A Note from History: The Link between Koilocytes and Human Papillomaviruses

Address correspondence to Steven I. Hajdu, M.D., 1759 Drumcliff Court, Westlake Village, CA 91361, USA; tel 805-496-0691; fax 805-496-0620 Condylomas (condylomata acuminata) and genital warts (verrucous papillomas) have been recognized as human diseases since ancient times [1]. The first microscopic illustration of the squamous cells of a verrucous lesion was published in 1845 [2]. In 1941, an innovative smear technique for vaginal cytology (later known as the “Pap Smear’) was introduced in New York City [3]. Within a few years, numerous cytologic observations were made on smear preparations by a new breed of physicians, ie, cytologists. In 1951, a Canadian gynecologistcytologist, J. Ernest Ayre, while working in Miami, Florida, first described and illustrated squamous epithelial cells with a perinuclear “halo” in smears of the uterine cervix [4]. He described the “halo cells” with perinuclear “clearing” as mononucleated or binucleated poorly keratinized squamous cells with hyperchromatic (atypical) nuclei. Ayre advanced the notion that the squamous cells with perinuclear halo or “vacuole” were “pre-cancer” cells and were always found in association with chronic inflammatory cells (Fig. 1). He believed that long-standing inflammation or infection (viral or some other kind) was involved in the occurrence of these odd looking squamous cells and that the perinuclear vacuoles represented degenerative changes [4]. Ayre’s observation attracted the attention of others and in 1956 Koss and Durfee [5], at the Memorial Sloan Kettering Cancer Center in New York City, named the squamous cells with enlarged nuclei and sharply demarcated perinuclear clear zone, surrounded by a rim of cytoplasm, “koilocytes” (from Greek, a hollow cell) [5]. The term koilocyte was promptly accepted as a descriptive name for the squamous cells with peculiar nuclear and cytoplasmic changes of unknown origin and uncertain significance. Although cytologists were occupied diagnosing koilocytes, atypical cells, and cancer cells, the cause of condylomas, squamous papillomas, and the source of the koilocytotic changes remained obscure for two decades. It was almost forgotten that in the Fig. 1. Atypical squamous cells (see arrows labelled 1, 2, and 4) with hyperchromatic nuclei and perinuclear vacuoles, which are so-called “halo” cells (later named koilocytes) in a cervical smear [1].