Pathway to the Papanicolaou smear: The development of cervical cytology in twentieth-century America and implications in the present day.

George Papanicolaou, a Greek immigrant and cytopathologist, was responsible for what is now colloquially known as the "Pap smear"-undoubtedly one of the greatest advances in medicine and public health of the last century. However, his landmark research on the development of cervical cytology for the detection of precancerous lesions of the cervix ("New Cancer Diagnosis," 1928) made a rather inauspicious debut in an unlikely venue: John Harvey Kellogg's Third Race Betterment Conference-a meeting devoted to the furtherance of the concept and implementation of eugenics. Herein, we discuss the stark juxtaposition of Papanicolaou's landmark discovery amid the pseudoscience of the third Race Betterment Conference. We discuss the latency of Papnicolaou's discovery-its potential implications unrealized-until co-publication with Herbert Traut, which catapulted Papanicolaou's research to the scientific foreground. This gave rise to public health initiatives aimed at establishing the Pap smear as a screening tool. We further delineate the progress made in recent decades with the identification of HPV as the etiological agent for cervical cancer, and the subsequent development of the HPV vaccine, and discuss ongoing research in the present day. In this way, we hope to provide a background and historical context for the development of the Pap smear.

New biological research and understanding of Papanicolaou's test.

The development of the Papanicolaou smear test by Dr. George Nicholas Papanicolaou (1883-1962) is one of the most significant achievements in screening for disease and cancer prevention in history. The Papanicolaou smear has been used for screening of cervical cancer since the 1950s. The test is technically straightforward and practical and based on a simple scientific observation: malignant cells have an aberrant nuclear morphology that can be distinguished from benign cells. Here, we review the scientific understanding that has been achieved and continues to be made on the causes and consequences of abnormal nuclear morphology, the basis of Dr. Papanicolaou's invention. The deformed nuclear shape is caused by the loss of lamina and nuclear envelope structural proteins. The consequences of a nuclear envelope defect include chromosomal numerical instability, altered chromatin organization and gene expression, and increased cell mobility because of a malleable nuclear envelope. HPV (Human Papilloma Virus) infection is recognized as the key etiology in the development of cervical cancer. Persistent HPV infection causes disruption of the nuclear lamina, which presents as a change in nuclear morphology detectable by a Papanicolaou smear. Thus, the causes and consequences of nuclear deformation are now linked to the mechanisms of viral carcinogenesis, and are still undergoing active investigation to reveal the details. Recently a statue was installed in front of the Papanicolaou's Cancer Research Building to honor the inventor. Remarkably, the invention nearly 60 years ago by Dr. Papanicolaou still exerts clinical impacts and inspires scientific inquiries.

The Pap Test: 20th Century Success Story, 21st Century Has-Been.

This old standby's ultimate demise will likely take place when cervical cancer incidence declines as the HPV vaccine starts to take effect at a population level. New guidelines are being written, but insurers could have a major influence on how closely those guidelines are followed. So far, though, they haven't waded very far into the Pap-HPV debate.

[History of the development of screening tests for cervical cancer]. / Historia de la evolución de las pruebas de tamizaje en el cáncer cervicouterino.

Cervical cancer (CC) is one of the best known malignancies. Currently, it is accepted that the etiological factor is persistent infection with high-risk human papillomavirus (HPV). Even before the identification of its etiological factors, methods such as Pap cytology and colposcopy were developed as tools for early diagnosis on CC and its precursor lesions. At the time when such tests were being developed, they were not fully accepted by the scientific community of the time; however, as time went by, the dissemination of knowledge, and more extensive application, these tests were finally included within the international guidelines. The implementation of programs with adequate coverage and quality allowed a significant reduction in the incidence and mortality of CC. However this did not occur widely, and CC is still a public health problem in developing countries. From the epidemiological and molecular viewpoint, knowledge on HPVs laid the foundations for the development of new prevention strategies based on vaccination and molecular detection of the causal agent, currently accepted as strategies for primary and secondary prevention. It is expected that the implementation of these strategies will have a greater impact on the control on CC and other malignancies associated with HPV infection.

El cáncer cervicouterino (CaCU) es una de las neoplasias mejor conocidas; actualmente es aceptado que el factor etiológico es la infección persistente por virus de papiloma humano (VPH) de alto riesgo. Sin embargo, aun antes de que se hubiera identificado el agente etiológico, se desarrollaron métodos, como la prueba citológica de Papanicolaou y la colposcopia, como herramientas para el diagnóstico temprano del CaCU y sus lesiones precursoras. En los inicios del desarrollo de ambas pruebas, estas no fueron del todo aceptadas por la comunidad científica de la época. Con el paso del tiempo, la divulgación del conocimiento y la aplicación más extensiva, se logró la aceptación y la inclusión de dichas pruebas en un gran número de guías a nivel internacional. La implementación de programas con cobertura adecuada y de calidad dio como resultado una reducción significativa en la incidencia y mortalidad por CaCU. Sin embargo, esto no se dio de manera generalizada y en países en vías de desarrollo es aún un problema de salud pública. El conocimiento sobre los VPH, desde el punto de vista epidemiológico y molecular, sentó las bases para el desarrollo de nuevas estrategias de prevención, basadas en la vacunación y en la detección molecular del agente causal, actualmente aceptadas como estrategias para prevención primaria y secundaria. Se espera que la aplicación de dichas estrategias tenga un impacto mayor en el control del CaCU y de otras neoplasias asociadas a la infección por VPH.

50 years after the death of George Nicholas Papanicolaou (1883-1962): evaluation of his scientific work.

The purpose of this review article is to summarise the scientific work of George Nicholas Papanicolaou, one of the most eminent figures in the 20th century history of clinical cytology and medicine. Fifty years after his death, his work still remains invaluable, from the early steps in biology and zoology to the application of the Pap test as the most important advancement in the prevention of cervical cancer. The publication of his Atlas was the first important step for the foundation of a new branch in medicine, that of exfoliative cytology. His contribution to cytology undoubtedly earned him the title of the "father of exfoliative cytology" and saved the lives of many women worldwide.

[Technology and disciplinary fields: cytotechnicians and implementation of the Pap test in Brazil]. / Tecnologia e campos disciplinares: os citotécnicos e a implementação do teste de Papanicolaou no Brasil.

The implementation of the Pap test as a primary technology in the control of cervical cancer in Brazil was the result of choices, agreements and disputes among certain professional groups, including physicians from various specialisations, pharmacists, biologists, biomedical scientists and cytotechnologists. The first part of the paper describes the process of formulating Brazil's first screening campaigns using the Pap smear, and the subsequent emergence of the profession of cytotechnology, whose practitioners interpret this test. Second, based on questions raised by international historiography in the field of science and technology, we explore in detail how the adoption of the Pap smear transpired within the Brazilian context, focussing on the debates among the various professional groups with an interest in the suitability of the test and on the relationships between the public and private healthcare sectors. We show that the professional career of cytotechnologists and the way in which the Pap smear has been implemented as a central technology for cervical cancer screening in Brazil have been shaped by the conflicting views of this technology held by different disciplines as well as by the relationship between these disciplines and labour market dynamics.

Cancer, women, and public health: the history of screening for cervical cancer / Câncer, mulheres e saúde pública: a história do exame para câncer cervical

Cytological screening for cervical cancer (the Pap smear), the first attempt at mass screening for a human malignancy, is often presented as a non-problematic demonstration of the feasibility of such screening. Screening for this tumor became a model for screening for other malignancies: breast, colon and prostate. My text follows the early history of the Pap smear and the conditions that led to its transformation into a routine screening test, despite persistent problems in stabilizing the readings of microscopic slides. It then analyzes the consequences of diffusion of the Pap smear, controversies surrounding this test, the mutual shaping of diagnostic tests and the disease cervical cancer, and the problematic extension of the lessons learned in screening for cervical tumors to other malignancies.

O exame citológico para verificação do câncer cervical (teste de Papanicolau), primeira tentativa de investigação em massa de um câncer humano maligno, é com frequência apresentado como demonstração não problemática da exequibilidade do exame. Ele se tornou um modelo para outros tumores malignos: seio, cólon, próstata. O presente artigo analisa a história inicial do teste de Papanicolau e as condições de sua transformação num exame de rotina, apesar de dificuldades de estabilizar as leituras das lâminas microscópicas. Analisa as consequências da difusão da técnica, as controvérsias a esse respeito, a modelagem articulada do teste diagnóstico e da doença câncer cervical e a problemática aplicação a outros cânceres das lições aprendidas com o exame de tumores cervicais.

Migrating techniques, multiplying diagnoses: the contribution of Argentina and Brazil to early 'detection policy' in cervical cancer / Técnicas que migram, diagnósticos que se multiplicam: a contribuição de Argentina e Brasil para a política de 'detecção precoce' do câncer cervical

This article on the early detection of cervical cancer focuses on the development of two leading diagnostic techniques - colposcopy and the Pap smear test - and their histories in Argentina and Brazil. It explores how diagnostic tools were transferred between Europe and the Americas, while examining the intersection of cultural and medical aspects and the processes of adaptation and resignification in the receiving countries. Colposcopy received little attention in the main Western medical centers until South American countries reasserted its significance in the 1950s. 'Peripheral' centers played a central role in early detection policies and the combined uses of these methods gave rise to a new stage of 'cumulative confidence' in cervical cancer diagnosis and screening.

Este artigo trata da detecção precoce do câncer cervical. Coloca em evidência as duas principais técnicas diagnósticas, a colposcopia e o teste de Papanicolau, e mostra suas trajetórias no Brasil e na Argentina. Analisa o modo como se deu a transferência de métodos diagnósticos entre a Europa e as Américas, procurando perceber a interseção de aspectos médicos e culturais e ainda os processos de adaptação e ressignificação nos países que acolheram as novas técnicas. A colposcopia recebeu pouca atenção nos principais centros médicos ocidentais até os países sul-americanos validarem sua importância nos anos 1950. Centros 'periféricos' desempenharam papel crucial nas políticas de detecção precoce, e o uso combinado desses métodos deu lugar a novo estádio de 'confiança cumulativa' no exame e diagnóstico do câncer cervical.