Cancer risk in men exposed in utero to diethylstilbestrol.

BACKGROUND: An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. METHODS: A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. RESULTS: Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. CONCLUSIONS: To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer.

INTRODUCTION: Patients with recurrent ovarian cancer were treated with a replication-deficient recombinant adenovirus containing the herpes simplex virus thymidine kinase gene administered intraperitoneally (i.p.) followed by administration of an anti-herpetic prodrug and topotecan. MATERIALS AND METHODS: A total of 10 patients with stage IIIc epithelial ovarian cancer underwent secondary debulking to < or =0.5 cm residual tumor. Patients with normal i.p. flow received i.p. delivery of adenovirus. Two patients each were treated on dose level 1 (2 x 10(10) vector particles (VP)), dose level 2 (2 x 10(11) VP), and dose level 3 (2 x 10(12) VP); four patients were treated on dose level 4 (2 x 10(13) VP). Acyclovir and topotecan were started 24 hours after vector delivery. RESULTS: No patient treated at any dose level incurred unanticipated toxic effects, and all side effects resolved. The most common adverse event was myelosuppression: grade 3 or 4 thrombocytopenia with grade 2-4 anemia in three patients and grade 3 or 4 neutropenia in eight patients. Three patients developed thrombocytosis and three patients had a mild elevation of serum glutamic pyruvic transaminase/alanine aminotransferase. Temperature elevations that were not associated with detectable infection occurred in two patients. DISCUSSION: I.p. delivery of adenoviral vector with concomitant topotecan chemotherapy was well tolerated without significant lasting toxicities. Side effects were independent of the dose of adenoviral vector.

Occurrence of endometrial adenocarcinoma during lactation.

Endometrial adenocarcinoma is commonly seen in the perimenopausal and postmenopausal age groups. Certain medical conditions (such as diabetes, hypertension, and obesity) are often associated with development of this disease. Consequently, when irregular bleeding develops, a decision to sample the endometrium is often predicated on the patient's age and the presence of these associated conditions. Often, healthy young women receive empirical hormonal therapy for irregular bleeding without prior endometrial sampling. An unusual case of endometrial adenocarcinoma arising during lactation in a young healthy woman is presented.

Effect of maternal alcohol exposure on fetal ovarian lactate dehydrogenase.

Pregnant inbred mice strain Balb/c injected intraperitoneally with 100 mu1 of 70% ethanol for 7 consecutive days (9th through 16th day of gestation). One group of mice were also injected with diethylstibestrol (DES) dissolved in 70% ethanol. The lactate dehydrogenase (LDH) activity was measured 90 days postpartum in the crude extracts of ovarian tissues (obtained from mothers and offspring) as well as in testicular tissues of the male offspring. The data show that the electrophoretic pattern of LDH in these tissues does not change, but the ovarian LDH is inhibited by alcohol. The testicular LDH on the other hand is not affected by the alcohol treatment. Because of the effect of alcohol itself, the effect of DES could not be determined.

Analysis of atypical squamous (glandular) cells of undetermined significance smears by neural network-directed review.

OBJECTIVE: The objective of this study was to evaluate the value of neural network-directed review of smears determined to contain atypical squamous (glandular) cells of undetermined significance to identify those cases most likely to be associated with cervical intraepithelial neoplasia. METHODS: One hundred sixty smears reported as atypical squamous (glandular) cells of undetermined significance on patients having colposcopy and directed biopsy within 1 year of the smear were identified. The smears were subjected to a neural network-directed review and classified according to findings on this review. The latter findings were related to those obtained on cervical biopsy. RESULTS: One hundred sixty smears originally reported as atypical squamous (glandular) cells of undetermined significance were subjected to neural network-directed review. The smears were upgraded in 20.6% of cases. Ninety-one patients were found to have normal biopsies, and 69 had biopsies reported as abnormal. Of the smears in patients with abnormal biopsies, 37.7% were upgraded, whereas only 7.7% of smears from those with normal biopsies were upgraded (P < .001). Nine patients were found to have cervical intraepithelial neoplasia-3 on biopsy. Six of the nine smears (66.7%) taken on these patients were upgraded. CONCLUSION: Neural network-directed analysis of smears conventionally diagnosed as atypical squamous (glandular) cells of undetermined significance will reveal findings suggesting a squamous intraepithelial lesion in a significant number of cases. This approach requires further study because it is a relatively cost-effective means of triaging patients with a cytologic diagnosis of atypical squamous (glandular) cells of undetermined significance.

Detection of human papillomavirus DNA before and after development of invasive vulvar cancer.

Biopsy and surgical specimens were studied from two patients with squamous cell carcinoma in situ of the vulva and one with verrucous carcinoma of the vulva. All three patients subsequently developed invasive squamous cell carcinoma of the vulva. In two, human papillomaviruses (HPVs) 16 and 18 were found in the lesions before the development of invasive carcinoma. In the specimens with invasive squamous cell carcinoma, HPV 16 or 18 or both was found. The third patient had HPV 18 DNA in the specimen demonstrating squamous cell carcinoma in situ; when invasive squamous cell carcinoma was diagnosed 9 years later, HPVs 16 and 18 were found in the latter lesion. These findings lend support to the role of HPVs 16 and 18 in the development of invasive squamous cell carcinoma of the vulva.

Cytologic diagnosis of endometrial adenocarcinoma using the Endo-pap sampler.

Six hundred ambulatory women were screened with the Endo-pap cytology sampler in two medical centers. None of the women developed complications from the use of the instrument. Their smears were routinely processed together with cervical cytology smears. One hundred fifty-three of these women had a tissue diagnosis by endometrial biopsy, dilatation and curettage, or hysterectomy. Adequate cytology specimens were obtained in 93% of these patients. In these 153 patients, 32 (18%) had a tissue diagnosis of endometrial adenocarcinoma, and 31 patients had a tissue diagnosis of endometrial hyperplasia. The cytology samples obtained with this device were diagnostic of endometrial adenocarcinoma in 30 (94%) of these 32 patients and ten (32%) of the patients with endometrial hyperplasia. Two patients (1.6%) were diagnosed falsely positive. The Endo-pap cytology sampler is considered a safe and effective screening tool for endometrial adenocarcinoma. Its value in diagnosing endometrial hyperplasia remains to be determined.

Vulvar vestibulitis: significant clinical variables and treatment outcome.

The subject of vulvar vestibulitis was reviewed in regard to clinical variables that may be associated with this problem as well as the success of available treatment modalities. Questionnaires were returned by 71 patients diagnosed as having vulvar vestibulitis. Identical information was obtained from a comparison group of individuals with no clinical or physical findings suggesting this diagnosis. A history of recurrent candidiasis and previous condyloma acuminatum were the only variables noted more frequently in patients with vestibulitis. Among the patients treated by perineoplasty, 66% reported complete or significant alleviation of vulvar pain; 78% of the women noted a significant decrease in dyspareunia. Of the patients treated with intralesional interferon, six (50%) reported significant improvement in dyspareunia. Vulvar vestibulitis is a puzzling clinical entity whose etiology is not well understood. Perineoplasty still appears to be the treatment of choice in properly selected individuals.

Vulvar histology after neutral red photoinactivation of herpes simplex virus.

The use of photodynamic dye and light inactivation for the treatment of genital herpes simplex virus infections has been associated with the risk of potential oncogenesis. Sixteen patients treated with neutral red and fluorescent light for documented herpetic infections were studied at intervals ranging from 9 to 52 months following treatment. Four patients treated with other modalities were included in the study. Biopsies of the treated areas were obtained, and 3925 tissue sections were examined. Mild atypical epithelial changes were focally present in most specimens regardless of therapy. Histologically identifiable premalignant change could not be demonstrated.

Persistence of virus shedding in asymptomatic women after recovery from herpes genitalis.

One hundred seventeen women were reexamined within 6 months after presenting with genital herpes. Swabs for virus isolation were taken from the cervix whether or not lesions were observed. Herpesvirus type II was isolated from 30 of 67 patients with recurrent disease, but also from 5 of 50 women during periods when there were no signs or symptoms of illness. The epidemiologic importance of virus shedding from asymptomatic women is discussed.

Intraepithelial carcinoma of the vulva with extension to the anal canal.

Ten patients with intraepithelial carcinoma of the vulva that extended to the anus were studied. The patients were seen and treated over a 3-year period, from January 1976 through December 1978. During the 10-year period before 1976 the authors had encountered no patients with this problem. Treatment consisted predominantly of a skinning vulvectomy with split-thickness skin graft and excision of the anal disease. Failure to recognize the extension to the anus will result in persistent disease following surgical therapy.

Urinary tract changes associated with exposure in utero to diethylstilbestrol.

Intravenous pyelograms were performed on 128 women who had been exposed in utero to diethylstilbestrol (DES). For comparison, intravenous pyelograms (IVPs) of 48 non-exposed women were reviewed: No difference in urinary tract abnormalities was noted. There was no significant increase in urinary tract abnormalities in women with upper genital tract abnormalities demonstrated by hysterosalpingogram as compared to a group of women whose x-rays of the uterus were normal.

Dermatomyositis and female malignancy.

All cases of dermatomyositis-polymyositis in women seen between 1970 and 1977 at Baylor Affiliated Hospitals were reviewed. Twenty-five patients were identified with this diagnosis. Of these women, 5 were found to have a malignant tumor: 3 ovarian carcinomas, 1 cervical intraepithelial carcinoma, and 1 colon carcinoma. Pertinent histologic and clinical findings in patients with dermatomyositis-polymyositis are discussed. The high prevalence of malignancy in these patients, previously recognized, is discussed. A case report is presented.

Human papillomavirus associated with vaginal intraepithelial neoplasia in women exposed to diethylstilbestrol in utero.

Five out of 959 young women, exposed to diethylstilbestrol (DES) in utero, developed vaginal intraepithelial neoplasia while they were under follow-up in the Diethylstilbestrol-Adenosis Project at Baylor College of Medicine, Houston, Texas. We suggest that the development of the vaginal intraepithelial neoplasia at a younger age than usual may be caused by a higher susceptibility of the DES-exposed patient to factors associated with the development of intraepithelial neoplasia. A common finding in all five women was the detection of the deoxyribonucleic acid (DNA) of human papillomavirus types 6 or 16 in their lesions, using high-stringency in situ hybridization. The role of human papillomavirus and herpes simplex virus in the etiology of intraepithelial neoplasia is discussed. Close follow-up is recommended for DES-exposed patients, especially those who have risk factors known to be associated with genital neoplasia.

A simple, inexpensive device for teaching the loop electrosurgical excision procedure.

OBJECTIVE: To develop an inexpensive and practical inanimate model to teach the loop electrosurgical excision procedure in a resident clinic. TECHNIQUE: A vaginal speculum is inserted into one end of a cardboard tube. At the opposite end, a piece of knockwurst sausage is inserted into the cardboard tube. A grounding pad is attached to the distal end of the sausage. The teaching session proceeds using a colposcope or direct visualization. After the training session, the excised and uncut portions of sausage can be examined. EXPERIENCE: Faculty found this inanimate model an excellent way to teach residents how to use the loop electrode, and the resident staff appreciated its merits as a useful prelude to treating cervical disease in women. The house staff adapted to the confines of the vagina and transferred skills acquired from working with the cardboard tube, where instruction and constructive criticism can be given without the presence of apprehensive patients. CONCLUSION: A simple, inexpensive, inanimate model has been developed to teach the loop electrosurgical excision procedure. The materials required to construct it are available to any colposcopy clinic.

Human papillomavirus DNA in tissue biopsy specimens of vulvar vestibulitis patients treated with interferon.

Thirteen women with the diagnosis of vulvar vestibulitis based on clinical symptoms, presence of vestibular tenderness on physical examination, and acetowhite changes of the vulvar vestibule were treated with intradermal injection of alpha-interferon. Biopsies of the acetowhite areas were analyzed for human papillomavirus (HPV) DNA using polymerase chain reaction amplification and dot blot hybridization. Eleven of 13 subjects harbored one of the HPV DNA types; six of these were type 16 and/or 18 and the others were unidentified. Five subjects (all HPV DNA-positive) reported resolution of symptoms with interferon therapy. Our results indicate the presence of HPV DNA in a subset of patients with vulvar vestibulitis, but its presence is not predictive of response to interferon therapy.

Development of clear cell adenocarcinoma in DES-exposed offspring under observation.

Two cases of clear cell adenocarcinoma of the vagina detected at follow-up in young women exposed in utero to diethylstilbestrol are reported. One patient, aged 23, had been followed for 2 years before carcinoma was diagnosed; the second patient, aged 22, had been seen on a regular basis for 5 years, 8 months. In both instances, suspicion of the presence of carcinoma was aroused by the palpation of a small nodule in the vaginal fornix. Hysterosalpingography was performed on both patients and, in 1 instance, an abnormal x-ray film was reflected by the gross appearance of the uterine cavity found in the surgical specimen.

Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring.

OBJECTIVE: To evaluate long-term pregnancy experiences of women exposed to diethylstilbestrol (DES) in utero compared with unexposed women. METHODS: This study was based on diethylstilbestrol-exposed daughters, the National Collaborative Diethylstylbistrol Adenosis cohort and the Chicago cohort, and their respective nonexposed comparison groups. Subjects who could be traced were sent a detailed questionnaire in 1994 that contained questions on health history, including information on pregnancies and their outcomes. We reviewed 3373 questionnaires from exposed daughters and 1036 questionnaires from unexposed women. RESULTS: The response rate was 88% among exposed and unexposed women. Diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ectopic pregnancies. Full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64. 1% of exposed women identified by record review (relative risk [RR] 0.76, confidence interval [CI] 0.72, 0.80). Preterm delivery of first births occurred in 4.1% of unexposed compared with 11.5% of exposed women, and ectopic pregnancies in 0.77% of unexposed compared with 4.2% of exposed women. Spontaneous abortion was reported in 19.2% of DES-exposed women compared with 10.3% in control women (RR 2.00, CI 1.54, 2.60). According to complete pregnancy histories (many women had more than one pregnancy), preterm births were more common in DES-exposed women (19.4% exposed versus 7.5% unexposed (RR 2.93 CI 2.23, 3.86). Second-trimester spontaneous pregnancy losses were more common in DES-exposed women (6.3% versus 1.6%; RR 4.25, CI 2.36, 7.66). More first-trimester spontaneous abortions occurred in DES-exposed women than in controls (RR 1.31, CI 1.13, 1.53), and DES-exposed women had at least one ectopic pregnancy more often than unexposed women (RR 3.84, CI 2.26, 6.54). CONCLUSION: Pregnancy outcomes in DES-exposed women were worse than those in unexposed women.

Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis (DESAD) project.

Initial clinical findings are reported for the 3339 young women enrolled in the Diethylstilbestrol Adenosis (DESAD) project. Changes in the vaginal mucosa (VEC--vaginal epithelial changes), which were detected by colposcopy or iodine staining, occurred in 34% of 1275 participants identified by review of prenatal records 59% of participants who themselves requested entry into the project, and 65% of participants referred by a physician. Analysis of data on the 298 women who were identified by record review and whose prenatal records contained complete information about drug exposure indicated that VEC is most closely associated with the timing of the onset of intrauterine exposure to diethylstilbestrol (DES), total dose, and length of exposure. Frequency of VEC was also found to decrease with age. No instances of severe dysplasia, carcinoma in situ, invasive squamous cell adenocarcinoma, or clear cell carcinoma were observed among the women identified by record review.

Nuclear DNA study of vulvar intraepithelial and invasive squamous neoplasms.

In this study, 59 vulvar intraepithelial squamous neoplasms (8 atypia and 51 carcinoma in situ) and 33 invasive squamous carcinomas were analyzed for their nuclear DNA content using Feulgen microspectrophotometry. Four cases of atypia had a polyploid DNA distribution. The remaining 4 cases of atypia and all cases of carcinoma in situ had an aneuploid pattern, and nearly two thirds of these had high ploidy stem cells (greater than 3N). This is in contrast to the low ploidy stem cells (less than 3N) seen in 70% of the invasive carcinomas and in 82% of the intraepithelial neoplasms in the vicinity of invasive carcinomas. This observation suggests that not all vulvar intraepithelial neoplasms have the same propensity to become invasive. Invasive carcinomas of comparable size and depth of invasion with low ploidy stem cells had a higher frequency of lymph node metastasis than those having high ploidy stem cells. The significance of nuclear DNA findings related to gynecologic neoplasms is discussed.