[Consequences of incorrect interpretation of vaginal smear tests in a screening program]. / Hvad betyder fejlklassificering af smearprøver i et screeningsprogram?

A nested case-control study was undertaken in the Maribo County cohort of 27,811 women with negative cervical smears. Fifty-three women who later developed invasive cervical cancer constituted the cases, and five matched controls were selected from the cohort for each case. A total of 633 previous negative smears for the cases and controls were reviewed independently by two pathologists. The review showed misclassification to be frequent in these smears, which were collected in the period 1966-82, and the odds ratio for patients compared with controls for having at least one positive smear was 22.12 (95% CI 7.54-64.94). The study thus shows that more cancer cases could have been prevented by the screening programme were the test to have been more sensitive. The study also shows, however, that the participating women would have to pay a considerable price in the form of unnecessary extra tests if the sensitivity was too high.

[Status of preventive screening for uterine cervix cancer in Denmark in 1994]. / Status for forebyggende undersøgelser mod livmoderhalskraeft i Danmark 1994.

In 1986 The National Board of Health published guidelines for cervical cancer screening in Denmark. These guidelines recommend organized screening with personal invitations every three years to women in the age group 23-59 years, and in the years to come also invitation of women aged 60-74 years. We studied the organization of cervical cancer screening in Danish counties at the beginning of 1994. Organized screening programmes are running in 15 out of the 16 "counties" (this include the municipalities of København and Frederiksberg). Four counties completely follow the national guidelines. Eight counties follow these guidelines in general, but they do not invite women above the age of 60 years. In total, 72% of women aged 25-74 years are at present invited for cervical cancer screening in Denmark.

Smear misclassification in a cervical cancer screening programme.

A nested case-control study was undertaken in the Maribo County cohort of 27,811 women with negative Pap smears. Sixty women who later developed invasive cervical cancer constituted the cases, and five matched controls were selected from the cohort for each case. A total of 633 previous, negative smears for the cases and controls were reviewed independently by two pathologists. The review showed misclassification to be frequent in these smears collected in the period 1966-82. Thirty-five smears were considered positive at the review. The misclassification was differential in respect to the women's later disease status. The odds ratio for patients compared with controls for having at least one positive smear was 22.12 (95% CI 7.54-64.94). We were unable to identify specific characteristics of misclassified smears coming from later cases. Koilocytosis/dyskeratosis, herpes virus changed cells and hyperkeratosis were equally rare in smears from patients and controls. The Maribo County data indicate that the fraction of preventable cases of invasive cervical cancer in women aged 30-64 within the first 5 years after a negative smear could be increased from 62-72% to 83-86%, if misclassification of true positive smears could be eliminated. As a rough estimate, this would be at the cost of a 2% increase in the work load. It should be remembered that there is a large element of extrapolation in applying these results based on relatively poor quality specimens from 1966-82 as compared to a modern screening service.

[Cervical cytological diagnosis of carcinoma]. / Den cervixcytologiske påvisning af karcinom.

The predictive value of specifically diagnosing carcinoma by cervical cytology and the sensitivity of the Pap smear in assessing cervical carcinoma were evaluated by retrieving all cytological diagnoses stating carcinoma and all histological diagnoses stating cervical carcinoma from our data files covering the period from 01.04.88 to 31.03.91. In 115 patients the specific cytodiagnosis was followed up by histology, and in 107 patients the histological diagnosis was preceded by a Pap smear no more than two months old. The cytological recognition of invasion depended on the depth of invasion. Macroinvasive squamous cell carcinoma was specifically diagnosed by cytology in 77 per cent of the cases, while the cytological prediction of squamous cell carcinoma was confirmed as invasive carcinoma in 83.3 per cent of the cases. Adenocarcinoma assessed by cytology was confirmed in 84.4 per cent of the cases, while the sensitivity in specifying the diagnosis cervical adenocarcinoma was 54.6 per cent. No false negative Pap smears were seen in the material.

Promotion pattern and tumour types in two-stage rat skin carcinogenesis.

Carcinogenic studies were performed on the skin of inbred male Lister rats using 7,12-dimethylbenz[alpha]anthracene (DMBA) in low doses (2.5 mg and 5.0 mg), followed by promotion with croton oil (CO) in one half of the animals. The clinically observed tumour rate did not differ after the two carcinogen doses and was practically unaffected by promotion, only a marginal increase in effect being noted after DMBA 2.5 mg. Also the latency periods were alike. The total tumour crop was increased by promotion, but histologically the predominant clinical skin tumour was a sebaceous proliferation with or without associated papillomatous squamous cell hyperplasia. This lesion did not in microscopic structure or cellular characteristics fulfil the criteria of a neoplastic tumour. Basal cell carcinomas, adnexal tumours and pure squamous cell tumours were rare and were not promoted by CO. CO had a marked promotion effect, but only on the mixed sebaceous-papillomatous hyperplasias, which were more than doubled in number. In conclusion, carcinogenesis was weak after the low DMBA-doses, and promotion by CO of neoplastic tumours was not seen.

[Status of preventive examinations against uterine cervix cancer in Denmark]. / Status for forebyggende undersøgelser mod livmoderhalskraeft i Danmark 1991.

In 1986, The Danish National Board of Health published guidelines for cervical cancer screening. These guidelines recommend organized screening with personal invitations every three years to women in the age group 23-59 years, and in the years to come also invitations to women aged 60-74 years. Five years have now elapsed since publication of these guidelines, and we have therefore studied the present organization of cervical cancer screening in Danish counties. Organized screening programmes are now, medio 1991, running in 11 out of the 16 "counties" (this includes the municipalities of Copenhagen and Frederiksberg). One county follows the national guidelines entirely. Six counties follow these guidelines in general, but they do not invite women over the age of 60 years. In all, 45% of women aged 25-74 years are at present invited for cervical cancer screening in Denmark. Two counties have decided to start organized screening programmes in 1992.

Adenocarcinoma in situ of the uterine cervix: a clinico-pathologic study of 36 cases.

Thirty-six consecutive cases of adenocarcinoma in situ (ACIS) of the uterine cervix, including 8 cases of early stromal invasion to a depth not exceeding 5 mm, were revised with specific reference to detection rate and treatment. The final histologic diagnoses were based on 31 cone biopsies, 1 hysterectomy specimen, and 4 endocervical curettings/punch biopsies. ACIS was localized in the transformation zone of all cone biopsies/hysterectomy specimen, with a mostly superficial spread in the glands. The mucosal surface was involved in 34 cases. In 29 cone biopsies, ACIS was found unifocal. ACIS was associated with lesions of the squamous epithelium, mostly severe, in 25 cases. On review, all cervical smears were positive and ACIS could be specifically diagnosed in 24 cases. Pretreatment biopsies showed ACIS in 28 cases. Detection of early invasive adenocarcinoma required cone biopsy in most cases. Colposcopy showed no characteristics of ACIS. The detection of ACIS depended on the extension of the lesion. Conization with uninvolved margins was an adequate treatment. Residual ACIS was only found in cases with coexisting early invasive adenocarcinoma. No recurrences or frankly invasive adenocarcinomas have been observed during the observation period.

A randomized study of cyclophosphamide and cis-platinum with or without doxorubicin in advanced ovarian carcinoma.

Two hundred sixty-seven patients with advanced epithelial ovarian carcinoma were randomized to cis-platinum and cyclophosphamide versus cis-platinum, cyclophosphamide, and doxorubicin. Complete pathological response, evaluated at second-look laparotomy and survival, showed no differences between the two treatment groups. Recurrence-free survival after negative second look was 61% at 24 months.

Endoscopic fine-needle aspiration cytology of the stomach. A new diagnostic procedure.

In order to improve the diagnosis of submucosal gastric malignancies, a new method of endoscopic fine-needle aspiration cytology was evaluated. The method is compared with conventional forceps biopsy and brush cytology, and technical problems are discussed. It is concluded that endoscopic fine-needle aspiration cytology is a simple and safe procedure, but further development of the method and more clinical experience are required before the diagnostic capability of the method can be established.

Skin carcinogenesis in rats by 3-methylcholanthrene and 7,12-dimethylbenz(alpha)anthracene. Influence of dose and frequency on tumour response and its histological type.

Skin tumours were induced in male inbred rats of the Lister and Wistar strains and in (WixBN) F1 hybrids by topical application of 3-methylcholanthrene (MCA) and 7,12-dimethylbenz(alpha)anthracene (DMBA). Several schedules of application were compared. At a weight basis DMBA was more potent than MCA and the tumour response to DMBA was most clearly related to total dose applied, while the frequency of application was very important for the tumour crop on MCA-treated rats. DMBA led to a marked predominance of squamous celled tumours (SQCT) when treatment was potent, while basal celled and adnexal tumours (BCAT) prevailed after any dosage of MCA. The carcinogenic effect of DMBA in a low total dose approached that of the most potent dosage of MCA. At this level of activity DMBA induced more BCAT than SQCT in both strains and in the hybrids, while MCA induced an increased number of SQCT. Strain differences did not interfere with these main results.

Effect of some fatty acid methyl esters on gastrointestinal carcinogenesis by N-methyl-N-nitro-N-nitrosoguanidine in rats.

Methyl linoleate hydroperoxide (MLHP) and native methyl linoleate (ML) were tested for carcinogenicity toward the gastrointestinal (GI) tract in male specific-pathogen-free outbred Wistar rats. N-Methyl-N-nitro-N-nitrosoguanidine (MNNG) was given in the drinking water in a dose of 20 mg/liter when cocarcinogenic properties of the test substances were to be tested. MLHP and ML were fed by stomach tube and had no effect as complete carcinogens. Given concomitantly with MNNG, ML did not enhance carcinogenesis. MLHP in conjunction with MNNG was the only treatment which, as treatment with MNNG in a dose of 83 mg/liter, led to an increase of GI cancers in animals that died before day 354. Cumulative results after a maximum of 612 days showed a distribution of GI cancers in favor of the glandular stomach only after MLHP was given with MNNG.

Influence of surface lipids on skin carcinogenesis in rats.

Skin tumours were indeuced in female Wistar SPF-rats by different polycyclic aromatic hydrocarbons, benzo[alpha]pyrene (BP), dibenz[alpha, h]anthracene (DBA), 7,12-dimethylbenz]alpha]anthracene (DMBA), and 3-methylcholanthrene (MCA) being applied on the dorsal skin of 20 rats each. DBA was not carcinogenic under the experimental conditions. DMBA proved the most potent carcinogen, and MCA was more potent than BP. Half of the animals in each group underwent skin-surface lipid extraction (SSLE) before the application of carcinogen. SSLE did not influence the cumulative number of rats with skin tumours during an observation period of 15 months nor the type of tumours induced. The lipid extraction, however, increased the latency period and decreased the rate of tumour development when BP and MCA acted as carcinogens. On the contrary, SSLE enhanced the rate of tumour production by DMBA and reduced the latency period. The role of sebum and its composition in skin carcinogenesis is discussed, and an explanation of the different influence of SSLE on BP and MCA carcinogenesis is discussed, and and explanation of the different influence of SSLE on BP and MCA carcinogenesis in contrast to DMBA carcinogenesis is sought in differences in metabolic activation of the carcinogens.

Evaluation of smears obtained by cervical scraping and an endocervical swab in the diagnosis of neoplastic disease of the uterine cervix.

A study of the supplementary value of an endocervical swab smear in addition to cervical scraping in the cytological diagnosis of cervical neoplasias is presented. The two sampling techniques were applied to a population with a high prevalence of neoplastic cervical disease. The endocervical swab smear was a useful adjunct in the detection of mild and moderate dysplasia, and a combination of the two sampling methods decreased the false negative rate in the diagnosis of intraepithelial, as well as invasive neoplasia. In the sphere of specific cytological diagnosis cervical scraping was found to be the more accurate method for diagnosing severe dysplasia and carcinoma in situ, while endocervical swab smears were more useful in diagnosing mild and moderate dysplasia. Differences between the results obtained in our study and comparable studies are discussed. It is concluded that the endocervical swab smear is a valuable adjunct to cervical scraping in the diagnosis of malignant cervical disease. It should not, however, be used as the only sampling method as it produces a higher proportion of unsatisfactory smears, and also because the severity of the epithelial lesion is more likely to be underestimated.

Carcinogenicity in mice of some fatty acid methyl esters. 2. Peroral and subcutaneous application.

Two fatty acid methyl esters, methyl oleate and methyl 12-oxo-trans-10-octadecenoate, have been tested for carcinogenicty by oral and subcutaneous administration in ST/a mice of both sexes. A positive effect of methyl oleate could not be assessed, while the results pointed to a promoter effect of methyl oxo-octadecenoate. Given in the diet, this compound increased the incidence and number of forestomach papillomas within 83 weeks after initiation by 4-nitroguinoline 1-oxide. Repeated injections of methyl oxo-octadecenoate in the inguinal area resulted in 2 local sarcomas in a group of 20 females which had previously received skin initiation by 7, 12-dimethylbenz [alpha] anthracene in the neck. In no other animal group did sarcomas appear at this location within the observation period of 2 years. An influence by the injected methyl esters on the initiated skin carcinogenesis was possibly, but weakly, present. The need for more extensive experiments is stressed, especially with a view to the possible carcinogenic hazards involved in dietary intake of oxygen-containing derivatives of oleic acid.