Gabriele Medley

Cervical cytology reported as negative and risk of adenocarcinoma of the cervix: no strong evidence of benefit

The relationship between negative cervical cytology reports and risk of adenocarcinoma of the cervix was evaluated in a case-control study of 113 cases and 452 controls. All cases and controls had received at least two negative cytology reports. There was no significant difference between the cases and controls in the number of negative cytology reports or in history of cervical abnormality; while a test for trend in the time since last negative cytology report was significant (P < 0.001), the estimated benefit was very modest. Although the estimates of relative protection were higher in women aged less than 35 years than in women aged 35-69 years, this difference was not statistically significant. These results suggest that cervical screening as practised in the 1970s and 1980s was much less effective in preventing adenocarcinoma than squamous carcinoma of the cervix.

PROSPECTIVE EVALUATION OF RISK OF CERVICAL CANCER AFTER CYTOLOGICAL EVIDENCE OF HUMAN PAPILLOMAVIRUS INFECTION

846 women with cytological evidence of human papillomavirus infection on their Papanicolaou smears in 1979 were followed for the subsequent development of cervical malignant disorders. Carcinoma-in-situ developed in 30 women during the next 6 years, compared with an expected number of 1.9 by general population incidence figures, giving a relative risk of 15.6. The risk was greatly increased (38.7) in women younger than 25 years when the cytological diagnosis of human papillomavirus infection was made.

Cervical cancers diagnosed after negative results on cervical cytology: perspective in the 1980s.

OBJECTIVES--To assess the magnitude of the problem of interval cancers of the cervix (those that are diagnosed within a short time after negative screening test results) in the 1980s, to compare the nature of interval cancers in younger women with that in older women, and, by reviewing negative cervical smears, to determine the proportion of interval cancers that might represent the development of malignancy anew compared with the proportion that might be associated with difficulties in sampling or errors in reporting. DESIGN--An audit of the interval cases of cervical cancer that had been diagnosed within 36 months of a smear having been reported as negative by the Victorian Cytology Gynaecological Service among women registered with cervical cancer during 1982-6. SETTING--The Victorian Cytology Gynaecological Service, a free public sector cytology laboratory in Victoria, Australia. SUBJECTS--138 Women, all of whom had had cervical cancer diagnosed during the 36 months after having had a negative cervical smear. Subjects were divided into two age groups: younger women, aged less than 35; older women, aged 35-69. INTERVENTIONS--Negative slides were reviewed for evidence of optimal sampling and for the presence of cellular abnormalities that had been missed at the time of the original reporting. MAIN OUTCOME MEASURES--The number of interval cases of cancer of the cervix registered during 1982-6. The proportion of interval cases occurring in younger women and the proportion occurring in older women. Division of women into three risk categories based on clinical history and screening history that broadly corresponded to the probability that a diagnosis of cervical cancer might be expected during the 36 months after the issuing of a negative smear report. RESULTS--138 Of 1044 (13.2%) women who had been registered with cervical cancer during 1982-6 had had one or more negative smears during the 36 months preceding the diagnosis of cancer. Interval cancers comprised a larger proportion of registrations of cervical cancer in women aged less than 35 years than in women aged 35-69 (21.1% v 11.0%, p less than 0.01). Women with interval cancer who had had at least three negative smears during the 10 years before the diagnosis of cancer were commoner in the younger age group than in the older age group (7.0% v 2.5%, p less than 0.01). When, however, the number of observed cases of squamous cell carcinoma was related to the number of expected cases in the absence of screening, no significant difference was found between the two age groups (6.8% v 4.8%, p greater than 0.10). The rate of diagnosis of interval cancer per 100,000 negative tests was lower among younger women than among older women (10/100,000 v 16/100,000). Review of the negative slides showed that 11.9% were again considered to be negative with an optimal sample having been obtained as evidenced by the presence of endocervical cells or metaplastic cells, or both. CONCLUSIONS--Interval cancers might comprise a larger proportion of all registered cases of cervical cancer among younger women owing to the larger proportion of such cancers being prevented in this age group. Among women with interval cancer review of the negative slides showed that most were accounted for by suboptimal sampling or by errors of reporting.

Accuracy and survival benefit of cytological prediction of endometrial carcinoma on routine cervical smears.

Summary:Among 359 women who received a cytology report of endometrial malignancy from the Victorian Cytology Service during 1982–87, the positive predictive value for a later histological diagnosis of endometrial malignancy was 64%. The positive predictive value was significantly higher for the group of women in whom the cytopathologists made definite predictions of endometrial malignancy as compared to the group where the cytologic features were only suggestive of endometrial malignancy (75% vs. 50%, X2 = 23.4; p > 0.001). The sensitivity of cervical cytology performed within two years of the diagnosis of endometrial malignancy was 28%. The odds ratio of death from endometrial cancer among women where the cytology may have allowed for an early diagnosis in comparison to women where cytology did not hasten the diagnosis was 0.78 (95% confidence interval = 0.25–2.47; p < 0.05). We conclude that while cervical cytology can predict the presence of malignancy for a small proportion of women with endometrial cancer, there remains no evidence that a cervical cancer screening program will make a major impact on reducing the morbidity and mortality from endometrial cancer.

Detection of Laboratory False Negative Smears by the PAPNET Cytologic Screening System

OBJECTIVE To evaluate the ability of PAPNET-assisted screening to identify abnormal slides that had originally been reported as negative on manual screening. STUDY DESIGN One hundred ninety-five abnormal slides were seeded into 20,000 slides that had been assessed as showing no abnormality on two occasions by manual screening. All slides were submitted for PAPNET review and the tiles assessed by trained cytotechnologists. RESULTS With a single assessment of the PAPNET tiles and when the prevalence of seeded abnormality was around 1%, only 44% of the seeded abnormal slides were recognized as abnormal. With multiple independent assessments and by increasing the prevalence of abnormality to 81%, 83% of the seeded abnormalities were recognized by at least one of three reviewing cytotechnologists. This increase in sensitivity appeared to be associated with a state of relative hyperalertness in the reviewing cytotechnologists. CONCLUSION The sensitivity of a PAPNET-assisted review was < 100% for the detection of seeded abnormal slides. Altering the format of presentation of information to the cytotechnologist may result in improved sensitivity.

Risk of subsequent cytological abnormality and cancer among women with a history of cervical intraepithelial neoplasia: a comparative study

A longitudinal study of 1,281 women with a histological diagnosis of cervical intraepithelial neoplasia (CIN) during 1974–76 is presented. After 12 years of follow-up, 30 percent of the women had further cytological abnormalities reported. The rate of subsequent abnormality was highest during the first 12 months of follow-up; thereafter, there was no evidence of any decline in the rate of subsequent abnormality with increasing duration of follow-up. Women from the CIN cohort had twice as many later cytological abnormalities as an age-matched cohort of women who were negatively screened during 1974–76 (excluding abnormalities within 12 months of entry to the study and after adjustment for smear frequency). The CIN cohort remained at substantially greater risk for a subsequent diagnosis of squamous cell carcinoma of the cervix compared with the control group of negatively-screened women (rate ratio 19.8, 95 percent confidence interval 2.4–163.6, P < 0.01). These results indicate that women who have received surgical intervention for CIN continue to have substantial morbidity from cervical abnormalities during medium-term follow-up.

Detection of Unsuspected Abnormalities by PAPNET-Assisted Review

OBJECTIVE To determine the positive predictive value of abnormalities detected by PAPNET-assisted review of slides considered to show no abnormality on two manual screenings and to evaluate the repeatability of technical codes assigned by the PAPNET scanner. STUDY DESIGN PAPNET-assisted review was performed on 19,805 slides that had been assessed as showing no abnormality on two occasions by manual screening plus 195 slides with abnormal cells seeded at random. Abnormalities detected by cytotechnologists were graded by cytopathologists and compared with the findings of later histology/cytology. RESULTS On PAPNET-assisted review, the cytotechnologists identified 212 slides as containing unsuspected abnormalities; cytopathologists agreed with 76% (162/212) of these predictions. Later histology/cytology confirmed 54% (14/26) and 32% (33/102) of the predictions of high and low grade abnormality, respectively. The PAPNET scanner gave concordant technical codes for 94.8% of 2,690 slides that were submitted twice for scanning. CONCLUSION Some additional abnormalities will be detected by a PAPNET-assisted review, even among slides considered negative on two manual screenings. However, many of these abnormalities will not be confirmed on later investigation and will thus appear to represent false positive cytology. The assigning of technical codes by the PAPNET machine is subject to a degree of variation on repeat evaluation of the same slides.

DIFFERENCES BETWEEN FALSE NEGATIVE AND TRUE POSITIVE PAPANICOLAOU SMEARS ON PAPNET ASSISTED REVIEW

This study explored whether there were differences between false‐negative and true‐positive Papanicolaou (Pap) smears in the number of abnormal images on a Papnet‐assisted review. The degree of agreement between cytotechnologists over Papnet tile status (normal/abnormal) was assessed. False‐negative and true‐positive Pap smears preceding a histologic diagnosis of carcinoma in situ were scanned by Papnet, and the resulting digital images and slides were assessed independently by three cytotechnologists. The median number of abnormal tiles was 7.3 for false‐negative slides and 29.7 for true‐positive slides. Three‐way agreement between cytotechnologists was better for true‐positive slides (kappa, 0.60) than for false‐negative slides (kappa, 0.47). These results confirm intrinsic differences between false‐negative and true‐positive Pap smears. The fair to good agreement beyond chance on tile status indicates that a cautious approach should be adopted if digital image review is performed in a judgemental manner. Diagn. Cytopathol. 1998;19:138–140.

AN AUDIT OF THE WOMEN WHO DIED DURING 1994 FROM CANCER OF THE CERVIX IN VICTORIA, AUSTRALIA

An audit of 73 Victorian women who died from cervical cancer during 1994 is presented. Seventy per cent of the deaths occurred in women who were 50 years at the time of cancer diagnosis. Younger women had significantly better screening histories than older women, but overall only 10% of the deaths occurred among women who were adequately screened. There was no excess of deaths in rural women or in women of non‐English speaking background. Four of the 6 deaths in women who were diagnosed with cancer while <35 years of age occurred in adequately screened women. If this finding is confirmed in a larger series, it raises questions about the ability of Papanicolaou screening to control disease in this age group.

Evidence Against Diathermy as a Beneficial Treatment for Human Papillomavirus Infection of the Cervix

EDITORIAL COMMENT: In recent years there have been numerous reports regarding human papillomavirus infection of the female genital tract and its possible association with preinvasive and invasive carcinoma of these sites (cervix, vagina, vulva). The most alarming information comes from studies of DNA hybridization techniques which indicate that a very high proportion of patients with apparently normal cervices on colposcopy and cytology harbour this virus. Many studies indicate that only a small proportion of patients who show clinical evidence of the papillomavirus have evidence of continuing infection or go on to develop intraepithelial or invasive carcinoma. The proportion of patients who spontaneously eradicate signs of the disease is not established, neither do we know why some patients cure themselves of the disease and why others do not. There is also confusion in the literature as to whether local treatment can eradicate this disease. This paper gives a very good account of the current state of knowledge about papillomavirus infection. It seems difficult to understand how diathermy to the cervix can eradicate this viral infection when many studies have shown that papillomavirus infection is usually present in the vagina and vulva when it involves the cervix, unless the cellular damage induced by the cautery enhances the patients immune response. There is evidence in numerous reports that biopsy of papillomavirus lesions and early dysplasias of the cervix modifies the natural history of these lesions, possibly by alteration of local immune function. The present study also indicates that treatment of the cervix for papillomavirus infection alone does not affect the incidence of subsequent development of intraepithelial neoplasia. These authors have stressed the fact that further long‐term follow‐up is required of patients with evidence of papillomavirus infection.