George Papanicolaou and the Pap Test

Contents

1. A zoologist arrives at Cornell
2. From guinea pigs to the 1943 monograph
3. How the smear changed cervical cancer
4. From cells to the virus

The Pap test has always been judged by a rate, the number of new cervical cancer cases in a population each year, and a result outside the normal range is a familiar reason for colposcopy, one of the office based treatments in Candace Cooley’s experience as an obstetrician and gynecologist. Measured in that unit, the history of the test is unusually clear. NPR’s timeline of cervical screening cites estimates of 24 to 37 cases per 100,000 women before 1933 and 7.5 per 100,000 by 2008, and describes the Pap test as still the most successful screening test introduced against serious cancers, judged by the precancers and early cancers it finds.⁵

The College of American Pathologists notes that in the early 1900s cervical cancer was the leading cause of cancer death among women in the United States, with an estimated 40,000 deaths a year, usually found only at an advanced stage. By the early 2000s new cases had leveled off at around 12,000 a year with roughly 4,000 deaths, a fall of nearly 90 percent from the years before the test, depending on the source.²

A zoologist arrives at Cornell

George Nicholas Papanicolaou was not trained to look at human cells. A biography in the Singapore Medical Journal, archived by the National Institutes of Health, records that he was born on May 13, 1883, in Kimi on the Greek island of Euboea, studied music and the humanities at the University of Athens before his physician father steered him toward medicine, graduated in 1904, and earned a doctorate in zoology at the University of Munich in 1910. He and his wife, Andromache, known as Mary, reached New York on October 19, 1913, speaking no English and carrying little more than the sum then needed to enter the country. In 1914 he found work in the pathology department at New York University and the anatomy department at Cornell University Medical College, where Mary joined him as a technician.¹

Before that, CNN recounts, he had sold rugs, played violin in a restaurant and clerked at a newspaper.¹⁰ At Cornell he worked under Charles Stockard, chair of anatomy, and Healio’s profile credits the work of his 45 years there with establishing modern diagnostic cytology.⁹

Figure

From guinea pig smears to a screening test

1. 01
   1913Arrives in New York from Greece
2. 02
   1916Finds that vaginal smears can time the reproductive cycle in guinea pigs
3. 03
   1920Turns to the cells of the human reproductive tract
4. 04
   1928Publishes the finding that malignant cervical cells can be told apart on a slide
5. 05
   1943Publishes Diagnosis of Uterine Cancer by the Vaginal Smear with Herbert Traut
6. 06
   1954Publishes the Atlas of Exfoliative Cytology

From guinea pigs to the 1943 monograph

The test began as a laboratory convenience. Papanicolaou needed guinea pig eggs harvested just before ovulation and had no way to time it without sacrificing animals. Healio describes how he used a nasal speculum to collect vaginal secretions, saw a daily sequence of distinctive cell patterns under the microscope, and learned to chart the cycle from them.⁹ The NIH biography dates that insight to 1916 and his turn to the human reproductive tract to 1920.¹

Human samples were hard to come by for a scientist without a license to practice medicine in the United States. The College of American Pathologists notes that from 1920 Mary served as his sole subject, giving daily samples and helping to prepare and read her own slides, then recruited friends; later the gynecology clinic at Cornell supplied samples, and in that larger group he found he could tell malignant cells from benign ones. He presented the finding in 1928 to a skeptical audience, partly because diagnosing from loose cells rather than whole tissue was new.² He was not the first to see cancer cells this way: the NIH biography credits the Romanian physician Aurel Babeş with sampling the cervix with a platinum loop in 1927, though history treats the two methods as distinct, and it notes that the British physician Walter Hayle Walshe had described identifying cancer cells under the microscope a century earlier, in a book on lung disease.¹

The proof came from a systematic study. Starting in 1939, Healio reports, Papanicolaou and the gynecologic pathologist Herbert Traut took a smear from every woman admitted to the gynecologic service of the New York Hospital, and the smears revealed cancers in women with no symptoms, some too early to show on biopsy.⁹ The Weill Cornell Medicine library dates the first clinical use of the test to 1943, the year their book, Diagnosis of Uterine Cancer by the Vaginal Smear, was published by the Commonwealth Fund.³

How the smear changed cervical cancer

The biology of the disease suited the test. A 1998 history indexed by PubMed explains that cervical cancer follows a predictable sequence, that precancerous changes invisible to the eye are readily found in sampled cells, and that the slow progression from precancer to cancer makes regular screening effective; it calls the discovery the most significant advance in cancer control in the twentieth century.⁴ The NIH biography adds that the smear cost little, was easy to perform and could be read accurately, which is why it spread so quickly.¹

Figure

Cervical cancer before and after the Pap test

estimated deaths a year in the early 1900s

40,000

new cases a year by the early 2000s

12,000

deaths a year by the early 2000s

4,000

By the end of the 1940s, the College of American Pathologists says, the test was in wide use and cervical cancer rates had dropped by half.² Healio credits it with a 70 percent reduction in cervical cancer deaths.⁹ Recognition followed: the NIH biography lists the Albert Lasker Award for clinical research in 1950 and a commemorative United States postage stamp in 1978.¹

The test was never perfect. A gynecologist quoted in the NPR timeline calls it a test with many false negatives that worked because it was repeated every year.⁵ Guidance from the American College of Obstetricians and Gynecologists, summarized in American Family Physician in 2003, linked sampling and reading errors to 30 percent of new cervical cancers each year, and explained that the long premalignant phase lets repeated tests offset any single false negative. That guidance still advised yearly cytology for women under 30 and allowed an interval of two to three years after 30 following three consecutive normal results.⁸ As late as 1990 The Washington Post still called the annual smear one of the oldest and most misunderstood cancer screening tests.⁶ Between 1996 and 1999, NPR notes, liquid based methods began to replace smearing cells directly onto a slide.⁵ A result that is not normal is often followed by a closer look at the cervix through colposcopy.

Figure

Two ways to screen the cervix

	Pap test	HPV test
What it looks for	Changed or abnormal cervical cells	Strains of the virus that can cause cancer
Method	Cells examined under a microscope	DNA test for viral types
Arrived	Late 1920s, widely used after 1943	Developed between 2006 and 2009
Role by 2014	Long the main screening tool	Approved as a primary screening test

From cells to the virus

The next turn came from virology. NPR’s timeline records that Harald zur Hausen proposed in 1976 that the human papillomavirus causes cervical cancer, that two strains, HPV 16 and HPV 18, were later found in about 70 percent of cases worldwide, and that in 2014 the Food and Drug Administration approved an HPV test as a primary screening tool.⁵ The story of that link is told in HPV and cervical cancer.

The two tests now sit side by side. The National Cancer Institute’s progress report describes screening with the Pap test alone every three years from 21 to 29, and from 30 to 65 either the Pap test every three years or HPV testing, with or without a Pap test, every five. It notes that the two tests feel identical to the woman having them, and that 75.8 percent of women aged 21 to 65 were up to date with screening in 2023.⁷ In 2019 CNN, citing the American Cancer Society, put the year’s estimates at about 13,200 new cases and 4,250 deaths.¹⁰

The next step in research builds on the virus rather than the cell. Studies now ask whether a sample a woman collects herself can stand in for one taken by a clinician, the subject of self collected HPV testing, and how the intervals described in how cervical screening guidelines changed should shift as vaccination spreads. Which test, and how often, is a question each woman settles with her own clinician. The slide Papanicolaou read under his microscope remains the starting point for all of it.