Part II

Last week we discussed the occurrence of a cluster or epidemic of eight cases of adenocarcinoma of the vagina that were diagnosed at the Massachusetts General Hospital in Boston between 1966 and 1969. This is an extraordinarily rare malignancy under normal circumstances and, even more so, it virtually never occurs in young women; these eight cases occurred in girls who were between the ages of 15 and 22 years as opposed to the usual older than 50 years.

The reason for this cluster was obscure so, in an effort to elucidate its etiology, the doctors at MGH conducted a case-control study. In such a study, the individuals with the disease are compared to controls, individuals without the disease, who are matched to the cases by age and gender. In this particular case-control study that was subsequently published in the New England Journal of Medicine in 1971, the case group consisted of the eight cases that we have described previously. To those eight cases 32 controls were matched—four controls for every case—in order to increase the statistical power of the study given the unusually small number of subjects.

All of the 40 subjects in the study, the eight cases and the 32 controls, were interviewed with a questionnaire that queried regarding a large panorama of lifestyle and environmental risk factors—as in the great quote from “Casablanca,” “Round up the usual suspects.” Thus, smoking, alcohol, diet, medications and the usual other risk factors were quickly eliminated as putative causes of this cluster. Most tellingly, as I suggested last week that we should focus on reproductive/sexual behavioral risk factors, only one of the eight cases had been sexually active; looking back from this era, that seems almost miraculous, but it was a different world.

So, in the end, what was in fact responsible for this cluster? The answer is that for seven of the eight cases, their mothers had ingested diethylstilbestrol (DES), a synthetic estrogen, during the first trimester of pregnancy, while none of the 32 controls had been similarly exposed. Before we go on to discuss this further, I will raise as a query for the reader to consider the question of how on earth did the investigators at MGH ever figure out the connection to this exposure? We virtually never inquire about maternal in utero exposures so how did anyone figure this one out? I will provide the answer at the end of the article.

To continue, in the past, estrogen was available for therapeutic purposes in only very small quantities and usually only by isolating it from the urine of pigs. In 1938, DES was successfully synthesized and went on the market in 1939 for any number of medical conditions. These included postmenopausal symptoms and hot flashes, vaginitis, and as an anticancer treatment. Indeed, DES was the first anti-cancer drug, as it was used for the treatment of advanced prostate cancer, for which it was highly effective. (We now utilize anti-androgenic drugs in much the same way.)

But for the purposes of this article, starting in the 1940s there was a belief promulgated by various clinical investigators that DES could be utilized to stabilize pregnancies at high risk of miscarriage—it was initially used off-label for this purpose and approved by the FDA in 1947 for pregnant women with a prior history of miscarriages, with vaginal bleeding, with diabetes, etc. For this indication it was prescribed to millions of pregnant women between 1940 and 1971 despite a randomized trial in the mid-1950s that showed that it was not actually efficacious for this purpose.

It is estimated that several hundred cases of adenocarcinoma of the vagina ultimately resulted from this exposure. Males who were exposed to DES in utero had an increased prevalence of undescended testes and other testicular abnormalities. And there was also an increased risk of breast cancer in later life to exposed females. This became another setting in which litigation was an end-result of the epidemiologic findings, with massive lawsuits resulting for the DES women against the various drug companies that produced and marketed the drug.

This brings us back to the question of how Arthur Herbst, Howard Ulfelder and David Poskanzer, the investigators who published the 1971 New England Journal article, which has become a classic of cancer epidemiology, figured out the connection to DES. The answer lies in maternal guilt—the first mother who brought in her teen-aged daughter, upon learning of the bizarre diagnosis, asked the gynecologic oncologist if it could have been due to the fact that she had taken this drug during pregnancy, something she had always felt bad about. The surgeon, of course, pooh-poohed the idea and reassured her. But he did ask the next mother. And so it went.

Sometimes great discoveries don’t come from being smart—they come from being open-minded and lucky.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.