A century of Cervical Cancer screening: The life-saving legacy of Andromachi Papanikolaou

January is Cervical Cancer Awareness month. 3,200 women are diagnosed with cervical cancer in the UK each year [1], and it is the leading cause of cancer deaths in women in the developing world [2].

Unlike most other cancer types, cervical cancer is mainly caused by persistent infection with a virus: human papillomavirus (HPV) [3] [4]. Vaccines can prevent persistent infection with high-risk strains of HPV, to reduce the likelihood of developing cervical cancer. Alongside vaccination, screening programmes are a vital tool in the effort to eliminate cervical cancer by detecting abnormal changes in cervical cells early.

In this article, we look at the history of cervical screening technology, and shine a light on Andromachi Papanikolaou, who paved the way for today’s cervical screening programme.

The Pap Smear

Named after Dr Georgios Papanikolaou, the “pap smear” was developed after Dr Papanikolaou’s discovery in the 1920s that changes in cervical cells could be identified through the microscopic examination of smears [5] [6]. After a landmark paper demonstrating the efficacy of the pap smear for detecting precancerous and cancerous cells was published in 1941, cervical screening programmes based on the pap smear became a routine part of women’s healthcare in many countries in the 1960s.

A centralised NHS cervical screening programme was launched in the UK in 1988, with women aged 20-64 invited to participate every 3-5 years. Within the first 25 years of the screening programme, the number of cervical cancer cases fell by a third. The first human HPV vaccine was developed in 2002 and was rolled out to girls and boys aged 11-13 in the UK in 2008 and 2019 respectively.

The pap smear test, which looks for abnormal cell changes in the cervix, has since been replaced with testing which checks directly for high-risk strains of the HPV virus [7]. Since HPV infection happens before abnormal cell changes develop, testing in this way means that people at a higher risk of developing cervical cancer can be identified earlier and invited for more frequent screening, and treatment if needed. Although superseded by HPV testing, the pap smear was revolutionary in establishing cervical screening.

A team effort

Andromachi Papanikolaou (known as “Mary”), was married to Georgios, and was a crucial partner in his research into vaginal smears. Working in the same laboratory as an unpaid laboratory technician [8] (Cornell Medical College had rules against paying spouses at the time [9]), she provided a vaginal sample every day for twenty-one years. She eventually encouraged her friends to provide samples too. Later, a larger trial began with women from the New York Women’s Hospital [10]. Mary also processed and stained her own samples in the laboratory, to enhance parts of the cells such as their nucleus, so that they could be more easily examined [11]. She continued the couple’s work after her husband’s death in 1962.

With a PhD in zoology, Dr Georgios Papanikolaou was not a clinician, so lacked access to patients, making Mary’s contribution even more valuable. She was quoted as saying “There was no other option but for me to follow him inside the lab, making his way of life mine”, and is reported to have decided not to have children so that she could continue collaborating with her husband [12]. Through his wife’s daily samples over more than two decades, Georgios was able to track the cellular changes from her reproductive years through menopause [13].

The samples provided by Mary and her friends led to Georgios’ discovery that the difference between normal and malignant cells on the cervix could be ascertained by viewing smears on a slide under a microscope. “The first observation of cancer cells in the smear of the uterine cervix”, he later wrote, “gave me one of the greatest thrills I ever experienced during my scientific career” [14].

A woman fighting alongside men

Dr Georgios Papanikolaou was nominated five times for the Nobel Prize, but never won – likely in part because the Nobel Prize is rarely awarded for diagnostic tools. Though, he received many other prestigious prizes and awards for his discoveries. By some accounts, the pap smear is considered the most significant advance in the control of cancer in the 20^th century. It has been shown to reduce cervical cancer deaths by up to 80 percent [15] [16].

Mary’s extraordinary contribution of daily samples for more than 20 years, which would amount to at least over 7,000 smear tests, was a key foundation in the couple’s scientific research [17], and has led to millions of lives being saved.

She received awards on behalf of her husband after his death, but her efforts for working alongside him in the fight against cancer were also honoured. In 1969, the American Cancer Society awarded Mary a special citation, saying she “recognised greatness and served it”. She continued to support cancer research until she died in 1982 at the age of 92 [18].

Sharing a surname, and both contributing to the invention of the smear test, it’s only right that the pap smear should therefore be considered as being named after both husband and wife: Dr Georgios Papanikolaou, and Andromachi Papanikolaou.

It is apt that Mary’s given name, Andromachi, in Greek means “a woman fighting alongside men” [19].

A lasting legacy

The pap smear laid the foundation for the modern cervical screening programme, and has saved millions of lives. A century later, women are continuing to work on life-saving research and engineering in the field of cervical cancer screening and treatment.

HPV home testing kits

Daye, founded by Valentina Milanova, works to address unmet needs in women’s health, including revolutionising period care and gynaecological health screening [20]. Daye has developed diagnostic tampons for at-home STI and HPV testing [21], which can screen for 14 high-risk HPV types, known to be associated with a higher risk of developing cervical cancer. The tampons can be used from the comfort of the user’s home or another safe space, in their own time.

With the NHS planning to offer people who are overdue a cervical screening test an at-home testing option [22], such as a vaginal swab used to take a small sample of cells from the vagina which can then be tested in a laboratory for signs of HPV, self-testing products will likely become more widely adopted.

Reinventing the speculum

A speculum is a medical instrument inserted into the body to widen the vaginal walls, so that the vagina and cervix can be examined.

Ceek Women’s Health was launched by Fahti Khosrowshahi, who was inspired to reinvent the traditional 180 year-old metal speculum design after experiencing anxiety-inducing internal pelvic exams that caused her pain, bleeding and soreness. Ceek’s Nella speculum [23] [24] [25] was redesigned for patient comfort, improving upon the centuries-old original design generally credited as being invented by J. Marion Sims, known as the “father of gynaecology”. Sims’ legacy is problematic due to his practice on enslaved women of vaginal surgical techniques without anaesthesia or consent [26] [27]. The Nella speculum was named one of Time magazine’s “Best Inventions of the Year” in 2020 [28]. Other modern reinventions of the traditional speculum include the Lilium, developed by researchers from Delft University of Technology [29] [30].

It is reported that one likely reason it has taken so long for the speculum to be reinvented is that cis men historically designed medical devices [31]. A lack of personal experience has inevitably led to the discomfort, pain, anxiety and sometimes trauma that patients can endure during vaginal examinations often being overlooked or dismissed in medical device design. But with pioneering women around the world now working to re-engineer the speculum, they are continuing the legacy started by Andromachi Papanikolaou to fight alongside men to save lives.

The next century

The World Health Organisation aims to eliminate cervical cancer within the next century[32], through vaccination, screening and treatment. Vaccination for the younger generation, as well as improved testing procedures to increase screening compliance particularly for women who have not been vaccinated, will be vital. With advancements in at-home testing, as well as the development of more comfortable speculums, it is hoped that the number of women participating in cervical cancer screening will increase [33], and many more lives will be saved.