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Cancer risk in diethylstilbestrol-exposed offspring
Cancer risk in diethylstilbestrol-exposed RICHARD
F. MATTINGLY,
ADOLF
STAFL,
Milulaukee,
Wisconrin
M.D.,
offspring
M.D. PH.D
The occurrence of columnar epithelium in the vagina (vaginal adunosis) in young women with intrauterine exposure to diethylstilbestrol (DES) during the first trimester of pregnancy was observed in 231 patients (82 per cent of 280 cases who underwent colposcopic study.) Extension of columnar epithelium onto the Portia of the cervix was prewnt in the remaining 18 per cent of the cases. Abnormal colposcop’cjvrdings were present in the transformation zone in 96 per cent of the patients with vaginal adenosis. Directed biopsy re&aled four cases of vaginal andlor cervical squam0u.s carcinoma in situ (CIS), &o cases severe dysplasia, jive cases of moderate, and 29 cases of mild dysplasia. The prwalence of CIS in DES-exposed girls (I .I per cent) was nearly j five times the preualenw rate of CIS in a control group of 5,808 DES-unexposed uwvnen (0.44 per cent). Th&jinding correlates ulell with the hypothesis that the genesis squamous intraepithelial nroplasia is speca$cally related to the extent and surface urea of the lw@nal transf&nation zone. .4n unusual case invasive squamous carcinoma in a DES-exposed young girl is presented, which represents the initial obsentation this assoriation to date. (AM. J. ORSTET. GYNECOL. 126: 543. 1976.)
of
of
of
of
WITH THE RECOGNITION oftheteratogeniceffectof diethylstilbestrol on the maldevelopment of the lower genital tract, the major clinical concern has been related to the association of vaginal adenosis and clearcell adenocarcinoma in DES-exposed young women.‘-3 In 19’74, Stafl and Mattingly” expressed the initial concern that the major clinical risk in DES-exposed women was the development of squamous neoplasia of the vagina and cervix, rather than clear-cell adenocarcinema. Our initial experience with 13 1 cases of DESrelated vaginal adenosis demonstrated two cases of vaginal carcinoma in situ and five cases of dysplasia. The hypothesis of an increased risk of squamous neoplasia was based on previous colposcopic, histologic, and vascular studies on the transformation zone of the cervix.“-’ However, at that time there were only short-term follow-up studies of the natural history of columnar epithelium in the vagina (vaginal adenosis) and the number of cases of vaginal intraepithelial neoplasia was limited. While the original
hypothesis lacked sufficient data for immediate confirmation, additional information from this clinic and from other institutions provides the background for this report.
Materials aftd methods Between June, 1971, and January, 19’76, 280 young women whose mothers were given diethylstilbestrol (DES) during the first trimester of pregnancy were examined. Their ages ranged from 13 tu 26. A total of 228 girls (81 per cent) were asymptomatic and were referred for colposcopic evaluation. Thirty-nine women (14 per cent) had a consistent mucous vaginal discharge and 13 girls (5 per cent) came for gynecologic consultation with the chief comptaint of dyspareunia. Clinical evaluation included a gynecologic history, cytology from the cervix and from the vagina, and a careful pelvic examination. Except for one case of a benign ovarian cyst, the pelvic examination in all girls was negative. After insertion of the self-retaining speculum, the cervix was grossly inspected and then colposcopic examination was performed. The colposcopic examination was done without anesthesia except in two girls who had a very tight hymen and where significant vaginal discharge was an indication for examination under anesthesia. The cervical mucus was cleaned from the cervix and vagina with gauze. Colposcopic
Presented a~ Gu& Speaker at the Thirty-eighth Annual Mwting of the South Atlantic Association of Obstetricians and Gynecologists, Hamilton, Brmuda, January 24-29, 1976. Reprint requests: Richard F. Mattingly, M.D., Depart. of Gynecology and Obstetrics, The Medical College of Wisconsin, 8700 West Wisconsin AlIe., M&a&e, Wiscon.tin 53226.
543
544
Mattingly
Table
and Stafl
I. Gross examination No. of patients
Vaginal hood Cock’s comb Erythroplakia Transverse septum No changes
Table
II. Extension
Per cent
61 35 15 3 166
of columnar
I
22 13 5 1 59
epithelium
No. of patients
Lower third of vagina Mid third of vagina Upper third of vagina Vaginal fornices Cervix, portio
I
17 57 74 83 49
Table III. Colposcopic vaginal adenosis
findings
6 20 26 30 18
in 231 cases of
No. of
patients
9(
4) 7 2
Abnormal coiposcopy White epithelium Punctation Mosaic
IV. Histologic
No. found
Per cent
Normal colposcopy Columnar epithelium Transformation zone
Table
Per cent
222 (96) 67 58 97
findings
I
No.
of patients
Mild dysplasia Moderate dysplasia Severe dysplasia Carcinoma in situ
29 5 2
4
examination was performed both before and after the acetic acid test. Full inspection of the vagina was achieved by rotation and slow withdrawal of the blades of the speculum. In patients where an abnormal colposcopic lesion was present, either on the cervix or in the vagina, a directed biopsy from the most suspicious colposcopic area was obtained without anesthesia with the Kevorkian forceps. A color colpophotograph of the cervical
and
vaginal
lesions
was
obtained
prior
to
biopsy.
Results Visual examination of the cervix and vagina revealed four atypical gross findings-a vaginal hood, cock’scomb appearance of the cervix, erythroplakia, and transverse vaginal septum-all of which have been
described previously.” The frequency of these findings is recorded in Table I. Colposcopic findings. The main objective of. the colposcopic examination was to identify the location of’ the original squamocolumnar junction. This was established by identification of the extent of the colposcopic transformation zone, the presence of gland openings and Nabothian cysts, and by the differences in the vascular pattern of the transformation zone and the original squamous epithelium. The location of- the original squamocolumnar junction is shown in l‘able II. In identifying the border between the cervix and vagina, we considered the area where the mucosa could be folded and was loosely attached to the stroma of the cervix. The vaginal hood was considered to be a portion of the vagina, which is an admitted difference in the interpretation of this study from the opinion of Herbst and co-workers.* In 231 patients (82 per cent), the original squamocolumnar junction was found in the vagina. In nine of the 231 cases (4 per cent), the colposcopic findings were normal with either normal columnar epithelium or a normal transformation zone. In 222 cases (96 per cent), the colposcopic findings in the vaginal transformation zone were abnormal and included a mosaic pattern in 42 per cent, punctation in 22 per cent, and white epithelium in 29 per cent of patients (Table III). Histologic findings. One of the initial objectives in the early part of this study was to demonstrate, histologically, the presence of the columnar epithelium in the vaginal mucosa, i.e., vaginal adenosis.” Because of the colposcopic accuracy in identifying the presence of the columnar epithelium (vaginal adenosis), the major emphasis of this study was directed toward the histologic changes associated with the abnormal colposcopic lesions in the vagina and cervix. Biopsies were taken from the most suspicious colposcopic lesion. While the abnormal colposcopic lesion in the vagina appears more significant to the less-experienced observer than the actual histologic changes. the liberal application of acetic acid produces blanching of’ the eplthelium and a marked color change. However, after careful evaluation of the important colposcopic factors for grading of the degree of neoplasia, mainly the vascular pattern and intercapillary distance, the diagnostic criteria are the same in the vagina as on the cervix. The directed biopsy revealed four cases of vaginal and/or cervical squamous carcinoma in situ (Figs. 1 and 2). two cases of severe dysplasia, five cases of moderate dysplasia, and 29 cases of mild dysplasia (Table IV). The
clinical
summary
of the
four
cases
of vaginal
car-
Cancer
Fig. 1. Large from
the cervx
risk in DES-exposed
offspring
545
area of mosaic pattern with significantly inc-reaslng intercapillar) clistanc t‘ c~xtc~ntlillg into the anterior vaginal fornix. Colposcopic imp]-ession, carcinoma in situ.
Fig. 2. Representative histologic of stratification. loss of cellular carcinoma in situ. (X400.)
changes from the biopsy polarization. and marked
cinema in situ and two cases of‘ severe dysplasia are included in Table V. An unusual case of‘ invasive squamous carcinoma of the cervix and Ivagina in a voung girl with DES exgosure is preselrted in detail. Case report 34. W., a I g-year-old. para I-0-2-1, white with doculnented intrauterine DES exposure.
\\.vman was ini-
described in Fig. 1 with Ml-thicknw nuclear
pleomclrphism,
comparihlc
loss M ith
tially seen iI1 anothw institution in ripril. 197.3, lxrcause of vaginal bleeding. A Pap smear \ViS repot~tedl~ negative 8 months earlier 11hen seen for protusr mucoid vaginal discharge. Colposcopic euaminatitm \\as not a\ailablc tt) the initial examilleiand !\a5 not perf’ormecl. The disease \~xs initiallv diagnosed as a11 invasive squamous carcinoma of the ccrvis with exlension into the posterior vagina, Stage II-.%. I‘hc tiopsy (Figs. 3 and 4) confirmed this diagnosis of ,trt infiltrating sc~uanio~~~-~~ell carcinoma. ~Tlie paticnl 83 rreatcd
546
Mattingly
Table
Nowmber
and Stafl
V. Clinical
Am. J. Obstct.
summary
of histologic
findings
colposcopy
Localizdion of squamocolumr~ar junction
Atypical
White epithelium
Upper third of vagina
0
0
yes
Suspicious
Mosaic punctation
Fornix
0
0
21
yes
Atypical
Mosaic
Fornix
2
0
K. C.
25
yes
Suspicious
Mosaic
Fornix
0
0
0
J. D.
20
yes
Negative
Mosaic
0
0
0
K. K.
21
yes
Suspicious
Mosaic
Lower third of vagina Fornix
2
0
0
Age
Sexually active
c. L.
22
yes
N. H.
22
T. R.
Initials
Table
VI. Cancer
PaP smear
risk in DES-exposed
women MCGH controls
MCGH DES exposed No. of patients No. of carcinoma in situ Prevalence rate (%) Increased DES cancer risk
280 4 1.4
DES unexposed
’
5,808 19 0.3
4.66*
*(p < 0.05).
with intracavitary radium and external beam irradiation therapy at another institution, receiving a combined midpelvic irradiation dosage of approximately 5,000 rads. A follow-up examination 5 months later, in September, 1975, revealed recurrent squamous-cell carcinoma on biopsy of the outer one third of the vagina. The patient was not a candidate for an exenteration, in view of the fixation of the tumor to the lateral pelvic wall and bilateral ureteral obstruction. The patient died with uremia in January, 1976, 9 months after the initial treatment.
Comment The current study of 280 young women with a positive history of intrauterine exposure to DES revealed observations similar to those previously reported from this clinic, including clinical symptoms, gross and histologic findings, and the extension of the transformation
zone.
The
challenging
1. lYi(i Gvncc (31.
finding
of
this
study was the occurrence of an invasive squamous-cell carcinoma of the cervix and vagina in a DES-exposed young girl. This report represents the initial observation of this association. Unfortunately, this patient did not have the benefit of a colposcopic examination prior
Parity
Symptoms
GWSS appearance
Cock’s comb 0
Hood
Hbtolog Squamous carcinoma in situ Squamous carcinoma in situ Squamous carcinoma in situ Squamous carcinoma in situ Severe dysplasia Severe dysplasia
to the diagnosis and treatment of this malignancy and, therefore, the development of an invasive squamous carcinoma in vaginal adenosis is not conclusive. However, this presumed association is based on the longstanding history of a mucoid vaginal discharge, the young age of the patient, the documented intrauterine exposure to DES during the first trimester, the extension of the lesion into the upper vagina, and the rarity of such an advanced stage of a primary cervical carcinoma in this age group. While the conclusive histologic evidence is lacking in this case concerning the development of invasive squamous carcinoma from pre-existing columnar epithelium in the vagina, this relationship was clearly documented in two recent cases of primary vaginal carcinoma as reported by Veridiano, Weiner, and Tancer.” In both of these latter cases, the cervix was histologically negative and the squamous-cell carcinoma originated in the vagina. Furthermore, in both of these cases, there was colpostopic and histologic documentation of benign adenosis on the margin of the squamous-cell carcinoma of the vagina. The association of prior DES exposure in these cases of primary squamous-cell carcinoma of the vagina is of clinical interest in the pathogenesis of squamous-cell carcinoma of the lower genital tract. While there is historical evidence of the absence of DES exposure in both of these latter cases, the presence of an extensive vaginal transformation zone was documented. It is clinically recognized that vaginal adenosis may be present in the absence of DES exposure, although this finding is uncommon (less than 3 per cent).“’ I2 However, the presence of vaginal adenosis is much more frequent in DES-exposed girls, in whom the frequency
Volume Number
126 5
Cancer
Fig.
3.
Low-power
histologic view of infiltrating
risk in DES-exposed
offspring
547
squamous-cell carcinoma
Infiltrating squamous-cell carcinoma involving a perivascular space. A tripolar mitotic figure is evident at the margin of the blood vessel. (x400.)
Fig. 4.
of this condition has been reported from 30 to 91 per cent of such cases.‘. 3. ‘. 13. ” Considering the potential cancer risk of these women with an extensive transformation zone, it is unimportant if the vaginal adenosis is DES related or not; more important is the extensiveness of the transformation zone. As previously proposed,4 the probability of neoplastic transformation by carcinogens present in the vagina is significantly higher when the transformation zone is extensive. This additional clini-
cal experience provides further support to the hypothesis that the biologic effect of DES is not carcinogenic. but teratogenic, and that DES induces an embryologic extension of columnar epithelium onto the ectocervix and vagina where the possibility of neopiastic change may occur at a later age by other mutangenic agent(s).’ From the previously reported cases of vaginal dysplasia and carcinoma in situ, the critical question arose if these changes represented true vaginal neoplasia or only immature metaplasia. Cnfortunatrly, rhe
548
Mattingly and Stafl
histology may not differentiate clearly between these two conditions. However, the cases of invasive squamous carcinoma of the vagina discussed in this report provide convincing evidence that squamous neoplasia can occur in these lesions. The data from this study show that among the 280 patients in this series, four cases of vaginal and cervical carcinoma in situ were found, a prevalence rate of 1.4 per cent. Experience from the Mayo Clinic’” also revealed four cases of cervical carcinoma in situ among 289 DES-exposed young women. a prevalence rate of 1.4 per cent. The similarity of the data from the Mayo Clinic and our clinic is striking. Among both stud! groups, eight cases of carcinoma in situ of the vagina and/or cervix were found in 568 patients for a prevalence rate of 1.4 per cent. As a control series, we revie\sed the prevalence rate of cervical neoplasia in a group of DES-unexposed women who were examined in the gynecologic screening clinic of Milwaukee County General Hospital (MCGH) during the 7 yeat period ending in 1971. During the first examination of “0,905 asvmptomatic women in this program, 93 cases of cervical carcinoma in situ were detected, for a prevalence rate of 0.44 per cent. Among these women. there were 5.808 women under the age of 30 years, itt whom 19 cases of.cervical carcinoma in situ were founcl for a prevalence rate of 0.3 per cent (‘rable VI). In comparing these data, the present study group of young DES-exposed patients had a nearly five titnes (4.66) higher prevalence rate of cat,cinc,ma’in situ than which is statistically the DES-unexposed women, significant (p < 0.05). The average age in the entirr DES study group was age 18. whereas the average age
of the 5,808 DES-unexposed patients flrom tht, gynecologic screening clinic was 27 years. The patients in the DES study group are therefore much vottnger than the control patienrs and it is reasonable to expect that a much higher frequency of carcinoma in situ ma!’ occur during the next decade when the women in thr DES group reach the comparable age group of. the controls. The experience of this ongoing colposcopic studv ot’ DES-exposed women provides additional evidence of the increased cancer risk in this group of patients. While the initial clinical concern centered on the infrequent occurrence of vaginal clear-cell adettocarcinema in these young women. the currenr concern of the teratogenic effect of DES exposure relates to the squamous neoplastic change of an extended vaginal transformation Lone by carcinogenic agents in the vagina. A nearly fivefold increase in the prevalence rate of carcinoma in situ of the lower genital tract in this DES stud!,, as compared with a similar age group of DES-unexposed Fvomen. correlates well with thr original hypothesis expressed from this clinic of rhe genesis of squatnoits intraepithelial neoplasia.’ This concept is specifically related to the extent and surface area of the transformation zone within the \,agina. .I‘he potential increased occurrence of intrarpithelial neoplasia of the lower genital tract during the next decade requires a critical refocusing of the initial concern for the infrequent occurrence of ;tclettocnrcinott~a of the vagina to the tnore frequent tlcvelopment of squamous neoplasia in this high-risk group of young women.
REFERENCES
I. Herbst, A. L.. Ulteltler, H., and Poskanzer, L). C.: Adenocarrinoma of the vagina, N. Engl. J. Med. 284: 878,
1971. A. L.. Kurman, R. J., Scully, R. E., and Poskall~er, D. C.: Clear-tell adenocarcinoma of the genital tract in young females. N. Engl. J. Med. 287: 1259, 1972. Ulfelder, H.: Stilbestrol, adenosis and adenocarcinoma, Au. J. OBSTET. GYNECOL. 117: 794, 1973. Stafl. A., and Mattingly. R. F.: Vaginal adenosis: A precat~u-ous lesion? Anr. J. OBSTFX. GYNECOI.. 120: 666. 1974. Stafl, A., Linhartova, A., and Dohnal. V.: Das Kolposkopische Bild der Feldorung und seine Pathogenese. Arch. GynPkol. 199: 223, 3963. Stafl, A., and Linhartova, A.: Die Umwandlunszone und ihre Genese. Arch. Gynakol. 204: 228, 1967. Stafl, A., Dohnal. V., and Linhartova. A.: I:ber Kolposkopische, Histologische und Gefassbefunde an der Krankhaft veranderten Portia. Geburtshilfe. Fraucnheilkd. 23: 437, 1963. Stafl. A.. Linharrova. A., and Dohnal. V.: Das Kolpos-
9.
2. Herbst, 3. 4.
5.
6. 7.
8.
IO.
Il. 12. 13.
14.
1.5.
kopische Bild des Grundes, des papilaren Grundes, der atypisc-hen Umwandlungszone und deren Pathogenesr, Arch. GyllBkol. 204: 212, 1967. Srafl. A., Mattingly. R. F., Foley, D. V., and Fetherston, W. C.: (Xnical diagnosis of vaginal adenosis. Ob5tet. Gl;necol. 43(l): 118, 1974. Veridiano, N. P.. Weiner, E. A.. and T’ancer, M. I,.: Squamous cell carcinoma of the vagina associated with vaginal adenosis, Obstet. Gynecol. 47: 689, 1976. Lilqharrova. A.: Congenital’ectopy of the uterine cervix, Int. 1. G~naecol. Obstet. 8: 653, 1970. Pixl&, E:: Personal communication, 1973. Herbst. A. L., Kurman, R. J., and Scully, R. E.: Vaginal and cervical abnormalities after exposure to stilbestrol in utero, Ohstet. Gynecol. 40: 287. 1972. Sherman, A. I., Goldrath. M., Berlin, A., Vakhariva, V., Banooni, F., Michaels, W.. Goodman, P., and Brown, S.: Cervical-vaginal adenosis in utero exposure to synthetic esrrogens. cbstet. Gynecol. 44: 531, i974. ’ Noller, K. I... Decker, D. G.. Fish. C. R.. and Gaffev. ‘r. A.: Presented at Annual Meeting of Sot. Gynecol. O~col.. Key Bisrayne, Florida, January. 1976.
F. MATTINGLY,
ADOLF
STAFL,
Milulaukee,
Wisconrin
M.D.,
offspring
M.D. PH.D
The occurrence of columnar epithelium in the vagina (vaginal adunosis) in young women with intrauterine exposure to diethylstilbestrol (DES) during the first trimester of pregnancy was observed in 231 patients (82 per cent of 280 cases who underwent colposcopic study.) Extension of columnar epithelium onto the Portia of the cervix was prewnt in the remaining 18 per cent of the cases. Abnormal colposcop’cjvrdings were present in the transformation zone in 96 per cent of the patients with vaginal adenosis. Directed biopsy re&aled four cases of vaginal andlor cervical squam0u.s carcinoma in situ (CIS), &o cases severe dysplasia, jive cases of moderate, and 29 cases of mild dysplasia. The prwalence of CIS in DES-exposed girls (I .I per cent) was nearly j five times the preualenw rate of CIS in a control group of 5,808 DES-unexposed uwvnen (0.44 per cent). Th&jinding correlates ulell with the hypothesis that the genesis squamous intraepithelial nroplasia is speca$cally related to the extent and surface urea of the lw@nal transf&nation zone. .4n unusual case invasive squamous carcinoma in a DES-exposed young girl is presented, which represents the initial obsentation this assoriation to date. (AM. J. ORSTET. GYNECOL. 126: 543. 1976.)
of
of
of
of
WITH THE RECOGNITION oftheteratogeniceffectof diethylstilbestrol on the maldevelopment of the lower genital tract, the major clinical concern has been related to the association of vaginal adenosis and clearcell adenocarcinoma in DES-exposed young women.‘-3 In 19’74, Stafl and Mattingly” expressed the initial concern that the major clinical risk in DES-exposed women was the development of squamous neoplasia of the vagina and cervix, rather than clear-cell adenocarcinema. Our initial experience with 13 1 cases of DESrelated vaginal adenosis demonstrated two cases of vaginal carcinoma in situ and five cases of dysplasia. The hypothesis of an increased risk of squamous neoplasia was based on previous colposcopic, histologic, and vascular studies on the transformation zone of the cervix.“-’ However, at that time there were only short-term follow-up studies of the natural history of columnar epithelium in the vagina (vaginal adenosis) and the number of cases of vaginal intraepithelial neoplasia was limited. While the original
hypothesis lacked sufficient data for immediate confirmation, additional information from this clinic and from other institutions provides the background for this report.
Materials aftd methods Between June, 1971, and January, 19’76, 280 young women whose mothers were given diethylstilbestrol (DES) during the first trimester of pregnancy were examined. Their ages ranged from 13 tu 26. A total of 228 girls (81 per cent) were asymptomatic and were referred for colposcopic evaluation. Thirty-nine women (14 per cent) had a consistent mucous vaginal discharge and 13 girls (5 per cent) came for gynecologic consultation with the chief comptaint of dyspareunia. Clinical evaluation included a gynecologic history, cytology from the cervix and from the vagina, and a careful pelvic examination. Except for one case of a benign ovarian cyst, the pelvic examination in all girls was negative. After insertion of the self-retaining speculum, the cervix was grossly inspected and then colposcopic examination was performed. The colposcopic examination was done without anesthesia except in two girls who had a very tight hymen and where significant vaginal discharge was an indication for examination under anesthesia. The cervical mucus was cleaned from the cervix and vagina with gauze. Colposcopic
Presented a~ Gu& Speaker at the Thirty-eighth Annual Mwting of the South Atlantic Association of Obstetricians and Gynecologists, Hamilton, Brmuda, January 24-29, 1976. Reprint requests: Richard F. Mattingly, M.D., Depart. of Gynecology and Obstetrics, The Medical College of Wisconsin, 8700 West Wisconsin AlIe., M&a&e, Wiscon.tin 53226.
543
544
Mattingly
Table
and Stafl
I. Gross examination No. of patients
Vaginal hood Cock’s comb Erythroplakia Transverse septum No changes
Table
II. Extension
Per cent
61 35 15 3 166
of columnar
I
22 13 5 1 59
epithelium
No. of patients
Lower third of vagina Mid third of vagina Upper third of vagina Vaginal fornices Cervix, portio
I
17 57 74 83 49
Table III. Colposcopic vaginal adenosis
findings
6 20 26 30 18
in 231 cases of
No. of
patients
9(
4) 7 2
Abnormal coiposcopy White epithelium Punctation Mosaic
IV. Histologic
No. found
Per cent
Normal colposcopy Columnar epithelium Transformation zone
Table
Per cent
222 (96) 67 58 97
findings
I
No.
of patients
Mild dysplasia Moderate dysplasia Severe dysplasia Carcinoma in situ
29 5 2
4
examination was performed both before and after the acetic acid test. Full inspection of the vagina was achieved by rotation and slow withdrawal of the blades of the speculum. In patients where an abnormal colposcopic lesion was present, either on the cervix or in the vagina, a directed biopsy from the most suspicious colposcopic area was obtained without anesthesia with the Kevorkian forceps. A color colpophotograph of the cervical
and
vaginal
lesions
was
obtained
prior
to
biopsy.
Results Visual examination of the cervix and vagina revealed four atypical gross findings-a vaginal hood, cock’scomb appearance of the cervix, erythroplakia, and transverse vaginal septum-all of which have been
described previously.” The frequency of these findings is recorded in Table I. Colposcopic findings. The main objective of. the colposcopic examination was to identify the location of’ the original squamocolumnar junction. This was established by identification of the extent of the colposcopic transformation zone, the presence of gland openings and Nabothian cysts, and by the differences in the vascular pattern of the transformation zone and the original squamous epithelium. The location of- the original squamocolumnar junction is shown in l‘able II. In identifying the border between the cervix and vagina, we considered the area where the mucosa could be folded and was loosely attached to the stroma of the cervix. The vaginal hood was considered to be a portion of the vagina, which is an admitted difference in the interpretation of this study from the opinion of Herbst and co-workers.* In 231 patients (82 per cent), the original squamocolumnar junction was found in the vagina. In nine of the 231 cases (4 per cent), the colposcopic findings were normal with either normal columnar epithelium or a normal transformation zone. In 222 cases (96 per cent), the colposcopic findings in the vaginal transformation zone were abnormal and included a mosaic pattern in 42 per cent, punctation in 22 per cent, and white epithelium in 29 per cent of patients (Table III). Histologic findings. One of the initial objectives in the early part of this study was to demonstrate, histologically, the presence of the columnar epithelium in the vaginal mucosa, i.e., vaginal adenosis.” Because of the colposcopic accuracy in identifying the presence of the columnar epithelium (vaginal adenosis), the major emphasis of this study was directed toward the histologic changes associated with the abnormal colposcopic lesions in the vagina and cervix. Biopsies were taken from the most suspicious colposcopic lesion. While the abnormal colposcopic lesion in the vagina appears more significant to the less-experienced observer than the actual histologic changes. the liberal application of acetic acid produces blanching of’ the eplthelium and a marked color change. However, after careful evaluation of the important colposcopic factors for grading of the degree of neoplasia, mainly the vascular pattern and intercapillary distance, the diagnostic criteria are the same in the vagina as on the cervix. The directed biopsy revealed four cases of vaginal and/or cervical squamous carcinoma in situ (Figs. 1 and 2). two cases of severe dysplasia, five cases of moderate dysplasia, and 29 cases of mild dysplasia (Table IV). The
clinical
summary
of the
four
cases
of vaginal
car-
Cancer
Fig. 1. Large from
the cervx
risk in DES-exposed
offspring
545
area of mosaic pattern with significantly inc-reaslng intercapillar) clistanc t‘ c~xtc~ntlillg into the anterior vaginal fornix. Colposcopic imp]-ession, carcinoma in situ.
Fig. 2. Representative histologic of stratification. loss of cellular carcinoma in situ. (X400.)
changes from the biopsy polarization. and marked
cinema in situ and two cases of‘ severe dysplasia are included in Table V. An unusual case of‘ invasive squamous carcinoma of the cervix and Ivagina in a voung girl with DES exgosure is preselrted in detail. Case report 34. W., a I g-year-old. para I-0-2-1, white with doculnented intrauterine DES exposure.
\\.vman was ini-
described in Fig. 1 with Ml-thicknw nuclear
pleomclrphism,
comparihlc
loss M ith
tially seen iI1 anothw institution in ripril. 197.3, lxrcause of vaginal bleeding. A Pap smear \ViS repot~tedl~ negative 8 months earlier 11hen seen for protusr mucoid vaginal discharge. Colposcopic euaminatitm \\as not a\ailablc tt) the initial examilleiand !\a5 not perf’ormecl. The disease \~xs initiallv diagnosed as a11 invasive squamous carcinoma of the ccrvis with exlension into the posterior vagina, Stage II-.%. I‘hc tiopsy (Figs. 3 and 4) confirmed this diagnosis of ,trt infiltrating sc~uanio~~~-~~ell carcinoma. ~Tlie paticnl 83 rreatcd
546
Mattingly
Table
Nowmber
and Stafl
V. Clinical
Am. J. Obstct.
summary
of histologic
findings
colposcopy
Localizdion of squamocolumr~ar junction
Atypical
White epithelium
Upper third of vagina
0
0
yes
Suspicious
Mosaic punctation
Fornix
0
0
21
yes
Atypical
Mosaic
Fornix
2
0
K. C.
25
yes
Suspicious
Mosaic
Fornix
0
0
0
J. D.
20
yes
Negative
Mosaic
0
0
0
K. K.
21
yes
Suspicious
Mosaic
Lower third of vagina Fornix
2
0
0
Age
Sexually active
c. L.
22
yes
N. H.
22
T. R.
Initials
Table
VI. Cancer
PaP smear
risk in DES-exposed
women MCGH controls
MCGH DES exposed No. of patients No. of carcinoma in situ Prevalence rate (%) Increased DES cancer risk
280 4 1.4
DES unexposed
’
5,808 19 0.3
4.66*
*(p < 0.05).
with intracavitary radium and external beam irradiation therapy at another institution, receiving a combined midpelvic irradiation dosage of approximately 5,000 rads. A follow-up examination 5 months later, in September, 1975, revealed recurrent squamous-cell carcinoma on biopsy of the outer one third of the vagina. The patient was not a candidate for an exenteration, in view of the fixation of the tumor to the lateral pelvic wall and bilateral ureteral obstruction. The patient died with uremia in January, 1976, 9 months after the initial treatment.
Comment The current study of 280 young women with a positive history of intrauterine exposure to DES revealed observations similar to those previously reported from this clinic, including clinical symptoms, gross and histologic findings, and the extension of the transformation
zone.
The
challenging
1. lYi(i Gvncc (31.
finding
of
this
study was the occurrence of an invasive squamous-cell carcinoma of the cervix and vagina in a DES-exposed young girl. This report represents the initial observation of this association. Unfortunately, this patient did not have the benefit of a colposcopic examination prior
Parity
Symptoms
GWSS appearance
Cock’s comb 0
Hood
Hbtolog Squamous carcinoma in situ Squamous carcinoma in situ Squamous carcinoma in situ Squamous carcinoma in situ Severe dysplasia Severe dysplasia
to the diagnosis and treatment of this malignancy and, therefore, the development of an invasive squamous carcinoma in vaginal adenosis is not conclusive. However, this presumed association is based on the longstanding history of a mucoid vaginal discharge, the young age of the patient, the documented intrauterine exposure to DES during the first trimester, the extension of the lesion into the upper vagina, and the rarity of such an advanced stage of a primary cervical carcinoma in this age group. While the conclusive histologic evidence is lacking in this case concerning the development of invasive squamous carcinoma from pre-existing columnar epithelium in the vagina, this relationship was clearly documented in two recent cases of primary vaginal carcinoma as reported by Veridiano, Weiner, and Tancer.” In both of these latter cases, the cervix was histologically negative and the squamous-cell carcinoma originated in the vagina. Furthermore, in both of these cases, there was colpostopic and histologic documentation of benign adenosis on the margin of the squamous-cell carcinoma of the vagina. The association of prior DES exposure in these cases of primary squamous-cell carcinoma of the vagina is of clinical interest in the pathogenesis of squamous-cell carcinoma of the lower genital tract. While there is historical evidence of the absence of DES exposure in both of these latter cases, the presence of an extensive vaginal transformation zone was documented. It is clinically recognized that vaginal adenosis may be present in the absence of DES exposure, although this finding is uncommon (less than 3 per cent).“’ I2 However, the presence of vaginal adenosis is much more frequent in DES-exposed girls, in whom the frequency
Volume Number
126 5
Cancer
Fig.
3.
Low-power
histologic view of infiltrating
risk in DES-exposed
offspring
547
squamous-cell carcinoma
Infiltrating squamous-cell carcinoma involving a perivascular space. A tripolar mitotic figure is evident at the margin of the blood vessel. (x400.)
Fig. 4.
of this condition has been reported from 30 to 91 per cent of such cases.‘. 3. ‘. 13. ” Considering the potential cancer risk of these women with an extensive transformation zone, it is unimportant if the vaginal adenosis is DES related or not; more important is the extensiveness of the transformation zone. As previously proposed,4 the probability of neoplastic transformation by carcinogens present in the vagina is significantly higher when the transformation zone is extensive. This additional clini-
cal experience provides further support to the hypothesis that the biologic effect of DES is not carcinogenic. but teratogenic, and that DES induces an embryologic extension of columnar epithelium onto the ectocervix and vagina where the possibility of neopiastic change may occur at a later age by other mutangenic agent(s).’ From the previously reported cases of vaginal dysplasia and carcinoma in situ, the critical question arose if these changes represented true vaginal neoplasia or only immature metaplasia. Cnfortunatrly, rhe
548
Mattingly and Stafl
histology may not differentiate clearly between these two conditions. However, the cases of invasive squamous carcinoma of the vagina discussed in this report provide convincing evidence that squamous neoplasia can occur in these lesions. The data from this study show that among the 280 patients in this series, four cases of vaginal and cervical carcinoma in situ were found, a prevalence rate of 1.4 per cent. Experience from the Mayo Clinic’” also revealed four cases of cervical carcinoma in situ among 289 DES-exposed young women. a prevalence rate of 1.4 per cent. The similarity of the data from the Mayo Clinic and our clinic is striking. Among both stud! groups, eight cases of carcinoma in situ of the vagina and/or cervix were found in 568 patients for a prevalence rate of 1.4 per cent. As a control series, we revie\sed the prevalence rate of cervical neoplasia in a group of DES-unexposed women who were examined in the gynecologic screening clinic of Milwaukee County General Hospital (MCGH) during the 7 yeat period ending in 1971. During the first examination of “0,905 asvmptomatic women in this program, 93 cases of cervical carcinoma in situ were detected, for a prevalence rate of 0.44 per cent. Among these women. there were 5.808 women under the age of 30 years, itt whom 19 cases of.cervical carcinoma in situ were founcl for a prevalence rate of 0.3 per cent (‘rable VI). In comparing these data, the present study group of young DES-exposed patients had a nearly five titnes (4.66) higher prevalence rate of cat,cinc,ma’in situ than which is statistically the DES-unexposed women, significant (p < 0.05). The average age in the entirr DES study group was age 18. whereas the average age
of the 5,808 DES-unexposed patients flrom tht, gynecologic screening clinic was 27 years. The patients in the DES study group are therefore much vottnger than the control patienrs and it is reasonable to expect that a much higher frequency of carcinoma in situ ma!’ occur during the next decade when the women in thr DES group reach the comparable age group of. the controls. The experience of this ongoing colposcopic studv ot’ DES-exposed women provides additional evidence of the increased cancer risk in this group of patients. While the initial clinical concern centered on the infrequent occurrence of vaginal clear-cell adettocarcinema in these young women. the currenr concern of the teratogenic effect of DES exposure relates to the squamous neoplastic change of an extended vaginal transformation Lone by carcinogenic agents in the vagina. A nearly fivefold increase in the prevalence rate of carcinoma in situ of the lower genital tract in this DES stud!,, as compared with a similar age group of DES-unexposed Fvomen. correlates well with thr original hypothesis expressed from this clinic of rhe genesis of squatnoits intraepithelial neoplasia.’ This concept is specifically related to the extent and surface area of the transformation zone within the \,agina. .I‘he potential increased occurrence of intrarpithelial neoplasia of the lower genital tract during the next decade requires a critical refocusing of the initial concern for the infrequent occurrence of ;tclettocnrcinott~a of the vagina to the tnore frequent tlcvelopment of squamous neoplasia in this high-risk group of young women.
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I. Herbst, A. L.. Ulteltler, H., and Poskanzer, L). C.: Adenocarrinoma of the vagina, N. Engl. J. Med. 284: 878,
1971. A. L.. Kurman, R. J., Scully, R. E., and Poskall~er, D. C.: Clear-tell adenocarcinoma of the genital tract in young females. N. Engl. J. Med. 287: 1259, 1972. Ulfelder, H.: Stilbestrol, adenosis and adenocarcinoma, Au. J. OBSTET. GYNECOL. 117: 794, 1973. Stafl. A., and Mattingly. R. F.: Vaginal adenosis: A precat~u-ous lesion? Anr. J. OBSTFX. GYNECOI.. 120: 666. 1974. Stafl, A., Linhartova, A., and Dohnal. V.: Das Kolposkopische Bild der Feldorung und seine Pathogenese. Arch. GynPkol. 199: 223, 3963. Stafl, A., and Linhartova, A.: Die Umwandlunszone und ihre Genese. Arch. Gynakol. 204: 228, 1967. Stafl, A., Dohnal. V., and Linhartova. A.: I:ber Kolposkopische, Histologische und Gefassbefunde an der Krankhaft veranderten Portia. Geburtshilfe. Fraucnheilkd. 23: 437, 1963. Stafl. A.. Linharrova. A., and Dohnal. V.: Das Kolpos-
9.
2. Herbst, 3. 4.
5.
6. 7.
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IO.
Il. 12. 13.
14.
1.5.
kopische Bild des Grundes, des papilaren Grundes, der atypisc-hen Umwandlungszone und deren Pathogenesr, Arch. GyllBkol. 204: 212, 1967. Srafl. A., Mattingly. R. F., Foley, D. V., and Fetherston, W. C.: (Xnical diagnosis of vaginal adenosis. Ob5tet. Gl;necol. 43(l): 118, 1974. Veridiano, N. P.. Weiner, E. A.. and T’ancer, M. I,.: Squamous cell carcinoma of the vagina associated with vaginal adenosis, Obstet. Gynecol. 47: 689, 1976. Lilqharrova. A.: Congenital’ectopy of the uterine cervix, Int. 1. G~naecol. Obstet. 8: 653, 1970. Pixl&, E:: Personal communication, 1973. Herbst. A. L., Kurman, R. J., and Scully, R. E.: Vaginal and cervical abnormalities after exposure to stilbestrol in utero, Ohstet. Gynecol. 40: 287. 1972. Sherman, A. I., Goldrath. M., Berlin, A., Vakhariva, V., Banooni, F., Michaels, W.. Goodman, P., and Brown, S.: Cervical-vaginal adenosis in utero exposure to synthetic esrrogens. cbstet. Gynecol. 44: 531, i974. ’ Noller, K. I... Decker, D. G.. Fish. C. R.. and Gaffev. ‘r. A.: Presented at Annual Meeting of Sot. Gynecol. O~col.. Key Bisrayne, Florida, January. 1976.