinoma (CSC) detection among CIN3 cases treated by hysterectomy. METHODS: A population-based, retrospective, descriptive (objective 1) and analytical (objectives 2 and 3) study was conducted by the Romagna Cancer Registry (Northern Italy). Included were 316 CIN3 patients (median age, 38.5 years; range, 21-80) registered between 1986 and 1993 and meeting one of the following eligibility criteria: histological diagnosis of CIN3 on biopsy with any subsequent treatment, histological diagnosis of CIN3 on conization, histological diagnosis of CIN3 on hysterectomy with previous negative/benign (< or = CIN2) biopsy or conization. Multivariate associations were evaluated by the multiple logistic regression. RESULTS: Of 316 patients, 264 (84%) were first diagnosed on biopsy, 39 (12%) on conization, and 13 (4%) on hysterectomy. Among the 264 patients diagnosed on biopsy, the first choice treatment was local destructive therapy for 16 (6%), conization for 155 (59%) and hysterectomy for 93 (35%). Age was the strongest uni/multivariate predictor of hysterectomy (the most frequent first choice treatment >40 years) followed by adequacy of biopsy (inverse association) and place of treatment (decreased probability for patients treated outside the area and in the private sector). Among the 93 CIN3 patients undergoing hysterectomy, 23 (25%) had a CSC diagnosed. Multivariate analysis showed that the probability of CSC detection was related to adequacy of biopsy (inverse association), year of registration, and biopsy-to-treatment interval (inverse association). CONCLUSION: Hysterectomy was a common treatment for patients with CIN3 on biopsy. Only in a minority of hysterectomized patients was a CSC diagnosed. Difficulties and inefficiencies in the biopsy and assessment procedure were found to be important factors in the management and outcome of CIN3 patients.

Steroid biochemistry and categorization of breast cyst fluid: relation to breast cancer risk.

Patients bearing macrocysts of the breast are at higher risk of later developing cancer. The fluid filling the cysts (breast cysts fluid, BCF) contains unusual amounts of steroid conjugates, first androgen and estrogen sulfates. Measuring BCF cations (K+,Na+) allows categorization of cysts into two major subsets (type I and type II) that are associated with a different degree and/or turnover of apocrine metaplastic cells in the lining epithelium. Type I cysts (high K+/Na+ ratio) accumulate hugh amounts of dehydroepiandrosterone sulfate, estrone sulfate, androstane-3 alpha,17 beta-diol glucuronide, androsterone glucuronide and contain more testosterone and dihydrotestosterone than type II. Conversely, type II cysts (low K+/Na+ ratio) contain more progesterone and pregnenolone. A cohort study was started in 1983 at the Cancer Prevention Center, Ravenna, Italy, with the aim of evaluating the relationships between the biochemistry of BCF and the incidence of breast cancer in women with gross cystic disease (GCD) of the breast. The bimodal distribution of the cationic pattern has been confirmed from data obtained in 798 patients aspirated. The risk of cyst relapse was significantly higher among women with type I cysts or with multiple cysts at presentation. Twelve incident cases of breast cancer have been diagnosed among women whose BCF was categorized. Eleven out of 12 cases had type I or multiple cysts. The cumulative incidence of breast cancer among patients bearing type I cysts was 2.5%. We conclude that women with GCD bearing type I cysts have an increased breast cancer risk when compared with the counterpart bearing type II cysts or the general population.

Critical effects of intense sun exposure on the expression of epiluminescence microscopy features of acquired melanocytic nevi.

BACKGROUND: Current knowledge of the histologic counterparts of epiluminescence microscopy (ELM) features in pigmented skin lesions is limited. As a particular aspect of this problem, the transient effects of intense sun exposure on the morphological characteristics of melanocytic nevi may influence the expression of ELM features as well as the demonstration of stable and consistent histologic correlates. OBSERVATIONS: Forty melanocytic nevi from 11 subjects living in Northern Italy were examined by digital ELM before and after 5 to 13 days of sun exposure at latitudes of 5 degrees north to 3 degrees south. A number of multifaceted changes were observed. In particular, 3 lesions showed the expression of some structures compatible with radial streaming, pseudopods, and gray-blue areas. These features are considered to have often severe histologic correlates. In a third image, obtained 5 to 6 weeks later, they showed partial or total regression. Another case showed a massive regression of the pigment network as a result of a progressive inflammatory reaction with marked asymmetry in the distribution of pigmentation. CONCLUSIONS: Digital ELM has the potential to detect subtle changes in the structure of nevi after intense sun exposure. The transient observation of certain ELM features often associated with severe histologic substrates casts doubts on the ability of ELM to characterize sun-exposed nevi by a single examination.

The cancer registry in the monitoring of cervical screening practice: the neglected value of the Pap smear in patients diagnosed with CIN3 on biopsy.

Patients diagnosed with CIN3 on biopsy without a Pap smear are an inevitable correlate of the extensive utilization of colposcopy as a basic screening test. In a series of 248 CIN3 cases diagnosed on biopsy and notified to the Romagna Cancer Registry between 1986 and 1993, we evaluated the independent association between the Pap smear result and (1) the final histology diagnosis, (2) the first choice treatment, and (3) the appropriateness of hysterectomy. The patients were grouped into the following categories: (1) no smear, ie colposcopy only (n = 40 or 16%), (2) CIN1, CIN2, LGSIL, and minor changes, (3) CIN3 and HGSIL, and (4) carcinoma. In multiple logistic regression analysis, patients without a Pap smear were used as a reference category. Patients with smears reported as CIN1-2/LGSIL or less as well as CIN3/HGSIL had a significantly lower probability of invasive squamous carcinoma (odds ratio = 0.26 for both categories) compared with those not undergoing cytology. The Pap smear result was not a determinant of the first choice treatment. Hysterectomy had a greater probability of being unnecessary if performed in patients with smears reported as showing CIN3/HGSIL (odds ratio = 5.05) or less. In conclusion, this registry-based study demonstrated that the Pap smear had an independent but neglected value in the assessment of cases reported as CIN3 on colposcopy-guided biopsy.

Probability of early repeat Pap smear in an integrated cervical screening programme.

The integration of routine Pap smear practice based on self-referral into an organized programme based on personal invitation is the recommended approach to cervical cancer screening. In this study, the cytology archive of the integrated cervical screening programme implemented in the Faenza district (northern Italy) was used to compare the population of women responding to invitation with that of self-referred women for the cumulative probability of early (< 36 months) repeat Pap smear after a negative result. Between 1995 and 1998, women aged 25-64 living in five municipalities of the district were targeted by the first round of the programme. Eligible for the study were 2356 women responding to invitation for screening and 2221 women not invited because of self-referral for Pap smear at any other setting. The probability of early repeat Pap smear was estimated by the life table method. Differences were evaluated by the Gehan test. Multivariate determinants were assessed by the Cox regression analysis. At 36 months' follow-up, the cumulative probability of early repeat Pap smear was 44% among self-referred women and 6% among women responding to invitation (relative hazard = 4.8). For self-referred women, the probability was related to age (with a peak at 35-44 years), previous Pap smear history and municipality of residence. Among women responding to invitation, only an inverse association with age was demonstrated. In conclusion, the observed differences in overall probability and determinants of early repeat Pap smear between the two screening populations provided important information on Pap smear usage in the total target population.

Performance indicators of organized cervical screening in Romagna (Italy).

The availability of published data from organized cervical screening programmes in southern Europe is scant. In the Italian area of Romagna, a first round of organized screening (based on a 3-yearly Pap smear for women aged 25-64 years) was initiated between December 1995 and January 1997 and was completed in an average of 42 months (range 36-48 months). The target population included 305 478 women. Of these, 253 949 were eligible and received a personal letter of invitation. Age-specific screening performance indicators were calculated according to standard methods. The response rate within 6 months of invitation was 49.1% (n=124 621). The total participation rate including women who presented later was 61.7% (n=156 735). The recall rate was 35.2 per 1000 of participants (n=5514). Positive cytology results were distributed as follows: atypical squamous cells of un-determined significance/atypical glandular cells of undetermined significance (ASCUS/AGUS) 40.1%, low-grade squamous intraepithelial neoplasia (LGSIL) 48.6%, high-grade squamous intraepithelial neoplasia (HGSIL) 10.7% and carcinoma 0.7%. Compliance to colposcopy follow-up was 93.4% (n=5149). The biopsy rate was 52.4% (n=2696) of patients undergoing colposcopy. The detection rate was 4.5 per 1000 of participants (n=707) for CIN2-3 and 0.5 (n=75) for invasive carcinoma. The proportion of microinvasive carcinomas was 36.0% (n=27). The positive predictive value for CIN2-3/carcinoma was 5.8% for the cytology reports of ASCUS/AGUS, 7.6% for those of LGSIL, 76.5% for those of HGSIL, and 100.0% for those of carcinoma (80.4% for combined HGSIL/carcinoma). The ratio of observed to expected (or prevalent to incident) cases of invasive carcinoma was 2.35 (95% confidence interval (CI) 1.85-2.95). In conclusion, most early results of the programme were compatible with an acceptable performance.

Epidemiology of digital epiluminescence microscopy features of acquired melanocytic naevi.

This study addressed the independent association of past and recent sun exposure indicators and other host factors with the prevalence of major digital epiluminescence microscopy (D-ELM) features such as the pigment network (PN), brown globules (BGs), and pigment dots (PDs) in acquired melanocytic naevi. In a consecutive series of 189 patients (median age 28 years; range 10-73 years) with one or more naevi as diagnosed on D-ELM, we evaluated 35 solitary lesions and one naevus randomly selected from each of the 154 patients with multiple lesions. D-ELM images were classified for the presence or absence of PN, BGs and PDs on two blind readings. Data analysis was based on multiple logistic regression. Patient age was positively associated with PN and inversely associated with BGs. The probability of PN increased with more than 110 days since last exposure to the sun, whereas a rapid decrease for BGs and PDs was observed after approximately 1 month. PDs were significantly more likely among lesions with 6-10 h/day of recent exposure. Sex, total lifetime hours of exposure, sunbed use, skin type and colour of hair exerted no effect. In conclusion, major D-ELM features appeared to differ in their relationship with sun exposure indicators.

Integrating self-referral for mammography into organised screening: results from an Italian experience.

OBJECTIVE: To compare self-referred screenees with respondents to invitation for main performance indicators of mammography screening. SETTING: First round of an organised, population-based screening programme in six districts of northern Italy. METHODS: The screening test was a two-view mammography. Eligible women aged 50-69 years were invited. Self-referred attendees were accepted if they were eligible for screening and had not yet been invited or had been invited >6 months before presentation. Age-specific performance indicators were compared with the calculation of their ratio and 95% confidence intervals (CIs). Total ratios were age standardised. In situ carcinomas were excluded. RESULTS: The eligible population was 183 542 women. There were 112 188 respondents to invitation and 20 280 self-referred attendees. Self-referral rate was inversely related to age. Performance indicators were as follows: recall rate, 5.6% for self-referred attendees vs 5.5% for respondents (ratio 1.02, 95% CI 0.96 to 1.08); total aspiration cytology rate, 37.3% vs 28.3% (1.37, 1.24 to 1.51); biopsy rate, 17.0 vs 12.6 x 1000 (1.51, 1.35 to 1.67); total detection rate, 10.7 vs 7.5 x 1000 (1.70, 1.48 to 1.94); detection rate of pT1 carcinoma, 7.0 vs 6.1 x 1000 (1.35, 1.14 to 1.59); detection rate of pT2-4 carcinoma, 3.5 vs 1.2 x 1000 (3.51, 2.75 to 4.43); false-positive rate, 4.5% vs 4.7% (0.93, 0.87 to 0.99); positive predictive value (PPV) of mammography, 19.1% vs 13.5% (1.59, 1.39 to 1.82); PPV of biopsy, 63.7% vs 60.6% (1.13, 0.98 to 1.29); detected:expected ratio, 5.02 vs 3.37 (1.49, 1.28 to 1.74). All differences were more pronounced among or restricted to women aged 50-54 years. CONCLUSIONS: Self-referred screenees were similar to respondents to invitation in main indicators of screening feasibility such as recall rate and PPV of biopsy, while showing important increases in detection rates and detected:expected ratios, especially among women aged 50-54 years.

Effect of routine mammography practice on tumour size of a registry-based series of breast cancer cases compared with those observed in a screening cohort.

Routine mammography (MX) practice based on self-referral is considered not to be susceptible to monitoring at the population level. Invasive breast cancer cases notified to the Romagna Cancer Registry between 1989 and 1991 (total 654) were stratified by MX experience and were compared for the proportion of lesions greater than 2 cm in size (T2+) with cases observed in the study group of the Swedish Two Counties Screening Trial (TCST). Any MX more than 6 months prior to diagnosis was considered a previous routine examination. The proportion of cases registered in Romagna within 6-11 months of the most recent MX was quite similar to that shown by the interval cases of the TCST (50% vs 53%). T2+ cases registered in Romagna 12-23 months (27%) and 24-35 months (19%) after previous MX were similar in frequency to those detected at second and later screens in the TCST (22%). For longer intervals, the percentage of large tumours in the Romagna series increased, up to 45% among the cases registered more than 48 months since last MX (p < 0.0001). The whole group of cases with previous MX in Romagna and its counterpart in the TCST (i.e. interval cases + cases detected at second and later screens) had the same size distribution (35% vs 34%). The frequency of large tumours in the total series from Romagna was greater than in the total study group of the TCST (45% vs 36%, p < 0.0001). The difference was entirely accounted for by the cases with no previous MX.

Epiluminescence microscopy features of melanoma in relation to tumor thickness. Current concepts and clinical examples.

Based on current information, the expression of ELM features as a function of tumor thickness seems to be consistent not only with the definition of main ELM features but also with the model of histogenesis of the disease. The published data and observations, however, are insufficient. The relationship between tumor thickness and the ELM picture needs to be the subject of further research.

Spontaneous screening for cervical cancer and diagnostic histories of incident cases.

Cytologic and colposcopic histories of cases of invasive cervical cancer and cervical intraepithelial neoplasia grade III (CIN III) registered in Ravenna (northern Italy) between 1986 and 1990 were evaluated. During the 5 years prior to diagnosis, 10/49 invasive cancer patients and 25/61 CIN III patients had had at least one pap smear reported as negative. At the time of the most recent false-negative report, 9/10 and 17/25 of these cases had been recommended for a repeat smear within 2 to 6 months. Of the 9 patients with invasive cancer, 5 had also undergone an inconclusive colposcopy (with biopsy unperformed). Among invasive cancer patients aged under 50, half of incident cases (7/14) and most of those with some cytologic experience (7/8) had had a false-negative report; each of these patients (7/7) had been recommended for an early repeat smear. For invasive cancer patients as well as for CIN III patients, the suggested intervals for the early repeat were largely exceeded. Median delay in diagnosis was about 2 years. Although the frequency of negative reports recommending repeat smears within a few months was estimated to be some 10% of total screening patients, current concepts in cervical cytology suggest that cancer cases with such false-negative reports should be regarded as follow-up failures rather than laboratory errors. In fact, they passed quite unnoticed. In unplanned (spontaneous) cervical screening practice, sensitivity needs to be maximized, but even the occurrence of false-negative cases is not monitored. The present study points out what may result from such a contradiction.