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Nine vulvar and three vaginal angiomyofibroblastomas from patients 23 to 71 years of age (mean, 46 yr) were analyzed. The tumors were well circumscribed and ranged from 0.9 to 11 cm (average, 4.7 cm) in maximal dimension. On microscopic examination, they had hypercellular and hypocellular areas. The neoplastic cells were spindle-shaped, plasmacytoid, or epithelioid; a variable number were binucleated or multinucleated cells. A focal storiform pattern was present in one tumor, and, in one tumor, the neoplastic cells formed a collar around a central area of dense collagen. There was no significant nuclear atypia, and there was less than one mitotic figure per 10 high-power fields. The tumors contained small- to medium-sized blood vessels, which were characteristically thin walled and, occasionally, ectatic and branching. The stroma was edematous, separated collagen fibers and contained a variable number of inflammatory cells, especially lymphocytes and mast cells. Three vulvar tumors contained a variable amount of fat. Ultrastructural study of three tumors showed intracytoplasmic, dilated, rough endoplasmic reticulum, moderate numbers of pinocytotic vesicles, and numerous filaments without dense bodies; rare intercellular rudimentary junctions were identified. Eleven of 11 tumors were immunoreactive for vimentin, 11 of 12 for desmin, three of 11 for muscle actin, one of 12 for smooth muscle actin, and four of 12 for CD34. There was no staining for factor XIIIa, keratin, S100 protein, Leu-7, glial fibrillary acidic protein, or CD68. Follow-up revealed no recurrences or metastases. Angiomyofibroblastoma is a distinctive benign tumor that arises most commonly in the vulva and vagina and has a diverse histologic and immunohistochemical profile.

Eleven malignant mesotheliomas of the testicular tunica vaginalis occurred in patients aged 12 to 76 (mean, 54.1) years. Hydrocele, with or without an associated mass, or appreciation of a paratesticular mass accounted for the clinical presentation. One patient had a history of asbestos exposure. Grossly, the tumors typically presented as multiple nodules studding a hydrocele sac, frequently associated with a mass infiltrating the spermatic cord or adjacent testis. Microscopically, five tumors were epithelial and six biphasic, with the typical architectural and cytologic features of mesothelioma. Mixtures of papillary, tubular, and solid patterns predominated in the epithelial areas; interlacing fascicles of spindle cells with scanty stroma characterized the sarcomatous components. All eight of the tumors that were stained for keratin (AE1/AE3) were positive, four of five for epithelial membrane antigen, and four of five for vimentin. Seven of seven tumors were carcinoembryonic antigen negative and five of five B72.3, Leu-M1, and Ber-Ep4 negative. Follow-up ranging from 1 to 15 (mean, 4.3) years was available for seven patients. Three died of disease after 4, 4, and 3 years, and three are alive with disease 2, 2, and 15 years after diagnosis. Two of the latter three patients had extensive local recurrences, one 15 years after the diagnosis of a well-differentiated papillary mesothelioma, the other 2 years following treatment with hydrocelectomy only. One patient who has been followed for only 1 year has no evidence of disease. This series emphasizes a number of important features of testicular mesothelioma; (a) a wide age range with occasional occurrence at a young age, (b) a wide morphologic spectrum with regard to degree of differentiation, and (c) an aggressive natural history with a potential for late recurrence or metastasis of even well-differentiated tumors, suggesting the need for initial aggressive surgical treatment.

Vaginal adenosis and clear cell adenocarcinoma of the vagina occurred in a 44-year-old woman after treatment for condylomata acuminata. She had no known exposure to diethylstilbestrol (DES) in utero. Biopsy-proven vaginal adenosis appeared 8 months after intravaginal 5-fluorouracil application for recurrent urogenital condylomata acuminata. Forty months later, biopsies showed residual adenosis with foci of clear cell adenocarcinoma. Although clear cell adenocarcinoma is associated with vaginal adenosis and cervical ectropion in DES-exposed women, its occurrence in adenosis after 5-fluorouracil therapy has not been reported to the authors' knowledge. In this report, this rare but serious complication of treatment of condylomata acuminata is highlighted, and the literature regarding the development of non-DES-associated vaginal adenosis is discussed.

The incidence of clear cell adenocarcinoma of the vagina and cervix associated with intrauterine exposure to DES and similar compounds during the first half of pregnancy has increased. Ninety percent of these cancers have occurred in patients 14 years of age or older. Although these carcinomas are exceedingly rare, nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the exposed population, particularly if the drug was administered early in pregnancy. Current evidence favors a disturbance in development of the müllerian duct as the explanation of these changes. Whether DES is only a teratogen or also a carcinogen is unknown, as is the possible role of other factors in the development of cancer. An increased incidence of cancer among exposed males has not been documented.

Squamous cell abnormalities of the vagina and cervix were evaluated in 1424 women exposed to diethylstilbestrol (DES) in utero. The prevalence of dysplasia was 2.1% and the incidence 0.85/100 person-years of followup. The dysplastic epithelial changes were almost always mild in women with no prior history of dysplasia and was slightly more frequent in the cervix than the vagina. Severe dysplasia and carcinoma in situ (CIS) were encountered only in those subjects specifically referred because of those abnormalities. The most common problem in the diagnosis of these squamous cell changes was the misinterpretation of mature and immature metaplastic cells for dysplastic squamous cells. Discordance between biopsy and cytology was common-place in the detection and followup of dysplasia, especially when it was mild. There were no instances in the study where cytology and biopsy samples from the vagina were both abnormal concurrently. Colposcopically directed biopsies did not increase the frequency of confirmation of cytologic findings. These data suggest that both cytology and biopsy of abnormal segments of the vagina and cervix remain an integral part of the examination of the DES-exposed female during long-term follow-up studies.

Twenty specimens of uterus and vagina removed because of clear cell adenocarcinoma of the cervix or vagina in women exposed prenatally to diethylstilbestrol were serially blocked and sectioned to study the topographic relation between the carcinoma and the cervical ectropion and vaginal adenosis. Three tumors were cervical; 17 were vaginal. Iodine staining performed on 8 specimens indicated that the carcinoma developed consistently just above the distal limit of the cervical or vaginal surface that failed to stain with iodine, a location that usually corresponds to the distal limit of abnormality visible by colposcopic examination. Microscopic examination disclosed the presence of both cervical ectropion and vaginal adenosis in all the specimens. Mucinous glands were abundant above the tumor. In 18 of the 20 cases, tuboendometrial glands were intimately related to the carcinoma, either surrounding it or abutting its inferior border. These data, in addition to other evidence, suggest that tuboendometrial epithelium, whether in the ectocervix or vagina, provides the bed from which clear cell adenocarcinoma develops.

Knowledge of the evolution of clear cell adenocarcinomas of the vagina and cervix in diethylstilbestrol-exposed progeny has remained elusive despite the known topographical association of these tumors with the tuboendometrial form of vaginal adenosis and cervical ectropion. Twenty radical hysterectomy or radical hysterectomy and vaginectomy specimens of clear cell adenocarcinoma of the vagina or cervix were serially blocked in toto; tuboendometrial epithelium was found in the vagina in 19 (95%) of the cases, usually in greatest concentration at the margin of the tumor, particularly inferiorly. Foci of atypical tuboendometrial epithelium were identified in 16 (80%) of the cases, almost always immediately adjacent to the tumor. Twenty-five of a second group of 47 specimens in which only substantial portions of the vagina or cervix adjacent to a clear cell adenocarcinoma were available for examination also had foci of atypical tuboendometrial epithelium. The frequency with which atypical tuboendometrial glands in the vagina and cervix were associated with the carcinomas and the proximity of the former to the latter provide strong evidence that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma.

Eight mixed tumors of the vagina are described. Seven of them were situated in or near the hymenal ring. All but one were well-circumscribed masses unconnected to the surface epithelium. They were composed of small stromal-type cells usually containing islands of mature squamous cells and glands lined by mucinous epithelium. Their histogenesis is not clear. Follow-up of 2--9 years in seven of the cases has revealed no evidence of recurrence or metastases after local excision.

Nine cases of endodermal sinus tumor of the vagina from children 6 months to 2 years of age are reported. The two patients treated before the advent of modern chemotherapy died 6 to 13 months postoperatively despite attempted complete surgical resection of the tumor in one of the cases. One patient who was treated initially by hysterectomy and vaginectomy had lung metastases 6 months postoperatively and died despite chemotherapy. Six patients who were treated by a surgical procedure and received vincristine, actinomycin D, and cyclophosphamide, with radiation therapy in two cases, were alive and free of disease from 2 to 9 years postoperatively.

In 1971, the development of clear cell adenocarcinoma of the vagina in young females was first linked to a history of intrauterine exposure to diethylstilbestrol (DES). This communication reviews data on cases accessioned in the Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females, findings in exposed female and male subjects without cancer, and discusses current concepts of the pathogenesis of the DES-related anomalies of the lower genital tract.

A variety of vaginal and cervical abnormalities have been encountered in the offspring of women who have taken stilbestrol or chemically related nonsteroidal estrogens during pregnancy. Cervical erosion has been noted most often, but vaginal adenosis has been proven by biopsy in over 30 percent, and transverse vaginal and cervical ridges have been seen in approximately 10 percent of the exposed population. Although the use of these drugs had been widespread during the last two decades, the Registry of Clear-Cell Adenocarcinoma of the Genital Tract in Young Females has been able to collect only 170 cases of vaginal and cervical cancers of this type from all over the world. It is important that cytologists and pathologists become familiar with the various non-enoplastic and neoplastic disorders related to these hormones in order that additional epidemiologic, clinical and pathological information be acquired without delay.

Three hundred and eight-four cases of clear cell adenocarcinoma of the vagina and cervix accessioned in the Registry as of December 31, 1978, have been analyzed. The annual incidence of these tumors has been found to correspond closely to the estimated usage of diethylstilbestrol (DES) for pregnancy support in the United States. The annual incidence of the DES-associated cases appears to have dropped in the United States in the past 2 years in comparison to 1973 to 1975. The risk of tumor development appears to be higher in young women exposed to DES early in intrauterine life than in those exposed later. The carcinomas are rare before the age of 14 years and an irregular peak in the age-incidence curve appears between 17 and 21 years followed by a decline. The 5-year survival rate is better for women over the age of 19 years than for younger patients, and a higher frequency oral contraceptive usage did not appear to influence the behavior of the tumor and the improved survival in those using this medication appears to be related to greater medical surveillance.

This study was based on cases accessioned in the Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females to ascertain the incidence of diethylstilbestrol (DES)-related cancers by age and year of birth. For accuracy in estimating the size of the reference population for the incidence rates, calculations were restricted to 127 white residents of the United States who were exposed prenatally to DES or other nonsteroidal synthetic estrogens. The disease is exceedingly rare prior to age 14 when the incidence rate begins to rise rapidly. The incidence peaks at age 19 (median 19.2 years) and then drops precipitately. Thus, DES-related clear cell adenocarcinoma is unusual in that nearly all cancers have been diagnosed in a narrow age range of 10 years (14 to 23 years). Women born in 1951 to 1953 have higher incidence rates than those born in the previous or subsequent three-year period. This suggests that the prevalence of pregnancy-related use of DES was at a peak in the early 1950's. The cumulative risk of this type of genital cancer, through age 24, for DES-exposed female subjects is estimated to be in the range of 0.14 to 1.4 per thousand. The wide limits are due to the fact that the number of young women exposed is not known precisly. The low risk of disease and the narrow age range of the cases, relative to the long latency period, suggest that DES is an incomplete carcinogen. Other factors, possibly related to puberty, may be involved in the causation of this disease.

Twenty-five cases of malignant lymphoma of the uterine corpus or cervix and the vagina, and one case of granulocytic sarcoma of the cervix were analyzed. The patients typically presented with vaginal bleeding and a subepithelial mass without obvious ulceration or other epithelial abnormality. Twenty-one of the 27 tumors appeared to originate in the cervix, 4 in the vagina, and 2 in the endometrium. Seven of them were nodular lymphomas, 17 diffuse large cell, or "histiocytic" lymphomas, 1 was a Burkitt's tumor, and 2 were granulocytic sarcomas. Sclerosis was a prominent histologic feature in lymphomas of the cervix and vagina. Twenty-one patients had disease confined to a single extranodal site (Ann Arbor Stage IE), and six had lymph node or ovarian involvement (Stages IIE + IV). The overall actuarial 5-year survival was 73%. The survival of patients with Stage IE tumors was 89%, compared with 20% for patients with lymph node or ovarian involvement. None of the 12 patients with Stage IE lymphoma of the cervix or vagina who received definitive initial local treatment (surgical and/or radiation therapy) relapsed. Nodular lymphomas and diffuse lymphomas with a preponderance of large cleaved cells were more often localized and had a better prognosis than large or small noncleaved and immunoblastic types. Lymphoma of the lower female genital tract is a rare, but treatable malignancy, which must be distinguished microscopically from inflammatory lesions and nonlymphoid tumors arising in this site.