Clinical studies on intravaginal administration of CDDP for dysplasia, carcinoma in situ and microinvasive carcinoma of the uterine cervix]

We attempted CDDP (cis-diaminedichloroplatinum) intravaginal administration by directly exposing the uterine cervix to CDDP in cases of dysplasia of the uterine cervix and cervical intraepithelial and micro-invasive carcinoma. Out of 12 patients, 7 had dysplasia of the uterine cervix (dysplasia was mild in 4, of an intermediate level in 1, 4 with mild dysplasia, 1 with and advanced in 2); 3 had carcinoma in situ, and 2 had microinvasive carcinoma. For CDDP intravaginal administration, a gauze tampon containing CDDP (5mg) was inserted into the vagina. CDDP administration was repeated daily for 10 days. The total dosage of CDDP administered was 50mg (new paragraph). During this period, vaginal cytologic examination was conducted and total plasma Pt content was determined daily for all. Following the completion of CDDP administration, the uterine cervices of those with dysplasia were histologically examined. For those with carcinoma in situ and microinvasive carcinoma, simple total hysterectomy was performed after intravaginal administration of CDDP to determine its therapeutic efficacy and the Pt concentration of the tissue; 1. In the 7 cases of dysplasia, dysplastic cell degeneration was observed 1-2 days after the start of intravaginal CDDP administration and these cells disappeared in all cases after its completion. 2. Sixteen histological sections of the resected cervical specimens from the 3 cases of carcinoma in situ showed complete disappearance of cancerous cells. 3. In the 2 cases of microinvasive carcinoma, no tumor cells were detected in one case; in the other case, tumor cells persisted in part of the resected specimen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cryosurgical treatment of cervical dysplasia

Seventy-seven women with mild-moderate to severe dysplasia and 4 women with squamous cell carcinoma in situ were treated with cryocautery of the cervix. Sixty-seven of the 77 women with dysplasia and 3 of the 4 women with in situ carcinoma have demonstrated no evidence of residual atypia by either cytologic follow-up or tissue examination over a period of 2 to 24 months. Three of the 4 women with in situ carcinoma had no residual disease left in the cervix when conization and hysterectomy were performed. Cryocautery, in our hands, has proved to be an effective means of eradicating cervical dysplasia. Precise and careful evaluation of the cervix must first be carried out prior to cryosurgical treatment if inadvertent treatment of invasive carcinoma is to be prevented.     

Human papillomaviruses in women with a history of abnormal Papanicolaou smears and in their male partners

Human papillomavirus infection of the genital tract was identified by the filter in situ hybridization test. Exfoliated cervical cells were tested separately for the prevalence of human papillomavirus 6/11 and 16/18. Human papillomavirus deoxyribonucleic acid (DNA) was identified in 70 and 92% of specimens of U.S. and West German women, respectively, who showed concurrent cytologic and colposcopic abnormalities, and in 50 and 54% of women, respectively, who showed neither cytologic nor colposcopic abnormalities at the time of examination. In the cytologic categories of condyloma, mild to moderate dysplasia (cervical intraepithelial neoplasia I/II), and severe dysplasia-carcinoma in situ (cervical intraepithelial neoplasia III), the overall DNA detection rate of human papillomavirus 6/11 and 16/18 varied between 75 and 83%; but human papillomavirus 16/18 was recovered relatively more frequently from the more severe lesions. Forty-eight West German women were monitored cytologically over a period of three to 24 months; progression to carcinoma in situ (cervical intraepithelial neoplasia III) was correlated with initial isolation of human papillomavirus 16/18. The vagina and vestibule were found to be frequent sites of human papillomavirus infection with the same virus type as in the cervix. In an investigation of male partners of 40 human papillomavirus-positive women, human papillomavirus was identified in exfoliated cells from 26; in 19 instances, the males harbored the same human papillomavirus types as their female partners.     

Cervical cancer epidemiology in historical perspective

In 1846, uterine cancer was the most frequently observed malignant tumor in western Europe. It accounted for nearly 1/3 of all reported deaths in Paris. The cervix was regarded as the primary source in most cases. Several etiological theories in vogue today were discussed then. The relative infrequency of cervical cancer among Jewish women was reported by numerous writers. The possible role of circumcision of husbands was not seriously considered until 1935. More recent such studies have been inconclusive. A definite reduction in the death rate from cervical cancer has been evident since 1950. The parallel rise in incidence is accounted for by the more numerous in situ cases detected through cytologic screening. Nonwhite women in America above age 60 as well as the elderly in England and Wales have not shown equally improved rates. The hypothesis that the genital strain of herpes simplex virus (HSV-2), a venereally transmitted virus, is associated with cervical cancer has been advanced and much new evidence has recently been reporte d. A positive association between cervical cancer and HSV-2 antibodies is evident. Progression of dysplasia and carcinoma in situ is of uncert ain occurrence. Prolonged periodic check-up studies are needed to deter mine this. If the facts warrant, follow-up by aggressive therapy is indicated. Observer variability has been a problem. 1 pathologists' interpretation of dysplasia may be another's carcinoma in situ. The more severe dysplasias have been more likely to progress. Periodic cytological screening has reduced the percentages of cases 1st diagnosed in the invasive stage to 1/2 on 1/3 of the former incidence. Increases in survival rates have followed. Patients with regional spread have experienced little gain. Women at highest risk have tended to elude examinations.     

Papilloma virus-induced changes in the uterine cervix. Histo- and cytologic and epidemiologic findings

In this epidemiological, cytological and histological study signs of papillomavirus infections were found in 128 cases (16,6 per cent) and dysplasia or carcinoma in situ in 713 cases in a series of 773 cone biopsies. Epithelial changes caused by papillomavirus were combined with preneoplastic lesions in 116 cases. Pretherapeutic cytologic examinations of the condylomatous epithelial changes secured histologically later on referred to cervical papillomavirus infections in 64 per cent. Epidemiological inquiries of patients with cervical papillomavirus infection correspond extensively to those with invasive carcinoma of the cervix and premalignant cervical lesions.     

Studies on the prevalence and incidence rate of epithelial neoplasia of the uterine cervix by mass survey using mobile units

In this paper, we analyzed the results obtained in a mass survey using mobile units. The survey covered 276,846 women of whrom 78,018 (24.6%) were women who were being screened for the first time and the other 208,828 had been screened previously. 1) The total detection rate was 0.04% for invasive cancer, 0.03% for carcinoma in situ and 0.06% for severe dysplasia of the uterine cervix. The prevalence rate for 1,000 women was calculated as 0.40, 0.30 and 0.63 respectively. 2) The detection rate for invasive cancer, carcinoma in situ and severe dysplasia was 0.08%, 0.07% and 0.08% respectively for women who were being screened for the first time and 0.03%, 0.02% and 0.06% respectively for repeats. Through the latter results, the incidence rate for 100,000 women was calculated as 30 for invasive cancer, 20 for carcinoma in situ and 60 for severe dysplasia. 3) The detection rate for invasive cancer and severe dysplasia increased abruptly above 60 years and that for carcinoma in situ at 65 years old and over. 4) The detection rate for invasive cancer, carcinoma in situ and severe dysplasia in previously screened women showed little fluctuation by age group.     

Cervical carcinoma in the aged

The previous impression that both carcinoma in situ and invasive carcinoma of the uterine cervix are rare in patients 65 years of age and older was not found to be correct. In fact, these lesions together were twice as common in women 65 and over than in women under 65. The invasive group, both early and late, was mainly responsible. Thus, Papanicolaou smear examinations must be continued in this older age group. Thirty-three cases of carcinoma in situ in the aged are reviewed in detail. It was found that (1) estrogens are apparently not needed in the morphogenesis; (2) that from the cytologic smear it is usually very difficult to separate the in situ carcinomas from the invasive carcinomas, this being principally due to the fact that most of the lesions in our present study group were at least questionably invasive by tissue studies.     

Results of colposcopic, cytologic and histological studies after treatment with ovulation inhibitors

Colposcopic, cytological and histological examinations were performed on 1746 women, 16-59 years of age, who had used oral contraceptives for 3 months to 6 years. The colposcopic tests performed on 1323 of the women showed a 4.16% incidence of characteristic indication results, which was lower than expected. Positive cytologic results were reported in 12 of the 1746 cases (.62%): 8 cases in group IV, 4 in group V. In 9 of these cases cytologic tests had not been taken before the patient began taking oral contraceptives, leaving a .23% rate of positive cytologic results attributable to oral contraceptive use. Histological examinations of 6 of the 12 cases with positive cytologic results showed 1 cervical microcarcinoma, 3 cases of carcinoma in situ and 2 cases of atypical epithelium. The incidence of epithelial carcinoma was .17%, slightly lower than expected.     

Results of prospective cytological diagnoses of cervical intraepithelial neoplasia

The value of prospective cytologic diagnosis in cervical intraepithelial neoplasia (CIN) is analysed by means of ROC (receiver operating characteristic) curves. Examined was a group of 160 women with subsequent cone biopsies. The result of a prospective cytologic diagnosis in moderate dysplasia, severe dysplasia and carcinoma in situ is analysed separately, taking into consideration the particular frequencies in the studied group. The most reliable prospective cytologic diagnosis is in moderate dysplasia, followed by carcinoma in situ a slightly more reliable prospective diagnosis than that in severe dysplasia.     

Pituitary gonadotropins during long-term Enovid therapy

4 patients receiving the oral contraceptive Enovid, 5 mg tablets Day 5-24 of the treatment cycle, were studied for 7 cycles after therapy for a minimum of 12 and a maximum of 31 (mean duration of 25) consecutive months of therapy. In addition 1 patient was studied for a control cycle before receiving medication and a second cycle while on medication. Total gonadotropins and luteinizing hormone (LH) were determined on 24 hour specimens. There was a slight depression of total gonadotropins in the patients receiving long-term cyclic therapy. The results of the LH excretion studies showed no evidence of a midcycle peak in the patients on medication. It was suggested that the loss of the midcycle LH peak and generally diminished total gonadotropin levels might be adequate explanation for ovulation suppression by Enovid.     

Cellular immunity to human basic myelin protein in women with dysplasia and carcinoma in situ of the cervix.

Sensitization to human myelin basic protein or encephalitogenic factor (EF), and antigen thought to be analogous to different human tumours, can be measured by the macrophage migration inhibition test (MMI). The MMI test was done on one occasion in 51 women with dysplasia and carcinoma in situ of the cervix; 20 women with non-malignant gynaecological conditions served as controls. Sensitization to EF was found in 71 per cent of women with carcinoma in situ and 42 per cent of women with dysplasia. None of the controls showed sensitization. Sensitization could not be related to histological evidence for cellular infiltration within the cervix.     

The cervix and hormonal contraception

This article reviews the histological effects of hormonal contraceptives on the cervix and assesses statistical studies examining the relationship between oral contraceptive (OC) usage and cancerous lesions of the cervix. The cervix acquires a pseudopregnant appearance under the influence of combined OCs. The Malpighian epithelium acquires a richly vascularized stroma characterized by accelerated maturation and the endocervical ectropion may be swollen, frequently with epidermoid metaplasia. Such changes increase with the duration of hormonal contraception and are more pronounced with combined than with sequential OCs. Among pathological changes that may occur are active adenomatous hyperplasia and epithelial abnormalities including dysplasia involving dyscaryotic cells with regular nuclei and no mitotic abnormality. Epithelial anomalies may present various histocytological features and are sometimes difficult to interpret. Epidemiologic study of the cervix is difficult because of the number of parameters to be considered: age at 1st intercourse, frequency of intercourse, number of partners, the formulation of the OC, and the variable duration of use which may have been interrupted by use of another method such as the IUD. Statistical studies have yielded contradictory results, with the earliest reports showing a higher incidence of dysplasia among women using OCs and most later studies showing a possible increased incidence of moderate dysplasia but no increased incidence of carcinoma in situ or invasive carcinoma. The recent study by Vessey et al. which compared 6838 parous OC users with 3154 parous IUD users over 10 years revealed invasive cancer in 13 women all of whom used OCs, with carcinomas in situ and dysplasias also more frequent in women using OCs. The duration of use was found to be a significant factor. Age and dates of marriage and 1st pregnancy were similar in subjects and controls, but no data were provided on age at 1st intercourse or number of partners. Regular cervical examinations and Pap tests should be performed for women using hormonal contraceptives to increase the probability of early detection of anomalies.     

Pathology of colposcopic findings in 2635 diethylstilbestrol-exposed young women

An analysis of 6055 colposcopically directed biopsy specimens from 2635 diethylstilbestrol (DES)-exposed women and 445 biopsy specimens from 277 nonexposed women was undertaken to correlate microscopic findings with colposcopic patterns. All examinations were performed using a standardized protocol which required that each participant have colposcopy, cytologic smears, and biopsy of abnormal colposcopic lesions. The findings of colposcopic "columnar epithelium, gland openings, and Nabothian cysts" correlated most often with glandular epithelium in the biopsy specimen. "White epithelium," which includes three related colposcopic patterns, mosaicism, punctation, and white epithelium, was associated most frequently (82-93% of cases) with squamous metaplasia, but occasionally with dysplasia and carcinoma in situ (CIS)(0-6%). The presence of dysplasia or CIS in any individual biopsy specimen occurred most frequently with the observation of higher graded lesions by colposcopy or a prior diagnosis of dysplasia.     

Symposium part I: adenocarcinoma in situ, glandular dysplasia, and early invasive adenocarcinoma of the uterine cervix.

A relative and an absolute increase in the incidence of adenocarcinoma of the uterine cervix has occurred in the United States since 1970. Currently, most pathologists recognize the histologic and cytologic features of invasive adenocarcinoma of the cervix, but there is confusion surrounding the histologic features and biologic behavior of adenocarcinoma in situ, endocervical glandular dysplasia, and the definition of microinvasive adenocarcinoma of the cervix. Similarly, the distinction of in situ adenocarcinoma from an early invasive adenocarcinoma of the cervix may be problematic. This article focuses on the histologic criteria, biologic behavior, and some approaches to therapy for these challenging lesions. General conclusions based largely on published studies include the following: 1) adenocarcinoma in situ (AIS) is a recognizable precursor to invasive adenocarcinoma and can be divided according to distinct histologic subtypes; 2) AIS is multifocal or involves multiple quadrants of the cervix in about half of cases; 3) AIS can be cured by simple hysterectomy and in many cases may be treated effectively by cone biopsy; 4) endocervical glandular dysplasia is not a reproducibly recognizable lesion, and its behavior and existence are undefined; 5) criteria exist to permit the distinction of early invasive adenocarcinoma from AIS in about 80% of cases; 6) microinvasive adenocarcinoma of the cervix is complicated by the presence of multiple definitions; clinical decision making is best guided by assessment and reporting of the depth, horizontal extent, and presence of lymphatic or vascular invasion.     

Risk of cervical cancer among an electrocoagulated population.

In Finland an organized mass screening program covers the total female population. Based on the material (429,832) from a nationwide mass screening registry it was estimated that the female population not subjected to electrocoagulation of the uterine cervix (362,511) had a sixfold risk of frankly invasive carcinoma, a fourfold risk of carcinoma in situ or dysplasia of high degree, and a twofold risk of dysplasia of low degree as compared with the female population subjected to electrocoagulation of the uterine cervix (67,321). The relative risk of cervical lesion varied by cytologic diagnosis, marital status, and Trichomonas vaginalis.     

Immunohistochemical demonstration of papillomavirus antigen in cervical dysplasia and vulvar condyloma

Biopsies from 30 cases of vulvar condyloma, 460 cases of cervical dysplasia, 30 cases of carcinoma in situ and 75 cases of invasive carcinoma of the cervix were screened for the presence of human papillomavirus (HPV) antigen by means of the peroxidase-antiperoxidase method. Positive reaction for HPV was detected in 14 cases of condyloma and 80 cases of dysplasia as a brown intranuclear precipitate in the superficial layer of the epithelium. None of the cases of carcinoma in situ and invasive cancer were positive for HPV. The mean age of the women with HPV-positive dysplasia was significantly lower than that of the women with HPV-negative dysplasia. Condylomatous dysplasia showed a significantly higher positive rate than did noncondylomatous dysplasia. Cases of condylomatous dysplasia with severe stromal inflammation were negative for HPV more frequently than those with mild stromal inflammation.     

Cytomegalovirus infection of the uterine cervix: Local cervical infection and antibody response

Thirty-three women were examined on three or more occasions, each at 2-month intervals. The overall recovery rate of cytomegalovirus (CMV) was 28% ($\text{60}\text{215}$). CMV was recovered from 53% of the cases where the local antibody was 1 : 64 or greater but the greatest difference occurred below titers of 1 : 32. Below that level virus was recovered in less than 5%, compared to a prevalence of 35% for cases with a titer of 1 : 32 (P < 0.001). Twenty-eight cases in whom CMV was sought underwent colposcopic examination and had cytologic smears examined by the papanicolaou method. The external uterine cervix with columnar cells only yield a CMV prevalence of $\text{3}\text{17}$ (18%). However, if colposcopy showed either atypical transformation or metaplasia the prevalence was $\text{4}\text{11}$ (36%). Similarly, it is provocative that the prevalence of CMV appears to increase with abnormal cytologic findings to 33% recovery in severe dysplasia or carcinoma in situ.     

Correlation of cellular atypia and human papillomavirus deoxyribonucleic acid sequences in exfoliated cells of the uterine cervix

Restriction enzyme digestion and Southern blot hybridization were used to analyze deoxyribonucleic acid (DNA) extracted from exfoliated cervical cells for the presence of human papillomavirus sequences and these results were correlated with cytologic findings on Papanicolaou smears. Specimens (N = 204) were obtained from a nonselected population of women undergoing routine cytologic screening and human papillomavirus DNA sequences were detected in 33 (16%) women. Thirteen smears contained atypical squamous cells, ranging from very mild dysplasia to moderate dysplasia; all showed associated morphologic evidence of human papillomavirus infection characterized by koilocytosis, nuclear enlargement, wrinkling, and hyperchromasia, and human papillomavirus DNA was demonstrable in 12 (92%) smears. Of the remaining 191 samples with normal cytology, 21 (11%) also contained human papillomavirus DNA sequences. Reevaluation of the smears from these women resulted in a revision of the cytologic diagnosis to very mild dysplasia in four cases. These data suggest that human papillomavirus infection occurs more frequently than predicted by cytologic screening.     

Laser miniconization in mild and moderate dysplasia of the uterine cervix

Mass cytologic screening for cervical cancer often reveals only mild dysplasia not indicating conization but necessitating continual checkup. Such routine checkups are often insufficient, beside which the patients find them frustrating. Therefore a new method, called miniconization, for treatment of patients with vaginal smears showing mild or moderate dysplasia (cervical intraepithelial neoplasia/CIN/I-II), was developed. With the CO2 laser handpiece a 5-mm-thick disc of the cervix, including the whole transformation zone, was removed. This was followed by endocervical curettage. The advantage of the method over cryosurgery, electrocoagulation, and laser vaporization, for example, is that the tissue specimen as a whole disc including the transformation zone can be sectioned and examined histologically. Another advantage is the decreased risk of postoperative bleeding, which enables ambulant care. One hundred and fifty-one patients have hitherto been treated and carcinoma in situ has been found in 15.2% and microinvasive carcinoma in 1.3% of all these patients in whom vaginal smears showed mild or moderate dysplasia (CIN I-II).     

Radioactivity in the breast milk of lactating women after oral administration of 3H-norethynodrel

In an investigation of the excretion of oral contraceptives in the milk of lactating women, tritiated norethynodrel (the progestin component of Enovid) was administered after 2 days of Enovid to 4 patients with stillbirths. An average of 1.1% (range .45-1.52%) of the radioactive norethynodrel was excreted in the breast milk; on the basis of 5.0 mg of norethynodrel per Enovid tablet this amounts to an excretion of 55 mg of the progestin and its metabolites. Since such products could affect the infant, caution is urged in administration of oral contraceptives during lactation.