Howard Ulfelder

Adenocarcinoma of the Vagina

Although cancer of the vagina is rare and occurs principally in women over age 50 in the form of epidermoid carcinoma 8 girls (15-22) between 1966 and 1969 with adenocarcinoma of the vagina (clear-cell or endometrial) were seen at 2 Boston hospitals. The 4 controls (female) for each case were born within 5 days of the patient and on the same type of service (ward or private). The association between treatment of the mothers (7 or 8) with estrogen diethylstilbestrol during the pregnancies and the development of adenocarcinoma of the vagina in the girls is highly significant (p less than 0.00001). All 7 mothers began therapy in the first trimester and received either a constant dose administered to term or a continually increasing dose given almost to term. Other factors with lower levels of significance are maternal bleeding in the study pregnancy (p less than 0.05) and any prior pregnancy loss (p less than 0.01). Non-significant factors include maternal age at time of birth smoking in parents intrauterine x-ray exposure and breast feeding.

Glassy cell carcinoma of the cervix

A clinicopathologic analysis of 13 cases of glassy cell carcinoma of the uterine cervix is presented. The glassy cell carcinoma is considered to be a poorly differentiated mixed adenosquamous carcinoma. Its histologic appearance is distinctive, being characterized by cells with a moderate amount of cytoplasm having a ground glass or finely granular appearance, a distinct cell wall that stains with eosin and PAS, and enlarged nuclei with prominent nucleoli. In the present study this tumor was associated with extrapelvic spread in 6/13 cases at diagnosis. Results were poor with either surgery and/or radiotherapy. Only four of 13 patients survived 5 years. The glassy cell carcinoma appears to be a distinct clinicopathologic entity which warrants a place in the classification of carcinoma of the cervix.

Primary carcinoma of the vagina. An analysis of 68 cases.

Abstract Data from 68 cases of primary carcinoma of the vagina are analyzed in detail. The tumors tend to occur beyond the fifth decade of life and are primarily epidermoid carcinomas. No etiologic factor for the development of these tumors was found. The International Staging Classification was utilized and found to be useful prognostically, but prospective application should provide more accurate statistics. The problems of therapy are discussed. Individualization of cases is necessary, and effective treatment was accomplished with radical surgery. Involvement of regional lymph nodes with tumor markedly worsens the prognosis. Recurrences usually occurred in the pelvis and with one exception were not effectively treated by operation or radiation.

The embryologic development of the human vagina.

Our present understanding of the sequence and mechanisms of human genital organogenesis is reviewed. Current theories about the derivation of the vaginal epithelium are examined and tested against two anomalous circumstances, congenital androgen insensitivity and agenesis of the lower vagina, which are presented as examples demonstrating the respective participation of the urogenital sinus or of the Müllerian ducts alone in the developmental process. The abnormalities recently described in the vagina and cervix of girls exposed in utero to diethylstilbestrol (DES) correspond remarkably with those encountered in lower vaginal agenesis, particularly with regard to the presence of vaginal adenosis, the deficiency of glycogen in the squamous cells (squamous metaplasia), and the abnormal response of the squamous epithelium to Schillers iodine test. It is concluded that the development of the human vagina is best explained by the theory which holds that the Müllerian ducts in fetal life extend caudally to the level of the future hymen. After fusion of these ducts, squamous cells arising in the epithelium of the urogenital sinus invade from below, advance, and replace completely the Müllerian mucosa up to the level of the external os of the cervical canal.

Agenesis of the vagina

Abstract Experience with the management of patients congenitally lacking the vagina is assayed to decide (a) the most satisfactory technique of reconstruction and (b) the degree to which the new epithelium mimics normal vaginal surface tissues. It is demonstrated that excavation of an adequate pocket and immediate insertion of a split-thickness autogenous skin graft on a mold rarely fails to give rapid healing and satisfactory function. Attention to technical details will facilitate this. Adherence to the concept that operation should be postponed until marriage is imminent is found to be unacceptable on emotional grounds. Comparison is made between normal and surrogate vaginal epithelia, cytologically, bacteriologically, and histologically, under endogenous and exogenous hormonal stimulation. Important differences are demonstrable between normal vaginal epithelium and grafted skin.

Pelvic Exenteration for Carcinoma of the Cervix

Pelvic exenteration for carcinoma of the cervix uteri carries a 15 per cent operative mortality and a 23.3 per cent five-year survival. Total exenteration, not anterior exenteration or modified exenteration, is the operation of choice in the heavily irradiated patient. The criteria for operability are proof of persistence of disease, proof of no extension of disease beyond the pelvis, proof of freedom of disease at the lateral margins of resection and proof that pelvic-lymph-node metastases are minimal. Only 2 of 33 patients with positive pelvic lymph nodes survived for five years. Ileal-loop urinary diversion has been a major factor in diminishing the complications and deaths from this procedure.

Stilbestrol, adenosis, and adenocarcinoma

Abstract A registry of cases of clear-cell adenocarcinoma of the genital tract in women under 30 years of age was established in 1971. The first years data amply confirmed the hypothesis that a simultaneous, nation-wide outbreak of this lesion had occurred and that, in 85 per cent of cases, exposure of the individual before the fourth month in utero to diethylstilbestrol or one of its congeners could be documented as an antecedent circumstance. General awareness of this new entity on the part of physicians and personal concern manifested by mothers who know that they were thus treated during pregnancy are bringing hundreds of the at-risk population group to medical attention. Gross and microscopic morphologic anomalies are being found in approximately 30 per cent of these girls and occasionally asymptomatic early carcinomas are detected. A study of 16 patients who give a history of no prior exposure to hormones of any description reveals a difference between them and the group with known exposure. This is in keeping with the literature published prior to the availability of diethylstilbestrol which indicated that primary vaginal adenocarcinoma in young women was unique, whereas such lesions of the cervix were only uncommon.

ENZYME-HISTOCHEMICAL OBSERVATIONS ON ENDOMETRIOSIS.

Abstract The enzyme profile of foci of endometriosis obtained during various phases of the menstrual cycle was studied in 11 cases and compared with that of the intrauterine endometrium in the corresponding cases. The histochemical techniques employed included those for alkaline phosphatase, acid phosphatase, lactic dehydrogenase, glucose-6-phosphate dehydrogenase, isocitric dehydrogenase and succinic dehydrogenase. The intensity of reaction of alkaline phosphatase in the ectopic endometrial epithelium, which in most cases was of an indeterminate cyclic appearance morphologically, was of the type ordinarily seen in proliferative and early secretory phase uterine endometrium. The acid phosphatase activity of the implants was equal to or somewhat less intense than that of the corresponding uterine mucosa; no consistent phasic pattern was evident. The differences noted in the oxidative enzyme activities in the uterine endometrium in these cases were slight during the various phases of the cycle, and the foci of ectopic endometrium differed only occasionally from the corresponding uterine mucosa.

The stilbestrol disorders in historical perspective.

In the late 1960s when a series of adolescent girls with adenocarcinoma of the vagina presented themselves to our hospital, we did not immediately suspect the cause. Previous experience with radical hysterectomy and with vaginal reconstruction had prepared us technically to treat them successfully. Then a clue to etiology from one mothers observation regarding DES as a pregnancy supportive medication was quickly and conclusively converted into fact by an investigation with case controls.

The stilbestrol-adenosis-carcinoma syndrome

This disease complex is one of the few entirely new and previously unsuspected discoveries of the recent past. The first case, seen in 1966, ushered in an era of suspicion. A study and report on the first seven cases published in 1970 inaugurated the era of hot pursuit which culminated in 1971 in an epidemiologically structured and controlled investigation of possible etiologic factors. With the establishment of the stilbestrol association a Registry of Cases was initiated, heralding the era of verification. This Registry, while accelerating and embossing confirmation of the suspected relationship, served an even more useful purpose by collecting under one roof and in front of one cluster of observers all the necessary and relevant data on a sufficiently large number of cases to enable rapid (1973–1974) wide dissemination of knowledge about the occurrence and behavior of the disease and its response to treatment. The behavior of these tumors is comparable to that of other cancers at this location. When they are still localized, cure is possible by either surgery or radiation therapy. Since all the individuals at risk can be identified by their clinical history, screening examination for presymptomatic cancer is entirely feasible. At the same time we can and should note the presence and nature of any morphologic anomalies of the kind, which are seen in a very high proportion of the women exposed before the 18th week of fetal life.