Microscopic observations of normal and abnormal human cells, either exfoliated or in imprints or scrapes, were steadily and independently recorded throughout the nineteenth century.^2–5 By the first decade of the twentieth century, exfoliated cancer cells had been described in all of the types of specimens in which we look for them today.⁶ One fine example, published in 1861,⁷ 22 years before the birth of Papanicolaou, featured an exquisite drawing of cancer cells in pharyngeal secretion obtained postmortem from a man who died with a growth in this throat (Fig. 1.1). To any of us looking at this illustration today, almost 150 years later, it is obvious that the patient died from keratinising squamous cell carcinoma.

Fig. 1.1 Pharyngeal secretion obtained postmortem showing keratinising squamous cell carcinoma. This drawing appeared in the medical literature 22 years before the birth of Papanicolaou.

For the most part, however, these early reports were regarded as scientific curiosities, of little or no practical value. A widely prevailing attitude underlay this situation, well-expressed by Gloyne in 1919 speaking of cancer cells in pleural fluids: ‘Most pathologists are now agreed that it is practically impossible to identify these cells in film preparations’⁸ and by Bland-Sutton in 1922: ‘in the appearance of a cell from cancer there is nothing characteristic of the disease, nothing that would lead a pathologist to identify it as a malignant cell’.⁹ However, at much the same time Professor LS Dudgeon proved these statements to be incorrect and began to use cytology at St Thomas’ Hospital for the diagnosis of a wide variety of neoplastic and inflammatory diseases from imprints of surgical specimens.¹⁰ According to a later article by John Bamforth of the same hospital, in which some of the original plates are reproduced, Dudgeon considered ‘that the stained films were much nicer to examine than paraffin sections’.¹¹ Many modern-day cytopathologists would agree and Dudgeon’s beautiful illustrations demonstrate the importance of good fixation and cell preparation. He died at the outbreak of the Second World War and his prediction that 20 years or more would elapse before the cytological method would be generally accepted was sadly only too true, at least in the UK. At much the same time in the USA, FNA cytology was being developed and the first series on aspiration of neoplasms was published from Memorial Hospital for Cancer and Allied Diseases in New York City.^12–14 Yet this experience was not taken forward at the time and one wonders if the method of cell preparation, which involved heating, alcohol fixation, dehydration and clearing to mimic histological sections could have rendered the cytomorphology less than satisfactory. Nevertheless, two important principles had been established: that needle aspiration could safely be carried out in living patients and that ‘diagnosis by aspiration is as reliable as the combined intelligence of the clinician and pathologist’¹⁴– an early example of a multidisciplinary team. Another half century had to pass before aspiration cytology became firmly established in the USA, perhaps as a testament to the importance of cell preparation.

A second era of cytopathology began in 1941 with the publication of an article on the diagnostic value of vaginal smears in carcinoma of the uterus by George N. Papanicolaou, an anatomist, and Herbert F. Traut, a gynaecologist.¹⁵ This article was followed in 1943 by their monograph Diagnosis of Uterine Cancer by the Vaginal Smear,¹⁶ with its superbly executed water-colour drawings of exfoliated cells and tissues. Gynaecologists, especially in the USA, were quick to grasp the significance of these two publications, which were succeeded over the next two decades by many more publications by Papanicolaou and his colleagues dealing with the cytological diagnosis of cancer in a variety of other organs. Although cancer cells in vaginal smears had been recognised and briefly described and illustrated in publications of the nineteenth century,^4,5 Papanicolaou’s contribution to this field was two-fold: he recognised the importance of wet fixation of cytological specimens and he systematically began to accumulate examples of cancer cells in vaginal smears, culminating in his paper New Cancer Diagnosis.¹⁷ Papanicoloau’s original research was on the oestrous cycle of mammals, using cellular samples from the vaginas of guinea pigs. Later, he extended this work to humans and, inevitably, received vaginal smears from women with cervical cancer and discovered by chance that he was able to recognise cancer cells in these smears. At virtually the same time, Aurel A. Babes (1885–1961), a distinguished academic pathologist in Romania, published a major article¹⁸ on the same subject, preceded by presentations at the Bucharest Gynaecology Society,^19,20 in which he accurately described the appearance of cells of squamous cell carcinoma in scrapings of the uterine cervix. However, these presentations made virtually no impact on the cytological scene. Babes’ technique of preparing, staining and examining vaginal smears was substantially different from Papanicolaou’s and would never have lent itself to mass screening for cervical cancer without modification.

The publications of Papanicolaou and Traut in 1941 and 1943 heralded the second era of cytopathology and the advent of screening for cervical cancer. The breakthrough was that ‘malignant cells’ could be observed in scrapings from a cervix that was entirely normal to the naked eye, taken from a healthy asymptomatic woman. The idea of pre-cancerous cell change was conceived. Concurrently with the development of cervical screening, the cytological method of cancer diagnosis began to be more widely applied to the respiratory, alimentary and urinary tracts as well as to the serous cavities and the central nervous system. In 1954, Papanicolaou published his magnum opus, the comprehensive Atlas of Exfoliative Cytology (Fig. 1.2).²¹ This emphasis on the development of cytology by Papanicolaou and his colleagues should not detract from many carefully executed earlier or contemporary studies of the cytology of other organs, reviewed in the publications of Grunze and Spriggs.^3,4 But unquestionably, the impetus of the development of cytopathology as we know it today resulted from the painstaking research of Papanicolaou in the USA. The journey of Papanicolaou, justly referred to as the father of cytopathology, from his birthplace in Kymi on the Aegean island of Evia to his position in the Department of Anatomy at Cornell University is documented by many cytopathologists, including Naylor and Koss.^1,22

Fig. 1.2

Reprinted by permission of the publisher from Atlas of Exfoliative Cytology by George N. Papanicolaou, Figure AIV, Cambridge, Mass: Harvard University Press, Copyright © 1954, 1956, 1960 by the Commonwealth Fund. Copyright © renewed 1982 by Mari Diane Murayama.

From the earliest days of cytology, there was scepticism among pathologists about the validity of the diagnosis of cancer by cytology alone. It almost smacked of fraud that cancer, whose unique attribute was its ability to invade tissue and metastasise, could be diagnosed by examining cells that had dropped off from an epithelial surface. Nevertheless, during the decades that followed the pioneering work of Papanicolaou, the widespread development both of population-based cervical screening and the cytological diagnosis of tumours resulted in the development of cytopathology as an established discipline.

The era of consolidation¹ was heralded by two publications: the first issue of Acta Cytologica in 1957, the oldest journal devoted exclusively to cytopathology; and in 1961, by the publication of Diagnostic Cytology and its Histopathologic Bases by Leopold G. Koss in association with Grace R. Durfee.²³ This book (Fig. 1.3), now in its fifth edition (2005), brought together under one cover not only a body of theoretical and practical knowledge of cytopathology but also the correlation between cytology and histopathology, the essential basis for all pathologists who have an interest in cytopathology. As might be expected, the last 60 years have seen an explosion in the literature of cytopathology, with thousands of articles and scores of books written on the subject. In the English language alone, there are now four journals devoted exclusively to cytopathology: Acta Cytologica, Diagnostic Cytopathology, Cytopathology and Cancer Cytopathology, begun in 1957, 1985, 1990 and 1997, respectively. Societies promoting cytology were founded locally, nationally and internationally. The forerunner of these was the Inter-Society Cytology Council, founded in 1951 and later known as the American Society of Cytopathology. Many other societies developed over the next few decades, for example the International Academy of Gynecologic Cytology (1957), later known as International Academy of Cytology, the British Society for Clinical Cytology (1961), the Australian Society of Cytopathology (1969), and the European Federation of Cytology Societies (1969). These societies now have major roles in maintaining high standards in cytopathology by their educational activities, their contribution to the certification of pathologists and technologists in cytopathology, their influence in research and their contribution to legislation that affects the practice of cytopathology.

Fig. 1.3 An important landmark in cytopathology: the first edition of Diagnostic Cytology and its Histopathologic Bases, published in 1961.

(With kind permission from Koss Leopold G. Diagnostic Cytology and its Histopathologic Bases, Lippincott, Williams & Wilkins, 1961.)

Until the effectiveness of cervical screening had been established in the mid-1980s, the main criticisms faced by cytopathologists had related to whether or not screening was necessary; whether it worked and whether it was ethical to treat lesions before they became invasive. There was a sudden change of emphasis in the mid–late 1980s when incidents in several different countries drew the attention of the media, public and lawyers to the consequences of cytological abnormalities being missed. In the UK, a damning editorial in the Lancet about the inefficiencies of the so-called national screening programme was the first indication that it was simply not working;⁴⁶ and was not controlling an increased risk of disease in young women.⁴⁷ At much the same time, a national enquiry in New Zealand followed publication of the outcome of a group of women with carcinoma in situ who had not received adequate treatment.⁴⁸ In 1987, the Wall Street Journal published an exposé about cancers being missed through the excessive demands made on their cytology technicians by certain for-profit commercial laboratories.⁴⁹ This article raised a huge outcry in the news media in the USA, resulting in stringent federal rules regulating the laboratory practice of gynaecological cytology and the imposition of proficiency testing. In the UK, a successful centrally organised NHS Cervical Screening Programme was launched in 1988, which resulted in a dramatic fall in incidence and mortality in all age groups screened (Fig. 1.4). Screening is thought to have prevented an epidemic of cervical cancer in recent generations at greater risk of disease.⁵⁰ The events of the 1980s should, however, serve as a warning to implement quality-assurance practices and not to demand excessive output from cytotechnologists, biomedical scientists and cytology screeners. Quality assurance practices are now documented in the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening.⁵¹

Fig. 1.4 Incidence of invasive carcinoma of the uterine cervix before, during and after the introduction of organised screening in the United Kingdom.

(Source: National statistics website: www.statistics.gov.ukStatBase/Product.asp?vlnk = 7720. Crown copyright material is reproduced with the permission of the Controller Office of Public Sector Information (OPSI))

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