Doctor's Review: Medicine on the Move

October 25, 2021
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The poppa of the Pap test

How a Greek MD living the American Dream helped stop countless cancer cases

Although cervical cancer remains a deadly disease and is one of the most common forms of cancer in women, it is also among the most preventable -- thanks to one man's study of the vaginal discharges of guinea pigs.

Physician-cum-zoologist George Papanicolaou is one of the most influential individuals in the fight against cancer. Thanks to his eponymous test, hundreds of thousands of women's lives have been saved over the last 50 years.

While George Papanicolaou did not invent the first or only way to diagnose cervical cancer, he did turn an almost certain killer into a largely preventable disease through his development of a non-invasive and inexpensive test that helps catch abnormal pre-cancerous cells early.

The Papanicolaou Test or Papanicolaou Smear, eventually called Pap Smear or Pap Test, has led to a drastic reduction in mortality rates in the developed world where the test is routinely used. The numbers don't lie: since Pap tests became part of women's yearly gynecological exams towards the middle of the last century, the rate of cervical cancer in North America has dropped by more than 70 percent.

Great Greek
Georgios Papanicolaou was born on May 13, 1883, on the island of Evia off Greece's Aegean coast. From an early age, he displayed two distinct sides: on the one hand, he was an intellectual with a deep love of music passed on to him by his mother --traits which drove him to study languages, the arts and the violin. On the other, he was physical, fearless and had a taste for the sea.

George's father, Nicolas, was a well-respected local physician who had his heart set on his son carrying on the family medical tradition.

With his father's encouragement, Papanicolaou would study at the University of Athens and earn his MD in 1904. After a compulsory two-year stint as a doctor in the Greek army, he'd had enough of military life. But he was far from convinced that the life of a clinical doctor was for him, so he turned down offers to join his father's practice. Instead, he convinced his reluctant dad to let him pursue his dream and head off to Germany to find his niche in research.

Papanicolaou settled in at the University of Munich, where he focused his research on sexual determination in the Daphnia, a species of water flea, earning his PhD in zoology in 1910. That same year, the young doctor eloped with the love of his life, Andromache Mavroyeni, whom he called Mary. She shared her husband's love of languages and music, and would be his companion and the subject of his research for 47 years.

Over the next several years, Papanicolaou took a position at the Oceanographic Museum in Monaco. Then, in 1911, he worked as a staff physiologist on an oceanographic expedition on Prince Albert of Monaco's yacht, the Hirondelle II. As his travels wound up, George returned to Greece in 1912. The Balkan Wars broke out shortly thereafter, and Papanicolaou ended up serving in the Greek army as second lieutenant in the medical corps. This latest tour of duty allowed him to meet many Greeks raving of the marvellous opportunities in America. Papanicolaou was convinced and, at the end of the war, he set his sights on starting a life there.

Miracles on 34th Street
When Papanicolaou and Mary landed at Ellis Island on October 19, 1913, they spoke no English, had no prospects whatsoever and had only enough money for their visas. The couple did what they could to survive in New York City. He sold rugs at Gimbel's department store, entertained diners with his violin at local restaurants, and wrote popular articles on marine bio-logy for a Greek newspaper.

Mary also took a job at Gimbel's, working as a seamstress to help make ends meet. But Papanicolaou's American dreams quickly became reality. He found work first at New York Hospital as an assistant in the Pathology Department, and then as an assistant in the Department of Anatomy at Cornell Medical College. His quick mind and strong research background served him well, and he moved up the ranks.


At the time, the Department of Anatomy at Cornell was studying the effects of alcohol on guinea pigs and their offspring, but George was still interested in sexual determination. He got the okay to conduct experiments on some of the female guinea pigs, whose near-constant state of intoxication presumably made them more willing subjects.

The ensuing research of Papanicolaou and colleague Charles Stockard called for the study of pre-ovulatory guinea-pig eggs, but the animals' absence of menstrual flow made deciphering their cycles difficult. Papanicolaou was certain that even lower animals had to have some sort of monthly discharge, but figured it wasn't visible externally due to a lack of volume.

Thanks to a stroke of genius and a pediatric nasal speculum picked up at a local medical-supply store, Papanicolaou ventured into the vaginas of the guinea pigs and obtained cellular samples in search of his answer. The samples were then examined by studying small "smeared" amounts under a microscope.

As suspected, the changes observed in the guinea pigs' discharge allowed their ovulatory cycles to be mapped out. This would prove to be of great value to later researchers trying to determine the menstrual cycles of rabbits, mice and other experimental animals. In this way, Papanicolaou indirectly helped in the discovery of estrogen and progesterone, and would forever lay claim to that catchy mon-iker: the Father of Exfoliative Cytology.

The Human Stain
By the mid-1920s, Papanicolaou had shifted his study to human smears. Since he wasn't a clinician, however, his access to human samples was limited only to those contributed by his wife. Eventually, an affiliation between Cornell and the gynecologists at the Women's Hospital of New York would provide Papanicolaou with a proper supply of human samples, from both healthy and pathological cases. He used a staining process on the slides to help distinguish between healthy and unhealthy cells.

One day, Papanicolaou observed some strikingly abnormal cells from a woman known to have cervical cancer. It didn't take long for him to realize that he had happened across an easy and virtually non-invasive way to detect cancer. The implications were immediately apparent to him -- this was a breakthrough in the fight against cancer.

Unfortunately, the medical and scientific communities were not quick to appreciate the magnitude of his discovery. Some even went so far as to smear Papanicolaou and his work, calling it insignificant. And so the traditional, invasive tissue biopsies used to detect the presence of cervical cancer would remain the norm for quite some time.

But Papanicolaou persevered and, by 1939, he teamed up with Cornell gynecologist Herbert Traut to convince New York Hospital to use the smear test on all female patients. Their findings regarding its efficacy published in 1941 proved undeniable: including the test as part of routine exams would detect abnormal cells in their pre-cancerous phase.

Since the test was adopted on a widespread basis some 40 years ago, the number of women in the United States who have died of cervical cancer has dropped from 20,000 to about 4000 a year, with similar results here in Canada. Even though the test is not without its share of controversy of late -- mostly because of the possibility of false negative results due to faulty lab-work -- it is far and away the best test out there for catching cervical cancer in its early stages when it is often symptomless.

Thankfully, George Papanicolaou lived to see the American Cancer Society put the full weight of its endorsement behind the Pap test in 1960. He was also up for the Nobel Prize in Medicine that year, but lost out to researchers in transplantation immunity.

Two years later, on February 19, 1962, at the age of 79, the doctor from Greece died of a massive heart attack. He'd worked at Cornell for 47 years -- reportedly having never taken a single day's vacation -- and had only recently moved to the University of Florida in Miami to direct its Cancer Institute, which was posthumously renamed in his honour.

His contribution to medical science was also honoured by his home country, which proudly displayed his picture on the 10,000-drachma note (before it was pulled from circulation when Greece adopted the Euro). In the United States, his adopted country, Papanicolaou was honoured with a postage stamp in 1978. Indeed, his stamp on the fight against cancer in the trail-blazing form of diagnostic and preventative cytology marks him as a true hero of modern medicine.


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