PAPANICOLAOU, GEORGE NICHOLAS

(b. Kimi, Greece, 13 May 1883; d. Miami, Florida, 19 February (1962)

anatomy.

The son of a physician, George Nicholas undertook the study of medicine and received the M. D. from the University of Athens in 1904. After postgraduate work in biology at the universities of Jena, Freiburg, and Munich, from which he received his doctorate in 1910, he returned to Greece and married Mary Mavroyeni, the daughter of a high-ranking military officer.

Papanicolaou decided to forgo the practice of medicine in favor of an academic career, in which his wife served as his lifelong associate. En route to Paris, Papanicolaou stopped for a visit at the Oceanographic Institute of Monaco and accepted an unexpected offer to join its staff. He worked for one year as a physiologist and then returned to Greece upon the death of his mother. After serving for two years as second lieutenant in the medical corps of the Greek army during the Balkan War, he immigrated to the United States.

In 1913 Papanicolaou was appointed assistant in the pathology department of New York Hospital, and in 1914 he became assistant in anatomy at Cornell Medical College. Until 1961 he conducted all of his scientific research, devoted almost exclusively to the physiology of reproduction and exfoliative cytology, at these two affiliated institutions, each of which named a laboratory in his honor. He was designated professor emeritus of clinical anatomy at Cornell in 1951. In November 1961 Papanicolaou moved to Florida and became director of the Miami Cancer Institute, but died three months later of acute myocardial infarction. The institute was renamed the Papanicolaou Cancer Research Institute in November 1962. An indefatigable worker, Papanicolaou is said never to have taken a vacation.

Papanicolaou is best known for his development of the technique, eponymically termed the Papanicolaou smear, or “Pap test”, for the cytologic diagnosis of cancer, especially cancer of the uterus— second only to the breast as the site of origin of fatal cancers in American women.

The history of cancer cytology dates from 1867, when Beale observed tumor cells in the smears of sputum from a patient with carcinoma of the pharynx. He suggested the microscopic examination of desquamated cells for the detection of cancer of other organs, including the uterus and urinary tract.¹ Friedlaender noted, in his subsequent microscopic examination of fluid exuding from ulcerating cancers of the uterus, distinctive cellular elements that helped establish the diagnosis.² In 1908 Koniger called attention to the striking differences in the size and shape of cancer cells obtained from serous cavities, the abundance of vacuoles and fatty droplets in the cytoplasm, the enlargement of the nucleus, and the presence of multiple nucleoli within it.³

Papanicolaou was invited by Charles R. Stockard, chairman of the Cornell Medical School department of anatomy, to join him in his work in experimental genetics. In 1917 he began a study of the vaginal discharge of the guinea pig, with the hope of finding an indicator of the time of ovulation; he would thus be able to obtain ova at specific stages of development. He sought traces of blood, as seen during estrus in certain other species, such as the cow and bitch, and in the menstrual discharge of primates and women. In the course of his daily examination of the guinea pig vaginal fluid, obtained through a small nasal speculum, Papanicolaou saw no blood. He noted instead a diversity in the forms of the epithelial cells in a sequence of cytologic patterns recurring in a fifteen- to sixteen-day cycle, which he was able to correlate with the cyclic morphologic changes in the uterus and ovary. Papanicolaou thus established the technique that became the standard for studying the sexual (estrous) Cycle in other laboratory animals, especially the mouse and rat, and for measuring the effect of the sex hormones.

In 1923 Papanicolaou extended his studies to human beings in an effort to learn whether comparable vaginal changes occur in woman in association with the menstrual cycle. His first observation of distinctive cells in the vaginal fluid of a woman with cervical cancer gave Papanicolaou what he later described as “one of the most thrilling experiences of my scientific career” and soon led to a redirection of his work.

His early reports on cancer detection, however, which appeared from 1928, failed to arouse the interest of clinicians. Cytologic examination of the vaginal fluid seemed an unnecessary addition to the proven procedures for uterine cancer diagnosis—cervical biopsy and endometrial curettage. In 1939, while collaborating with the gynecologist Herbert Traut, Papanicolaou began to concentrate his studies on human beings. Their research culminated in the publication of Diagnosis of Uterine Cancer by the Vaginal Smear. This monograph encompassed a variety of physiologic and pathologic states, including the menstrual cycle, puerperium, abortion, ectopic pregnancy, prepuberty, menopause, amenorrhea, endometrial hyperplasia, vaginal and cervical infections, and 179 cases of uterine cancer (127 cervical and 52 corporeal). The work was instrumental in gaining clinical acceptance of the smear as a means of cancer diagnosis, for superficial lesions could thus be detected in their incipient, preinvasive phase, before the appearance of any symptoms.

The Papanicolaou smear soon achieved wide application as a routine screening technique. The death rate from cancer of the uterus among women aged thirty-five to forty-four who were insured under industrial policies by the Metropolitan Life Insurance Company was almost halved in the decade from 1951 to 1961, decreasing from 16.0 to 8.2 per 100,000; while the corresponding reduction in the death rate from cancer of all sites was from 74.0 to 66.0.

Although the Atlas of Exfoliative Cytology lists the criteria for malignancy in the shed cells, Papanicolaou used to state that he could not explain how he recognized a smear as positive for malignancy any more than he could explain how to recognize an acquaintance by describing his facial expression. Yet he taught thousands of students how to detect cancer cells under the microscope, and they carried his teachings to all parts of the world. Papanicolaou’s technique was rapidly extended to the diagnosis of cancer of other organs from which scrapings, washings, or exudates could be obtained. The principal value of the Papanicolaou smear lies in cancer screening, but it is also applied to the prediction of cancer radiosensitivity, the evaluation of the effectiveness of radiotherapy, and the detection of recurrence after treatment.

It has been suggested that Papanicolaou’s work ranks with the discoveries of Roentgen and Marie Curie in reducing the burden of cancer. Cancer of the uterine cervix is nearly 100 percent curable when recognized in its incipiency.

NOTES

1. Beale, L. S., The Microscope in Its Application to Practical Medicine, 3rd ed. (Philadelphia, 1867), p. 197.

2. Friedlaender, C., The Use of the Microscope in Clinical and Pathological Examinations, 2nd ed., trans. by H. C. Coe (New York, 1885), pp. 168–169.

3. Königer, H., Die Zytologische Untersuchungsmethode, ihre Entwicklung und ihre Klinische Verwerthung an den Ergüssen Seröser Höhlen (Jena, 1908), pp. 99–100.

BIBLIOGRAPHY

I. Original Works. Papanicolaou’s works include “The Existence of a Typical Oestrous Cycle in the Guinea Pig—With a Study of its Histological and Physiological Changes,” in American Journal of Anatomy,22 (1917), 225–283, written with C. Stockard; “New Cancer Diagnosis,” in Proceedings. Third Race Betterment Conference, January 2–6, 1928 (1928), 528–534; Diagnosis of Uterine Cancer by the Vaginal Smear (New York, 1943), written with H. Traut; and Atlas of Exfoliative Cytology (Cambridge, Mass., 1954).

II. Secondary Literature. On Papanicolaou and his work, see “Dedication of the Papanicolaou Cancer Research Institute,” in Journal of the American Medical Association,182 (1962), 556–559; H. Speert, Obstetric and Gynecologic Milestones (New York, 1958), 286; and D. E. Carmichael, The Pap Smear; Life of George N. Papanicolaou (Springfield, Ill., 1973).

Harold Speert