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

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). In occasional neo plasms the characteristic clear and hobnail cells are absent or can be found only after prolonged search. Such tumors may have the appearance of a poorly differentiated carcinoma or an adenocarcinoma resem bling to various degees the classic adeno carcinoma of the uterine corpus. Mucus is often present in the lumens of the tubules and cysts, but not within the cytoplasm of the cells on light-microscopical examina tion. Psammoma bodies are occasionally encountered. The tumors spread from their superficial sites of origin into the underlying walls of the cervix and vagina to varying depths. The cervical Stage I and IIA tumors that have been treated by radical operations, so that careful examination of the entire tu mor has been possible, have infiltrated F ig u r e 4. Cystic pattern of tumor. (X80) 226 SCULLY

Various types of treatment have been employed.15’18 Surgical therapy, usually consisting of a vaginectomy and hysterec tomy with a pelvic lymph node dissection, but without removal of the adnexa, and radiation therapy have been the two most frequent initial approaches. Various com binations of operation and radiation, some times with additional chemotherapy, have also been used. The length of follow-up of the treated patients has not been suffi ciently long to permit a definite conclusion about the optimal mode of therapy at the present time. F i g u r e 5. Cytologic smear. A nest of carcinoma cells characterized by large nuclei with prominent nucleoli. (X1210) Reprinted with the permission N o n -N e o p l a s t i c A l t e r a t i o n of Acta Cytol. Vaginal adenosis has been found in al cases they are considerably smaller with most all cases of vaginal clear-cell adeno relatively inconspicuous nucleoli. No fea carcinoma in which adequate vaginal tissue tures of the cells have permitted a specific uninvolved by tumor has been available diagnosis of the clear cell type of adeno for microscopical examination.15 As noted carcinoma. above, this abnormality has also been dem Stage I vaginal and Stage I and IIA cer onstrated by biopsy in approximately one- vical carcinomas have been demonstrated third of asymptomatic girls who have had to metastasize to lymph nodes in 17 and 28 percent, respectively, of the cases in which surgical exploration and microscopical ex amination of lymph nodes have been done.21 The more advanced cancers have often been complicated by intractable spread of tumor, recurrences in the vagina or elsewhere in the pelvis and/or métas tasés outside the abdomen. Distant métas tasés, particularly in the lungs and the supraclavicular lymph nodes, have been encountered significantly more frequently than in reported series of squamous cell carcinoma of the cervix and vagina.21 As of August 1973, 10 of the 100 vaginal carcinomas and 14 of the 70 cervical carci nomas have been fatal, and another 13 of the 170 patients were alive with persistent .18 or recurrent tumor However, many of F i g u r e 6. Adenosis. Several glands of irregular the patients in the Registry who are pres shape lie beneath a thickened, hyperplastic squa ently free of demonstrable disease have mous epithelium. An intense inflammatory infil trate lies between the glands. (X90) Reprinted been followed for less than two years after with the permission of Obstet. Gynecol. 40:287— the institution of therapy. 298, 1972. ADENOCARCINOMA BELATED TO PRENATAL EXPOSURE TO STILBESTROL 227

F i g u r e 7. A. Opening of gland onto surface. (X95) Reprinted with the permission of Amer. J. Obstet. Gynecol. 118: 607-615, 1974. B. Mu cin-filled cells overly squamous lining. (X490)

a screening examination only because of a to have been produced by a subepithelial history of intrauterine exposure to stilbes- cyst. trol or related drugs.16 Adenosis can be Microscopical examination of an area of visualized by the gynecologist on either di adenosis may reveal two basic patterns. In rect or colposcopic examination of the va one, single or multiple glands, some of gina. On direct inspection, red granular which may be cystically dilated, lie super patches, sometimes covered with exudate, ficially in the vaginal wall (figure 6 ).16 A may appear in contrast to the pale pink number of these glands may have visible color and smooth surface of the normal openings onto the surface (figure 7A). The vaginal mucosa (figure 1). Smaller foci of second pattern of adenosis is characterized adenosis are often manifested by tiny red by the presence of glandular epithelium spots. If no lesions are visible on direct lining the surface of the vagina for varying inspection, painting the mucosa with Schil distances with or without underlying squa ler s or Lugol’s iodine solution may reveal mous epithelium (figure 713). Mixed pat nonstaining areas, which usually prove to terns are often encountered. be involved by adenosis on biopsy exami The glandular epithelium is of two types. nation. Finally, on occasion the entire va One resembles the normal endocervical lin gina may appear normal both before and ing, with picket-fence-type cells containing after the use of an iodine solution, but cytoplasm rich in mucin and small basal careful palpation discloses a minute nod nuclei (figures 7B and 8, inset). The other ule, which on histological evaluation proves epithelium is simple or pseudostratified and 228 SCULLY

in the associated squamous epithelium (fig ure 6 ). The inflammatory cell infiltrate, which may be dense, is composed predom inantly of round cells, but polymorphonu clear leukocytes may be present in small numbers and, in occasional cases, may be numerous. The squamous epithelium over- lying an area of adenosis is characterized typically by a replacement of the super ficial, well glycogenated layer of cells by glycogen-poor cells, which have prolifer ated from the deeper layers of the epithe lium (figures 6 and 9). This change ac counts for the failure of the mucosa to stain with iodine solutions in at least some of the cases. Likewise, the glands of adenosis are often obliterated to varying degrees by nests of squamous cells (figure 9). In a given microscopical section these cells may appear in the form of solid pegs without

F i g u r e 8. Gland lined by mucin-free cells, some of which are ciliated. Scattered cells have abun dant clear cytoplasm. ( X 4 9 0 ) Reprinted with the permission of Obstet. Gynecol. 40:287-298, 1972. (Inset) Mucinous lining of gland. ( X 7 8 0 ) Re printed with the permission of Amer. J. Obstet. Gynecol. 118:607-615, 1974.

is characterized by cells with mucus-free eosinophilic cytoplasm and more centrally located nuclei; the luminal surfaces of these cells often bear cilia (figure 8 ). Cells of the second type resemble both endome trial and tubal lining cells. Both mucinous and mucin-free elements may be present within a single gland. Occasionally cells with abundant clear cytoplasm are seen among the more frequently encountered mucin-free cells (figure 8 ). Unlike endo metriosis, adenosis is not associated with periglandular stroma of endometrial type, nor are secretory changes of a cyclical form observed in the glandular epithelium. F i g u r e 9 . Gland partly replaced by squamous Adenosis is usually accompanied by an epithelium. The surface epithelium is composed inflammatory reaction as well as alterations of glycogen-free squamous cells. ( X 2 5 0 ) ADENOCARCINOMA RELATED TO PRENATAL EXPOSURE TO STILBESTROL 229 easily recognizable remnants of pre-exist- ing glandular epithelium (figure .10). In such cases careful high-power examination, aided by special staining, may reveal drop lets of mucus surrounded by atrophic mu cus-containing epithelial cells in the centers of the pegs. Thus, an interplay of glandular and squamous epithelium can be seen in vaginal adenosis that is similar to the more familiar type encountered in cervical ero sion. The replacement of the glandular by squamous epithelium may be a mechanism by which adenosis heals, and evidence sug gests that the disappearance of the process is facilitated by a decrease in the inflamma tory cell infiltrate. Thus, in five cases of F i g u r e 10. Biopsy specimen of vaginal adenosis vaginal adenosis in which the use of in- sectioned in oblique plane. Squamous pegs replac travaginal progesterone-theobroma-oil sup ing glands should not be confused with squamous cell carcinoma. (X35) Reprinted with the permis positories has resulted in a partial or sion of Amer. J. Obstet. Gynecol. 118.-607-615, complete disappearance of areas of in 1974. volvement on both clinical and microscop ical examination, the earliest microscopic mous cell carcinoma. Another lesion, which alteration has been a striking clearing of must be distinguished from adenocarci the inflammatory cell infiltration.17 noma, is the distinctive microglandular hy Although areas of adenosis have been perplasia of the type described in the cer observed commonly at the margins of or vix in women ingesting an estrogen and a within clear-cell adenocarcinomas of the progestin. One case of this type has been vagina, careful examination of the speci reported10 and the authors have encoun mens has not yet revealed clearcut transi tered two examples of this reaction. Also tions between the adenosis and the carci it is conceivable that a variety of other nomas. In some of the exposed girls without lesions, similar to those seen in the cervix, cancer, atypical nuclei have been seen will eventually be found to involve the either in the glands of adenosis on histo glands of vaginal adenosis, and the pathol logical examination or on cytologic smears. ogist must be alert to the possible occur However, without a long follow-up exam rence of such changes. ination of a large number of cases of this The vaginal and cervical transverse type, it is difficult to be certain whether ridges that have been observed in exposed such alterations are premalignant or en patients are typically low, fibrous bars that tirely benign and possibly related to the involve part or all of the circumference severe inflammation that is so commonly (figure ll).16’20 On occasion, a vaginal present. ridge may be so prominent that the cervix The pathologist should be aware of is invisible before the ridge is divided. A changes other than carcinoma that can de cervical ridge can give the portio central to velop in vaginal adenosis. The aforemen it the misleading appearance of a cervical tioned squamous peg formation (figure 10) polyp protruding through the external os; must not be confused with infiltrating squa- this finding has been called “pseudopolyp 2 3 0 SCULLY

cal erosion that may be observed in non exposed girls. The glandular epithelium of adenosis can often be identified in cytologic smears.27’30 It has not been possible, however, to dis tinguish the cells of adenosis from normal epithelial cells originating in the cndocer- vix. When a direct scrape of the vaginal mucosa yields large numbers of glandular epithelial cells and particularly when such cells are sparse or absent in a vaginal pool specimen, one can be highly suspicious of the diagnosis of adenosis. However, in our experience smears prepared by scraping the vaginal surface have yielded glandular epithelial cells in less than half the biopsy- proven cases.27

D iscussion Although cervical erosion, vaginal adeno sis, vaginal and cervical ridges and vaginal and cervical clear-cell adenocarcinomas are associated with intrauterine exposure to stilbestrol and related non-steroidal syn thetic estrogens in a high proportion of cases, the mechanism by which these drugs F i g u r e 11. Uterus and vagina opened along left lateral margin. A transverse vaginal ridge is lo play a role in the development of such ab cated above a broad dark band of adenosis. A normalities has not been elucidated and Nabothian cyst lies above the ridge at the level of remains a subject for speculation at the the cervix. Reprinted with the permission of N. Eng. J. Med. 287:1259-1264, 1972. present time. In view of the fact that the exposure in these patients has consistently begun in the first four months of preg of the cervix.”16 On microscopical examina nancy,18 it is reasonable to assume that tion, the ridges are composed of dense con alterations in the development of the lower nective tissue and are usually involved by genital tract are produced during that pe adenosis. riod of time. However, no observations The appearance of glandular epithelium have been made on fetuses or infants ex on the portio may be similar to that of posed to these drugs, so it cannot be stated vaginal adenosis or to congenital erosion of categorically that the abnormalities de the cervix. When the distribution of the tected later in life are congenital in origin. glandular tissue is patchy and it is well Indeed, the earlier literature on adenosis removed from the typical site of erosion, suggested that with the rare exceptions of the process is more apt to be akin to vagi isolated vaginal cysts found in fetuses, ad nal adenosis. However, in many cases the enosis is not congenital, but is acquired cervical disorder in exposed patients has after the onset of puberty.22 The possibility been indistinguishable on both clinical and that this was true stimulated a recent histo microscopical examination from the cervi logical reinvestigation of vaginas from 100 ADENOCARCINOMA RELATED TO PRENATAL EXPOSURE TO STILBESTROL 2 3 1 unselected autopsies of fetuses and post . n ■ jm ' * s a s s s a i natal females up to the age of 25 years.19 9 fij -gm i ’ .-.ft ■ & ~ **■ Five of the 33 subjects under the age of m one month had diffuse or focal adenosis o W ' (figure 12), it was not observed in the 43 s® 0 specimens from patients between one month and 12 years of age, the average age • 0 ^ A of puberty, but it was seen again in diffuse fife # or focal form in three of the 24 patients 9 between the ages of 13 and 25 years. These findings clearly indicate, then, that vaginal * adenosis can be a congenital anomaly. * A review of vaginal embryology is essen a & ** *. tial before one can speculate on the patho sST«»*# ■» genesis of adenosis. Although this subject is controversial, most authorities agree that M ~ 0 the vagina has two anlage, the caudally . '■h E m fused portions of the mullerian ducts and F i g u r e 12. Vaginal adenosis in 28 week old either the urogenital sinus or the wolffian fetus. (X400) Reprinted with permission of Hu ducts.7’9’31 Early in development the vagi man Path. 5:265-276, 1974. nal epithelium is entirely mullerian, but subsequently squamous epithelium extends genital or wolffian anlage.16 The nature of upward from the urogenital sinus or wolf the factor or factors responsible for the de fian ducts to replace it. It is possible that velopment of clear-cell adenocarcinoma in exposure to non-steroidal estrogens either rare cases of vaginal adenosis is unknown. stimulates the mullerian glandular epithe The observation that these carcinomas have lium, causing it to persist, or inhibits the been most frequent during the several upgrowth of the squamous epithelium so years after the onset of puberty, suggests that varying amounts of glandular epithe the possible pathogenetic role of estrogens lium remain in the vagina at birth. Experi of ovarian origin, although other factors are mental evidence suggesting that one or the undoubtedly also involved.15 other of these mechanisms may be opera The location of most early clear-cell ad tive has been provided by the production enocarcinomas of the vagina on its anterior of adenosis by the administration of estro wall, the superficial site of origin of these gens to newborn mice.8 In these animals tumors and their high association with ad vaginal development is incomplete at birth enosis of a mullerian type (epithelium re and continues for a short period thereafter. sembling that of endocervix, endometrium Strong evidence that exposure to stilbestrol and fallopian tube) attest to their mul interferes with the normal development of lerian nature. Although these carcinomas the vagina in the human is the frequent have been termed “mesonephromas” or association of such exposure with vaginal “mesonephric carcinomas” by many au and cervical ridges, which appear almost thors, we have never observed one that certainly to be congenital anomalies5 and was related topographically to mesonephric are almost always the site of adenosis. duct remnants, which are found relatively These ridges may be produced by an ab rarely and are situated for the most part normal proliferation of connective tissue at deep within a lateral wall of the cervix the junction of the mullerian and the uro- or vagina. The conclusion that the clear 2 3 2 SCULLY cell adenocarcinomas of the cervix and va 3. Adenocarcinoma Registry. Amer. J. Obstet. gina are of müllerian origin is consistent Gynecol. 113:718, 1972. 4. Annual Report on the Results of Treatment in with strong evidence for a similar nature Carcinoma of the Uterus and Vagina. Vol. 14. of carcinomas of identical microscopic ap Kottmeier, H. L., ed. Stockholm, Kungl Bok- pearance arising in the ovary and the uter tryckeriet P. A. Norstedt and Seiner, 1967. 5. Deppisch, L. M.: Transverse vaginal septum. ine corpus.23’24’25 The significance of the Histologic and embryologic considerations. clear and hobnail cells characteristic of Obstet. Gynecol. 39:193-198, 1972. these tumors and the correspondence of 6. Diethylstilbestrol contraindicated in preg nancy. FDA Drug Bulletin, Nov. 1971. these cell types, if any, to nonneoplastic 7. F o r s b e r g , J. G.: Origin of vaginal epithelium. müllerian elements are incompletely under Obstet. Gynecol. 24:787-791, 1965. stood. However, the neoplastic clear and 8. F o r s b e r g , J. G.: The development of atypical epithelium in the mouse uterine cervix and hobnail cells do resemble closely, both on vaginal fornix after neonatal oestradiol treat light-microscopical and electron-microscop ment. Brit. J. Exp. Path. 50:157—195, 1969. ical examination, the clear cells and hob 9. F o r s b e r g , J. G.: Cervicovaginal epithelium: its origin and development. Amer. J. Obstet. nail cells that may be seen in the endome Gynecol. 115:1025-1043. trial glands in cases of intrauterine and 10. G r a h a m , J., G r a h a m , R., and Hirabayashi, ectopic pregnancy ( Arias-Stella reaction).28 K.: Reversible “cancer” and the contraceptive pill. ReDort of a case. Obstet. Gynecol. 31: 190-192', 1968. Conclusions 11. G r e e n w a l d , P . , B a r l o w , J. J., N a s c a , P . C., The pathology of prenatal exposure to a n d P i c k r e n , J. W.: Vaginal cancer after ma ternal treatment with synthetic estrogens. N . non-steroidal estrogens is a continuously Eng. J. Med. 285:390-392, 1971. unfolding story. Pathologists will be receiv 12. H e n d e r s o n , B . E., B e n t o n , B . D. A., ing increasing numbers of vaginal and cer W e a v e r , P. T., L i n d e n , G., a n d N o l a n , J. F.: vical specimens sampled to confirm the Stilbestrol and urogenital tract cancer in ad olescents and young adults. N . Eng. J. Med. presence of adenosis or clear-cell adeno 288:354, 1973. carcinoma. In all probability some of the 13. H e r b s t , A. L. a n d S c u l l y , R. E.: Adenocar lesions, both benign and malignant, that cinoma of the vagina in adolescence: a report of 7 cases including 6 clear-cell carcinomas will be encountered have not yet been de (so-called mesonephromas). Cancer 25:745- scribed, nor has the nature of the relation 757, 1970. between non-steroidal estrogen administra 14. H e r b s t , A. L., U l f e l d e r , H , , a n d P o s k a n - z e r , D. C.: Adenocarcinoma of the vagina. tion, adenosis and clear-cell adenocarci Association of maternal stilbestrol therapy noma been fully elucidated. Careful study with tumor appearance in young women. N. of the vagina in exposed and non-exposed Eng. J. Med. 284:878-881, 1971. 15. H e r b s t , A. L., K u r m a n , R. J., S c u l l y , R. E., human females at various ages as well as a n d P o s k a n z e r , D. C.: Clear-cell adenocarci imaginative experimental approaches will noma of the genital tract in young females. be required in order to enhance our knowl Registry Report. N. Eng. J. Med. 287:1259- 1264, 1972. edge of these phenomena. Likewise, ex 16. H e r b s t , A. L., K u r m a n , R. J., a n d S c u l l y , posed patients will have to be followed for R. E.: Vaginal and cervical abnormalities after many years as it is possible that other por exposure to stilbestrol in utero. Obstet. Gyne tions of the female and even the male col. 40:287-298, 1972. 17. H e r b s t , A. L., R o b b o y , S . J., M a c d o n a l d , genital tract12 may prove to be affected as G. J., a n d S c u l l y , R . E.: The effects of local this population ages. progesterone on stilbestrol-associated vaginal adenosis. Amer. J. Obstet. Gynecol. 218:607— 615, 1974. R eferences 18. H e r b s t , A. L., R o b b o y , S . J., S c u l l y , R . E., 1. Adenocarcinoma Registry. Obstet. Gynecol. a n d P o s k a n z e r , D. C.: Clear-cell adenocarci Surv. 27:395, 1972. noma of the genital tract in young females. 2. Adenocarcinoma Registry. Obstet. Gynecol. Registry Report II. Amer. J. Obstet. Gynecol, 39:841, 1972. (in press). ADENOCARCINOMA BELATED TO PRENATAL EXPOSURE TO STILBESTROL 2 3 3

19. K u r m a n , R. J. a n d S c u l l y , R. E.: The inci genesis of clear-cell carcinoma of the ovary. dence and histogenesis of vaginal adenosis. An Amer. J. Obstet. Gynecol. 225:394-400, 1973. autopsy study. Human Path. 5:265-276, 1974. 26. T a f t , P. D . , R o b b o y , S . J., H e r b s t , A. L., 20. P o m e r a n c e , W.: Post-stilbestrol secondary a n d S c u l l y , R. E.: Cytology of clear-cell ad syndrome. Obstet. Gynecol. 42:12-18, 1973. enocarcinoma of the genital tract in young 21. R o b b o y , S . J., H e r b s t , A. L., a n d S c u l l y , females. Report of cases from the Registry. R . E.: Clear-cell adenocarcinoma of the gen Acta Cytol. (in press). ital tract in young females. Analysis of 37 27. T a f t , P. D.: Personal Communication. tumors that persisted or recurred after primary 28. T h r a s h e r , T . V . a n d R i c h a r t , R. M.: Ultra therapy. Cancer (in press). structure of the Arias-Stella reaction. Amer. J. 22. S a n d b e r g , E. C.: The incidence and distribu Obstet. Gynecol. 112:113-120, 1972. tion of occult vaginal adenosis. Amer. J. Ob 29. U l f e l d e r , H . : Stilbestrol, adenosis, and ad stet. Gynecol. 202:322—334, 1968. enocarcinoma. Amer. J. Obstet. Gynecol. 117: 23. S c u l l y , R. E. a n d B a r l o w , J. F.: “Meso- 794-798, 1973. nephroma” of ovary. Tumor of miillerian na 30. V o o i j s , P. G., N g , A. B. P., a n d W e n t z , ture related to the endometrioid carcinoma. W. B.: The detection of vaginal adenosis and Cancer 20:1405-1417, 1967. clear-cell carcinoma. Acta Cytol. 27:59-63, 24. S i l b e r b e r g , S . G . a n d D e G i o r g i , L. S .: 1973. Clear-cell carcinoma of the endometrium. 31. W i t s c h i , E.: Development and differentiation Clinical, pathologic, and ultrastructural find of the uterus. Prenatal Life, Mack, H . C., ings. Cancer 32:1127-1140, 1973. Chapter 1, Detroit, Wayne State University 25. S i l b e r b e r g , S . G.: Ultrastructure and histo Press, pp. 11-35, 1970.