Vaginal and Cervical Abnormalities, Including Clear-Cell Adenocarcinoma, Related to Prenatal Exposure to Stilbestrol*

A n n a l s o p C l i n i c a l a n d L a b o r a t o r y S c i e n c e , V o l. 4, N o . 4 Copyright © 1974, Institute for Clinical Science Vaginal and Cervical Abnormalities, including Clear-Cell Adenocarcinoma, Related to Prenatal Exposure to Stilbestrol* ROBERT E. SCULLY, M.D., STANLEY J. ROBBOY, M.D., AND ARTHUR L. HERBST, M.D. Department of Pathology, Harvard Medical School, the James Homer Wright Pathology Laboratories and the Department of Gynecology, Massachusetts General Hospital (Vincent Memorial Hospital), and the Registry of Clear-Cell Adenocarcinoma of the Genital Tract in Young Females, Boston, Mass. 02114 ABSTRACT A variety of vaginal and cervical abnormalities have been encountered in the offspring of women who have taken stilbestrol or chemically related non steroidal 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 has been widespread during the last two decades, the Registry of Clear-Cell Adeno carcinoma 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-neoplastic and neoplastic disorders related to these hor mones in order that additional epidemiologic, clinical and pathological infor mation be acquired without delay. Introduction sence of any similar cases in this age group In 1970 seven cases of clear-cell adeno in the records of that hospital during the carcinoma of the vagina that had devel half-century prior to 1966, as well as the oped in girls between the ages of 15 and failure to uncover more than a handful of 22 years were reported.13 These patients cases in a review of the world literature, had been seen at a single Massachusetts suggested the possibility that some sub hospital between 1966 and 1969. The ab stance recently introduced into the environ ment might have accounted for the sudden * This investigation was supported by grant outbreak of this very rare form of cancer. H01CA13139-02, National Cancer Institute grant In 1971 the results of an epidemiologic ET-52, American Cancer Society and a Junior Faculty Fellowship from the American Cancer study of these seven cases, in addition to Society (S.J.R.). an eighth case treated at a nearby hospital, ADENOCARCINOMA RELATED TO PRENATAL EXPOSURE TO ST1LBESTR0L 2 2 3 disclosed that seven of the eight girls were and Obstetrics, which designates a carci products of pregnancies during which their noma that involves both the vagina and mothers had been treated with diethystil- the cervix as cervical if it involves the ex bestrol.14 This drug had been administered ternal os.4 Accordingly, 70 of the 170 clear because of threatened abortion or prior cell adenocarcinomas were classified as cer pregnancy loss, beginning in the first tri vical even though it is probable that some mester. No such history was obtained in of these actually arose in the vagina and 32 carefully matched control cases. A con extended onto the cervix. The cervical can firmatory investigation was soon published cers had a highly significant association from New York State.11 Shortly after the with documented exposure to non-steroidal completion of the initial epidemiologic estrogens (52 percent), but a less impres study a Registry of Clear-Cell Adenocarci sive one than that of the vaginal carci noma of the Genital Tract in Young Fe nomas (73 percent).18 This difference is males* was established in order to cen not surprising in view of the fact that cer tralize information about this unusual form vical cancers of the clear-cell type in young of cancer in girls under the age of thirty females had been reported in the literature years, whether or not a history of drug much more frequently than their vaginal exposure can be elicited.1’2’3 counterparts in the prestilbestrol era.29 In November 1971, the Food and Drug The discovery of the association between Administration, recognizing the validity of these tumors and nonsteroidal estrogen ex the association between intrauterine expo posure in utero has led to a number of sure to stilbestrol or chemically related investigations in which asymptomatic ex non-steroidal estrogens and clear-cell ad posed girls have undergone screening ex enocarcinoma of the lower genital tract, aminations to exclude the presence of notified physicians in the United States carcinoma.16 These have revealed the ab that the administration of these drugs was normal presence of biopsy-verified gland contraindicated during pregnancy.6 ular epithelium in the vagina (vaginal By August 1973, the Registry had accu adenosis) in approximately 30 percent, mulated varying amounts of data on 170 tranverse vaginal or cervical fibrous ridges cases of clear-cell adenocarcinoma of the in about 10 percent and glandular epithel genital tract in young females.18 Investiga ium on the portio of the cervix in almost tion of the maternal history in 146 of these all of the cases. Although the last of these has disclosed an intrauterine exposure to three findings is occasionally encountered stilbestrol or the related drugs, hexestrol or in the form of congenital erosion in unex dienestrol, in 65 percent. A history of med posed girls in this age group, vaginal ad ication for the treatment of high-risk preg enosis and transverse ridges have proven nancy was obtained in an additional 12 to be extremely rare in girls whose mothers percent of the cases, but the specific drug did not receive these drugs during preg administered could not be identified. Thus, nancy. 78 percent of the patients were known to Now that gynecologists are examining have been exposed to some type of drug and biopsying the vaginas of young females during intrauterine life. exposed to non-steroidal estrogens with in The tumors in the Registry have been creasing frequency, pathologists are being classified according to the criteria of the confronted with diagnostic problems that International Federation of Gynecology were rarely encountered as recently as * Warren 275, 275 Charles Street, Boston, MA three years ago. The purpose of this paper 02114. is to discuss the pathology and clinical 224 SCULLY features of clear-cell adenocarcinomas of the vagina and cervix, vaginal adenosis and transverse ridges in this age group, based largely on the Registry cases and on screen ing examinations of the vagina in both live and autopsy populations. Observations C a r c i n o m a s On gross examination these tumors have been characteristically superficial and either polypoid, papillary or nodular, ranging in diameter from less than one to over 10 cm (figure l ).15 Occasionally, a small super ficial carcinoma has been removed almost entirely by biopsy so that no residual tumor F i g u r e 2. Clear-cell pattern of tumor resem bling renal cell carcinoma. (X300) is identifiable on gross examination of the resection specimen. A few of the tumors have been flat or ulcerated. Most of the vaginal carcinomas have been situated in the upper or middle thirds and have occupied primarily the anterior wall (figure 1). Almost all the cervical can cers have involved the exocervix, but many have affected the endocervix as well. In an occasional case, the latter has been the major site of involvement. On microscopical examination the tu mors have the features of clear-cell adeno carcinomas that have been encountered elsewhere in the female genital tract, par ticularly in the ovary. Characteristic pat terns are tubule and cyst formation, some times associated with a highly developed papillary architecture, and diffuse and in sular solid epithelial aggregates. The most common cell types are clear cells filled with glycogen, resembling those of the renal cell F i g u r e 1. Uterus and vagina opened along left lateral margin. Polypoid carcinoma is present on carcinoma (figure 2 ), and hobnail cells anterior wall. Patch of adenosis on posterior wall lining the tubules and cysts and character and at margin of tumor. The cervical portio is extensively eroded. Reprinted with the permission ized by bulbous nuclei that protrude into of Cancer 25:745-757, 1970. the lumens beyond the apparent cytoplas- ADENOCARCINOMA RELATED TO PRENATAL EXPOSURE TO STILBESTROL 225 more deeply than the Stage I vaginal car cinomas, many of which have invaded the wall less than two mm.15 Examination of cytologic smears has re vealed the presence of malignant cells in most of the cases that have been reviewed, although many of the smears had been ob tained only after clinical visualization of the tumor.20 Although a positive smear was occasionally the first clue to the diagnosis, negative results were sufficiently frequent to invalidate cytology as a uniformly reli able method of detection. False negative smears may have been related to an ab sence of tumor cells or a high degree of differentiation, or to the presence of numer ous inflammatory cells, which tend to ob scure the neoplastic elements. The tumor cells occur both singly and in clumps and F i g u r e 3. Tubules lined by hobnail cells. (X180) in general resemble endocervical cells, par ticularly when well differentiated. Typ ically the nuclei are large and contain mic limits of the cells (figure 3). The hob nail cells of the tubules are generally prom prominent nucleoli (figure 5), but in some inent, while those lining cysts, which are more often present in the deeper portions of the tumor, are sometimes so flattened that they appear innocuous on superficial examination (figure 4).

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