George N. Papanicolaou developed a cytological technique called the Papanicolaou smear (Pap test) for diagnosing uterine cancer, the second most common type of fatal cancer in American woman.
Cancer, first named by the Greek physician Hippocrates of Cos (c. 460-c. 370
Development of cancer cytology began in 1867, after L. S. Beale
Modern cytological detection of cancer evolved from the work of George N. Papanicolaou, a Greek physician who trained at the University of Athens Medical School. In 1913, he emigrated to the United States and began his American career as an assistant in the pathology department of New York Hospital. Papanicolaou entered the arena of cytological examination of cells when he began working, in 1917, with Charles Stockard at New York’s Cornell Medical College. Stockard, chairman of the anatomy department, allowed Papanicolaou to study sex determination in guinea pigs. Papanicolaou’s efforts required him to obtain ova at a precise period in their maturation cycle, a process that required an indicator of the time at which the animals ovulated. In search of this indicator, Papanicolaou designed a method that involved microscopic examination of the vaginal discharges from female guinea pigs. Initially, he sought traces of blood, such as those seen in the menstrual discharges of both primates and humans, but he found no blood in the guinea pig vaginal discharges. Instead, he saw temporal changes in the size and shape of the uterine cells shed in the discharges. The changes he noted recurred in a fifteen- to sixteen-day cycle. This cycle correlated well with associated changes of uterus and ovaries during the fifteen- to sixteen-day guinea pig menstrual cycle. The findings of Papanicolaou’s research, published in 1917 in the American Journal of Anatomy, laid the basis for the study of the sexual cycle in laboratory animals. It also became a standard method for the identification of the effects of sex hormones in these animal species. Its use was instrumental in the first isolation of sex hormones (estrogens) by Edgar Allen
Papanicolaou next extended his efforts to the study of humans. His original intent was to identify whether comparable changes in the exfoliated cells of the human vagina occurred in women. His end goal was to gain an understanding of the human menstrual cycle similar to that he had obtained in the animal studies. In the course of this work, Papanicolaou observed distinctive abnormal cells in the vaginal fluid from a woman afflicted with cancer of the cervix. This led him to begin to attempt to develop a cytological method for the detection of uterine cancer, the second most common type of fatal cancer in American women of the time.
In 1928, Papanicolaou published his cytological method of cancer detection in the Proceedings of the Third Race Betterment Conference, held in Battle Creek, Michigan. The work was received well by the news media (for example, the January 5, 1928, New York World credited him with a “new cancer detection method”). Nevertheless, the publication—and others he produced over the next ten years—were not very interesting to gynecologists of the time. Rather, they preferred use of the standard methodology of uterine cancer diagnosis (cervical biopsy and curettage). As Papanicolaou said, “I failed to convince my colleagues of the practicability of the procedure.” Consequently, in 1932, Papanicolaou turned his energy toward studying human reproductive endocrinology problems related to the effects of hormones on cells of the reproductive system. One example of this work was published in the American Journal of Anatomy (1933), where he described “the sexual cycle in the human female.” Other such efforts resulted in better understanding of reproductive problems that include amenorrhea and menopause.
It was not until Papanicolaou’s collaboration with gynecologist Herbert Traut (beginning in 1939), which led to the publication of Diagnosis of Uterine Cancer by the Vaginal Smear (1943), that clinical acceptance of the method began to develop. Their monograph documented an impressive, irrefutable group of studies of both normal and disease states that included nearly two hundred cases of cancer of the uterus. Soon, many other researchers began to confirm their findings; by 1948, the newly named American Cancer Society
With widespread use of the Pap test came many honors for Dr. Papanicolaou. Some of them included the Cross of a Grand Commander of the Greek Royal Order of the Phoenix, the Lasker Award of the American Public Health Association, the Honor Medal of the American Cancer Society, the Bordon Award of the American Association of Medical Colleges, and the Amory Award of the American Association of Arts and Sciences. In time, Papanicolaou became one of the best-known members of the American medical profession.
At the end of 1961, he became the director of the Papanicolaou Cancer Research Institute in Miami, Florida. Unfortunately, he died shortly thereafter; however, he has not been forgotten: At the posthumous dedication of the Papanicolaou Cancer Research Institute, he was eulogized as “a giver of life—one of the elect men of earth who stand for eternity like solitary towers along the way to human betterment.” This sentiment remains throughout the biomedical community.
Many physicians have cited the Pap test as the most significant and useful modern discovery in the field of cancer research. One reason for its impact is that the test allows the identification of uterine cancer in a presymptomatic stage, long before any other methodology can be used. With such early diagnosis, the disease can be cured in more than 80 percent of all cases identified by Pap test. In addition, Pap testing allows the identification of cancer of the uterine cervix so early that its cure rate can be nearly 100 percent.
Another measure of the efficacy of the Pap test comes from actuarial examination of the consequences of its widespread utilization in routine cancer screening technique, beginning in the early 1950’s. For example, several insurance companies reported that the 1951 death rate from uterine cancer of insured thirty-five- to forty-four-year-old women (160 per million) was halved by 1961 (80 per million). In contrast, the reduction in the death rate from cancer of all types was only about 11 percent in that time period.
Papanicolaou extended the use of the smear technique from examination of vaginal exudates to diagnosis of cancer in many other organs from which scrapings, washings, and exudates can be obtained. These tissues include the colon, the kidney, the bladder, the prostate, the lung, the breast, and the sinuses. In most cases, such examination of these tissues has made it possible to diagnose cancer much sooner than is possible by other existing methods. The smear method has thus become a keystone of cancer control in voluntary and required national health programs throughout the world.
The principal use of Pap testing has traditionally been in cancer screening. The test is utilized successfully in evaluation of the effectiveness of both cancer radiotherapy and cancer chemotherapy, and in the early detection of recurrence of cancer after surgery. Papanicolaou’s 1928 prediction has come to pass: “A better understanding and more accurate analysis of the cancer problem is bound to result from use of this method. It is possible that analogous methods will be developed for the recognition of cancer in other organs.”
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Berkow, Samuel G. “After Office Hours: A Visit with Dr. George N. Papanicolaou.” Obstetrics and Gynecology 16 (1960): 248-252. Personal interview with Papanicolaou shows him both as a man and as a medical scientist. Provides insight into Papanicolaou’s great contributions to endocrinology in general and to cancer research in particular. Describes the overall value of the Pap test. -
Carmichael, D. Erskine. The Pap Smear: Life of George N. Papanicolaou. Springfield, Ill.: Charles C Thomas, 1973. Brief but thorough biography describes the life and career of Papanicolaou and chronicles his development as a man and as a scientist. Contains excellent documentation of his research efforts. -
Papanicolaou, George N. “New Cancer Diagnosis.” In Proceedings of the Third Race Betterment Conference. Battle Creek, Mich.: Race Betterment Foundation, 1928. Describes Papanicolaou’s study of the existence of distinctive cells in the vaginal fluid of humans with cancer and describes a new method for diagnosing cancer of the genital tract. Suggests that a better understanding of the cancer problem will come from the use of this method. -
_______. “The Sexual Cycle in the Human Female as Revealed by Vaginal Smear.” American Journal of Anatomy 52 (1933): 519-637. Lengthy article presents a compendium of normal cytological changes seen in human vaginal discharges. Describes the use of the smear test to identify normal cytological changes in the human reproductive cycle. This report established human cytology on a firm basis. -
Papanicolaou, George N., and Charles Stockard. “The Existence of a Typical Estrus Cycle in the Guinea Pig: With a Study of Its Histological and Physiological Changes.” American Journal of Anatomy 22 (1917): 225-283. Describes a study of the vaginal fluid of guinea pigs and sets down the sequence of cytological patterns of shed cells occurring in fifteen- to sixteen-day cycles correlatable with changes in the reproductive system of the guinea pig. Establishes the technique used for the study of the sexual cycle in laboratory rodents. -
Papanicolaou, George N., and Herbert F. Traut. Diagnosis of Uterine Cancer by Vaginal Smear. New York: Commonwealth Fund, 1943. Describes the exfoliate cytology of many normal and disease states, including the menstrual cycle, abortion, ectopic pregnancy, menopause, several vaginal and cervical infections, and cases of cancer of the uterus. This monograph was instrumental in clinicians’ acceptance of the Pap test as a means for cancer diagnosis.
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