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Abstract Adenocarcinoma of the vagina in young women had been recorded rarely before the report of several cases treated at the Vincent Memorial Hospital between 1966 and 1969. The unusual occurrence of this tumor in eight patients born in New England hospitals between 1946 and 1951 led us to conduct a retrospective investigation in search of factors that might be associated with tumor appearance. Four matched controls were established for each patient; data were obtained by personal interview. Results show maternal bleeding during the current pregnancy and previous pregnancy loss were more common in the study group. Most significantly, seven of the eight mothers of patients with carcinoma had been treated with diethylstilbestrol started during the first trimester.

None in the control group were so treated (p less than 0.00001). Maternal ingestion of stilbestrol during early pregnancy appears to have enhanced the risk of vaginal adenocarcinoma developing years later in the offspring exposed. Methods Four matched controls for each patient with vaginal carcinoma were selected by examination of the birth records of the hospital in which each patient was born. Females born within five days and on the same type of service (ward or private) as the eight propositae were identified. Women who gave birth to daughters closest in time to each patient with carcinoma were first considered.

Interviewing of all mothers was done from a standard questionnaire by personal interview carried out by a trained interviewer. In addition to the seven cases cited above, an eighth identical case of clear-cell adenocarcinoma of the vagina occurred in 1969 in a 20-year-old patient, who was treated at another Boston hospital. † Because she and her family with their matched controls were as available as our own cases, this patient has been included with the original group, and these eight cases form the basis of this study. Comparison of the data obtained from patients and controls was carried out with the use of the paired t-test for parametric data and the matched control method suggested by Pike and Morrow for nonparametric data. Unpaired t-tests and chi-square tests with Yates correction were also carried out but were not significantly different from the results obtained with the paired methodologies.

Results Table 1 Summary of Cases with Carcinoma. Summarizes chronologic details of each patient with her therapy and results. The table demonstrates the clustering of patients for time of birth and occurrence of tumor. In Table 2 Summary of Data Comparing Patients with Matched Controls. The data for seven pertinent areas of inquiry for each patient and her matched controls are displayed, including maternal age at the birth of the child, maternal smoking (at least 10 cigarettes per day before the birth of the child), bleeding during study pregnancy, any prior pregnancy loss, maternal estrogen therapy during study pregnancy, breast feeding of infant and intrauterine x-ray exposure. There is a highly significant association between the treatment of the mothers with estrogen diethylstilbestrol during pregnancy and the subsequent development of adenocarcinoma of the vagina in their daughters (p less than 0.00001). Other factors found to be different between propositae and controls but at 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).

No significant differences between the populations were found for maternal age at time of birth of patient, smoking in parents, intrauterine x-ray exposure and breast feeding. Other topics covered in the questionnaire that also were not statistically significant are listed in Table 3 Additional Factors Compared in Patients and Controls Not Found to Be Significantly Different.*. All the mothers who took stilbestrol began therapy in the first trimester of pregnancy. They received either a constant dose administered throughout the pregnancy, or a continually increasing dose given almost to term. Six of the seven mothers volunteered the information that stilbestrol had been prescribed for them.

The seventh was uncertain, but her obstetrician identified the drug as diethystilbestrol. Bleeding during this pregnancy or previous pregnancy loss (or both) led to the administration of stilbestrol in all seven cases. The programs of management for these pregnancies occasionally included vitamins, iron or calcium. *From the Vincent Memorial Hospital (Gynecological Service of the Massachusetts General Hospital) (address reprint requests to Dr. Herbst at the Vincent Memorial Hospital, Fruit St., Boston, Mass.

Supported by a grant (1393-C-1) from the American Cancer Society (Massachusetts Division), Inc. †We are indebted to Dr. Goldstein, of Boston, for permission to include his case in this study. We are indebted to Miss Jean Sheridan, who carried out the interviews and helped with analyses and preparation of the manuscript, to Dr.

Theodore Colton, of the Department of Preventive Medicine, Harvard Medical School, for helpful suggestions with statistical analysis, to Dr. Scully, of the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, for assistance, and to the directors and record librarians of the participating hospitals for co-operation. References • 1 Herbst AL, Green TH Jr, Ulfelder H:. Primary carcinoma of the vagina: an analysis of 68 cases. Am J Obstet Gynecol 106:210–218, 1970 • 2 Herbst AL, Scully RE:. Adenocarcinoma of the vagina in adolescence: a report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer 25:745–757, 1970 • 3 Plaut A, Dreyfuss ML:.

Adenosis of vagina and its relation to primary adenocarcinoma of vagina. Surg Gynecol Obstet 71:756–765, 1940 • 4 Novak E, Woodruff JD, Novak ER:. Probable mesonephric origin of certain female genital tumors. Am J Obstet Gynecol 68:1222–1242, 1954 • 5 Studdiford WE:.

Vaginal lesions of adenomatous origin. Am J Obstet Gynecol 73:641–656, 1957 • 6 Nix HG, Wright HL:.

Mesonephric adenocarcinoma of the vagina. Am J Obstet Gynecol 99:893–899, 1967 • 7 Droegemueller W, Makowski EL, Taylor ES:.

Vaginal mesonephric adenocarcinoma in two prepubertal children. Am J Dis Child 119:168–170, 1970 • 8 Sandberg EC, Danielson RW, Cauwet RW, et al:. Adenosis vaginae. Am J Obstet Gynecol 93:209–222, 1965 • 9 Pike MC, Morrow RH:. Statistical analysis of patient-control studies in epidemiology: factor under investigation an all-or-none variable. Br J Prev Soc Med 24:42–44, 1970 • 10 Smith OW:.

Diethylstilbestrol in the prevention and treatment of complications of pregnancy. Am J Obstet Gynecol 56:821–834, 1948.