Cytology and Cervical Cancer: 1922 to 2022

By Charles Sturgis - July 05, 2022

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Editor's note: This essay is part of an ongoing series about the evolution of the laboratory over the past century, and part of ASCP's 100th Anniversary celebration.

If one knew a reproductive-age female family member, coworker, caregiver, neighbor, teacher, or friend with “cancer” 100 years ago, her specific disease was most likely squamous carcinoma of the uterine cervix. In the early decades of the 20th century, cervical cancer was both endemic and epidemic. The cause was not known. Cervical cancer was a common cause of death for women, and the incidence of cervical cancer in the United States continued to rise until the development of cervicovaginal cytology screening programs. These programs were made possible by the groundbreaking work of Dr. George Papanicolaou (1883-1962) and his wife Mache “Mary” Papanicolaou (1890-1982). Through collaborations with laboratory and clinical colleagues, Dr. Papanicolaou published seminal articles and texts in the 1930s and 1940s. These works resulted in acceptance of the concept that precancerous changes in the cervix could be identified by exfoliative cytology, and the “Pap” test became recognized as a valuable tool in cervical cancer prevention.   

In the early days of follow up for abnormal Pap tests, conization was the answer. This therapy had attendant downsides such as cervical insufficiency. With the introduction of colposcopy in the 1960s and 1970s, directed biopsied allowed for destruction of focal lesions and diminished the need for conizations. The human papillomavirus (HPV) was identified in the 1950s, and in the early 1970s studies on the possible role of papillomaviruses in human cancers were initiated. It was in the 1970s that koilocytic cells found in cytology preparations from women with dysplastic cervical lesions were shown to represent the cytopathic effect of papillomavirus infection.  Morphologic descriptions by Papanicolaou and others that predated discovery of causation are still valuable today. 

The evolution of study, testing   

As Pap tests became standard of care, large numbers of patients presented annually for screening. This resulted in rapid growth of laboratories and the need for preparatory, technical and diagnostic staff. Out of this environment, concerns for quality and reproducibility grew and ultimately resulted in implementation of the Clinical and Laboratory Improvement Amendments (CLIA) of 1988. These federal statutes led to cytopathology laboratories being among the most stringently regulated clinical laboratories in the country.  

I began working in cytology in the early 1990s. During my residency training at Northwestern University in Chicago, I studied “old fashioned” conventional slides. These slides were prepared at the bedside by mechanically transferring cells from the specimen collection device to the surface of a glass microscope slide. The slide was then rapidly fixed, often using an alcohol containing aerosol. The labeled slides were then sent to a laboratory for staining, coverslipping, screening and diagnosis.  

During my cytopathology fellowship at the University of Texas, M.D. Anderson Cancer Center in the late 1990s, I worked with liquid-based cytology for the collection and processing of exfoliative cervicovaginal cytology specimens. Proprietary liquid-based collection systems changed cervicovaginal cytology, allowing for greater uniformity of cell distribution and staining, centralizing the cellular content in a focused region of the slides and providing a repository for either reflexive testing or co-testing for specific pathogens, such as HPV and other sexually transmitted infections. The ability to work with these cellular suspensions allowed cytopathologists to think in correlative fashions, akin to hematopathologists seeking molecular and genetic markers of disease and prognosis from their tubes of blood and aspirated bone marrows.  

Today, aliquots from liquid-based cytology specimens are used for cytochemical stains, immunocytochemical studies, cell blocks, in situ hybridization tests and many types of molecular and proteomic triage.  In some laboratories, cytopathology specimens have become the main vehicle for molecular testing in not only cervicovaginal cytology but also in the diagnosis and management of lung carcinomas and other solid tumors. A great deal can be accomplished with small specimens that many anatomic pathologists would historically have considered paltry.  

Prevention strategies save lives  

It is known that cervicovaginal cytology has saved more lives than any other clinically utilized cancer prevention test. When coupled with molecular HPV testing and genotyping, this test is superlative. As cervical cancer prevention strategies for populations that have been vaccinated for high-risk HPV move forward, approaches to prevention and management of disease will continue to change. Population-based benefits of vaccination are best achieved if everyone in the population participates. Advocating for vaccination of young people (females and males) is important. It is difficult to imagine what George and Mache Papanicolaou would have thought about the possibility of widespread vaccination and the advent of molecular testing… 

Current American Society for Colposcopy and Cervical Pathology (ASCCP) and American College of Obstetricians and Gynecologists (ACOG) cervical cancer screening recommendations mirror United States Preventative Service Task Force (USPSTF) guidelines that expand the recommended options for cervical cancer screening in average-risk individuals aged 30 years and older to include screening every five years with primary high-risk human papillomavirus (hrHPV) testing. Primary hrHPV testing uses high-risk HPV testing alone (no cytology) with a test that is approved by the FDA for standalone screening. While there are now three options for cervical cancer screening in individuals aged 30–65 years—primary hrHPV testing every 5 years, cervical cytology alone every three years, or co-testing with a combination of cytology and hrHPV testing every five years—it seems that much of primary screening in the future will become molecular rather than or in addition to morphologic.   

One thing is certain. Change will continue. It is important to learn from the past and to transmit that knowledge to today’s cytopathology residents and fellows. Many existing cytotechnologists have acquired new and additional skills in molecular diagnostics, education, laboratory management and other areas. Accredited schools of cytology are attuned to the need for multiskilled and adaptable cytologists for the future. In regard to the next century, it seems likely that anything that could be imagined pertaining to cellular diagnostics, prognostics and molecular genetic manipulations could become possible realities.   

One of the beauties of the study of human cells is that cells do not make decisions centered on nonsensical politics or religion or ethnicity or economics or favoritism. Cells are doing their things, working together to survive in complex environments. Many human organisms (all of which are comprised of cells) would benefit from recognizing and remembering the harmony, interconnectedness and interdependence of their microscopic constituents.  



Davey DD, Austin RM, Birdsong G, et al. The impact of Clinical Laboratory Improvement Amendments of 1988 on cytopathology practice: a 25th anniversary review. Journal of the American Society of Cytopathology.2014;3:188-198. 

Doxtader EE, Cheng WY, Zhang Y. Molecular testing of non-small cell lung carcinoma diagnosed by endobronchial ultrasound-guided transbronchial fine needle aspiration: the Cleveland Clinic experience. Archives of Pathology and Laboratory Medicine. 2019:143:670-676. 

Hausen HZ.  Papillomaviruses in the causation of human cancers – a brief historical account. Virology.2009;384:260-265. 

Mammas IN, Koutsaftiki C, Papatheodoropoulou A, et al.    Mache Papanicolaou (1890-1982), the dedicated companion of the great benefactor, An interview with Dr. Julie Kokkori, one of the only living relatives of George N. Papanicolaou. Experimental and Therapeutic Medicine.2019;18:3248-3251. 

Mammas IN, Spandidos DA. George N. Papanicolaou (1883-1962), an exceptional human, scientist and academic teacher: an interview with Dr Neda Voutsa-Perdiki. Experimental and Therapeutic Medicine.2017;14:3346-3349. 

Naylor B. The century for cytopathology. Acta Cytlogica.2000;44:709-725. 

Pantanowitz L. Digital cytology: look how much has been achieved. Cytopathology. 2020;31:370-371. 

Swailes AL, Hossler CE, Kesterson JP. Pathway to the Papanicolaou smear: the development of cervical cytology in 20th century America and implications in the present day. Gynecologic Oncology.2019;154:3-7. 

Traut HF, Papanicolaou GN. Cancer of the uterus: the vaginal smear in its diagnosis. California and Western Medicine.1943;59:121-122. 

Charles Sturgis

Professor of Pathology