The Cervix and the lower female genital tract

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Soon after the reported association between diethylstilbestrol (DES) and clear-cell adenocarcinoma, large numbers of women exposed in utero to DES underwent screening examinations. Almost no cases of cancer were detected during this screening, but various epithelial abnormalities were found in many exposed women. Cervical and vaginal epithelial and structural abnormalities found in many DES-exposed women are described. Some of these abnormalities can be seen only with the aid of the colposcope, but many are visible to the naked eye. The identification of potentially exposed women should become a part of every physician's pelvic examination of women born since 1940. The 1st part of the examination of any DES-exposed women should be palpation of the vaginal vault with the index finger. This is done before speculum examination to identify any ridges, constrictions, or masses so that these can be visually inspected. Following vaginal palpation a bivalve speculum is introduced into the vagina in the routine fashion. At this point it is sometimes possible to observe a structural abnormality of the vagina and/or cervix. Any reddened area in the vagina or on the cervix is suspicious for the presence of glandular epithelium. Cytologic specimens should be obtained; it is important to sample all abnormal areas. Many DES-exposed women require sampling of the complete cervix, cervical side walls, vaginal fornices, and the vaginal vault to the point at which normal glycogenated squamous epithelium appears. The largest DES project in the US, "The DESAD Project," recommends taking 1 sample from the cervix wall and a separate sample from the vagina in those women who have vaginal abnormalities. These specimens should be handled in the usual way. It is recommended that whenever a cytologic sample from a DES-exposed woman is reported as being abnormal, the sample be sent to a DES center where it can be reviewed by a cytologist who has seen many samples from exposed women. Colposcopy has been a useful technique for the examination of DES-exposed women, but the findings are often confusing since many "abnormal" areas may be seen in women in whom no pathology is demonstrated. The 1st finding that will be seen by the colposcopist is a widened transformation zone. This may be located only on the cervix or may extend quite far into the vagina. When the glandular epithelium begins to mature, areas stimulating intraepithelial neoplasms may be seen. The areas of vaginal squamous metaplasia may mature with time.
 
Our study involved 996 women living in the Florence area using intrauterine contraceptive devices (IUD) for at least 6 months and 623 women using the pill or barrier contraceptives. Cervico-vaginal smears were screened to detect inflammation, reparative cellular changes (both in columnar and squamous cells), histiocytes, endometrial cells, and finally cervical intraepithelial neoplasias (CIN) grades. II, III. Screening of Pap-stained smears pointed out a different incidence of inflammation in IUD users and in women using other contraceptive methods. The most impressive result was the occurrence of actinomyces infection only in IUD users (5.20%). Reparative cellular changes also increased in IUD users. Comparative incidence of CIN I, II and III showed a higher incidence (2.51%) in IUD users than in pill (0.34%) and barrier contraceptive (1.17%) users.
 
Twenty-seven patients presenting with lichen sclerosus (LS) were enrolled in this study. In 11 women, clobetasol propionate 0.05% cream (Dermovate, Glaxo) was used as a first-line therapy, while 16 patients were given the drug after the failure of other medications. Patients age ranged between 33 and 85 years and the disease lasted from 6 months to 12 years. Dermovate cream was prescribed for topical application twice a day from the beginning of the treatment, and then, if successful, as a maintenance twice a week. Minimal duration of the treatment was 19 months and the longest follow-up has been 34 months. In 25 patients (93%), dramatic success was achieved. In two cases (7%), the treatment was stopped because of local side effects. Repeated biopsies showed a histological improvement of the disease in more than 60% of the cases. Sustained treatment of LS with Dermovate, followed for a short period of time, appears to be a very effective and safe remedy.
 
In Treviglio, a town with 25,000 inhabitants in the Bergamo province (Italy), a part of the same computerized archives used for choice/revocation of general practitioners, has been employed for a 3 year interval screening programme based on an 'active call' system. This was applied in one of the Health Units of the Treviglio District, experimentally, involving 2,493 women aged 25-64 years. The 1st invitation, by letter, was sent to all women who had never had a smear, or for whom more than 3 years had passed since the last test. A 2nd invitation was sent out to non responders, and in cases in which even it remained unanswered, the general practitioner was notified. Acceptance of the screening programme was good in all age groups, and the protected population rate rose from 26.5% before the programme to 60.5% after the 1st invitation and to 68.6% after the second. Only 10 women (0.97%) were found to have cytological atypicalities necessitating a second level (colposcopic) investigation. This result might be related either to the efficacy of the educational campaign promoted by the District Authority before our programme, or to cancer protection assured by Pap smears taken at longer than 3 year intervals. So, our results highlight that: i) the computerized archives already used for choice/revocation of general practitioners are useful to rationalize the screening interventions (the incorrect addresses were less than 3%); ii) for population of relatively high educational level, more than 3 year screening intervals may be quietly recommended.
 
Metastasis to the spleen, especially from cervical cancer, is extremely rare. A case of solitary splenic metastasis from cervical carcinoma is described. The diagnosis was made in a patient who was free of disease for over 5 years. Presenting symptoms were left upper abdominal pain and splenomegaly. The patient was treated by radical surgery and chemotherapy. The management of this case is described and the literature reviewed.
 
In Italy, there is not a common programmed population-based screening for cervical cancer. So, two different 'opportunistic' strategies were compared in an area of the North of Italy. According to the first, 2201 women aged 25-70, admitted to Rovereto Hospital between May 1985 and May 1986 with conditions other than malignancies, were questioned on their previous screening practice. A Pap smear was offered to subjects that had not had one in the last twenty months. According to the second strategy (by far the most widespread screening strategy in Italy), 386 women attending the local outpatient clinic in the same period were similarly investigated. Inpatients turned out top be a group at higher risk of cervical cancer than outpatients, as regards age (mean age 49.3 and 34.5 respectively), proportion of never-screened subjects (28% and 16% respectively), number of previous Pap smears and time elapsed since the last one. In the 462 inpatients, it was possible to arrange a Pap smear during their stay in hospital. In comparison with the 362 Pap smears taken from outpatient women, a higher number of cervical intraepithelial neoplasias (CIN) was found (3 versus 0). Two additional inpatients showed microinvasive cervical carcinomas. Hospital admission seems to offer a better opportunity than gynecology outpatient clinic to reach women outside their reproductive age, likely to have had none or very few Pap smears in the past.
 
Seven women aged 20-36 years, selected among 760 females affected by cervical intraepithelial neoplasia (CIN) associated with human papillomavirus (HPV) infections have been studied. HPV infections were diagnosed by colposcopic-cytologic examinations and 'Vira Type' HPV DNA typing tests. CIN and vulvar intraepithelial neoplasia (VIN) were histologically graded. Four patients showed HPV 16, 18 associated with CIN 3 and VIN 3. In one case HPV 16, 18 and 6, 11 were detected along with CIN 2 and VIN 1. In two cases HPV 6, 11 and CIN 2 and VIN 1 were encountered. Out of the five examined sexual partners, three demonstrated foci of penile papillomata. Concomitant occurrence of intraepithelial cervical/vulvar neoplasia and HPV infections may support the etiologic relationship between HPV infections and CIN and VIN.
 
The authors points out the increasing role of colposcopy in the diagnosis of papillomatous or condylomatous lesions of the uterine cervix and vagina. Five exemplary cases, which were colposcopically and histologically documented, are presented to highlight: a) the importance of the vascular pattern in differentiating benign from malignant lesions; b) the possible spontaneous regression of condylomatous lesions; c) the features of 'atypical condylomas'.
 
In 14 healthy women, the changes in number and morphology of Langerhans cells in the human uterine cervix have been investigated. Epithelial sheets obtained from cervical biopsies taken at different phases of the menstrual cycle were immunostained and then studied planimetrically and by means of a computerized image analysis. The density of CD1a positive Langerhans cells increased significantly towards the ovulatory peak. After ovulation, during the luteal phase, LCs lowered their density and lost a great deal of their cytoplasmatic arborizations.
 
The results of a teaching program on colposcopy, self-administered by a computerized interactive program have been evaluated. The course was based on digitalized colposcopy images and consisted of teaching and testing files for a total of 362 cases. Colposcopy performance was determined according to sensitivity for CIN II-III lesions and agreement with reference report (kappa statistic), the minimal standards being 100% and 0.40, respectively. Twenty- four gynecologists attended the course in 1993. Colposcopy performance improved significantly through sequential tests but only 12 trainees scored over minimal standards. Previous experience in colposcopy was associated with better results (9 of 12 experienced trainees scored over minimal standards compared with 3 of 12 nonexperienced trainees). This study confirms the poor quality of colposcopic performance in the current practice and stresses the need for proper training and quality control.
 
The immune response of vaginal mucosa by local immunoglobulin (Ig) secretion has been studied in a group of 106 apparently healthy women (64 were in fertile age and 42 in the postmenopause). Samples for IgA determinations were collected by vaginal washing, and a nephelometer analysis using specific antisera was carried out. The basic observation was the relatively stable levels of vaginal IgA during the woman's life, being the mean values around 1 mg/dl. Only fine variations, statistically not significant, were observed in relation to age, menstrual cycle and contraceptive methods. IgA concentrations, in fact, weakly increased mostly over 40 years and in the postmenopause, and in fertile women they were higher in the peri-ovulatory days, showing decreasing values in the premenstrual days and the lowest at the beginning of the new cycle. Finally, higher values were observed in the users of coitus interruptus.
 
The efficacy and toxicity of intramuscularly (i.m.) administered beta-interferon (IFN) ('Frone(®)', Serono) were evaluated in the treatment of 21 women with genital papillomavirus (HPV) infections (11 with multicentric lesions, and 10 with cervical HPV lesions associated with cervical intraepithelial neoplasia, CIN). A series of 6 patients affected by HPV lesions received placebo and served as a control group. The protocol consisted of i.m. injections of 2 x 106 units of beta-IFN, daily for 10 consecutive days. Prior to therapy, all patients were examined by colposcopy, cytology, and punch biopsy for routine histology. HPV typing was completed on paraffin sections using in situ DNA hybridization with 35S-labelled probes (HPV 6, 11, 16, 18, 31, 33). Follow-up was performed at the end of treatment and every 2 months for 6-12 months. Efficacy of the therapy was evaluated as complete (CR), partial (PR) and no response (NR). A total of 5-6 patients with vaginal lesions showed CR, all lesions disappearing between 2 and 6 months, with no recurrences found during the follow-up. All 5 women with vulvar lesions showed CR as well. Of the 8 cases with cervical HPV infections, 4 (50%) did not respond to therapy. No significant differences in the success rate could be attributed to HPV type, equal numbers of CR being found in lesions associated with HPV 6, HPV 11 or HPV 16. In the placebo group, treatment failures were found in the single vulvar case, in all the 6 cervical and in 3 of the 4 vaginal cases. All 6 women with HPV-CIN II showed CR of their CIN between 2 and 10 months after beta-IFN therapy, but the viral cytopathic effect (VCE) was still observed in 5 of them. Three out of the 4 patients with HPV-CIN III showed a persistent viral and CIN lesion after beta-IFN treatment. The most resistant HPV-CIN lesions were those associated with the high risk type HPV 16. All the side-effects subsided with termination of the treatment and required neither a therapy nor a suspension of the drug. Thus, satisfactory results were obtained in treating vulvar and vaginal condylomata as well as HPV-CIN II lesions. The success rate was less satisfactory for the flat HPV lesions of the cervix, especially when associated with high grade CIN.
 
A case of intraepithelial neoplasia of the vulva ( VIN) and oral cavity of the patient's husband is reported. In both lesions HPV type 16 was detected by in-situ hybridization. The possibility of an HPV auto-vs. hetero-inoculationis discussed.
 
Top-cited authors
Silvano Costa
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Grazia Grazzini
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Pietro Muretto
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Ami Fishman
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