This WHO/ISUP system is an attempt to develop as broad a consensus as possible in the classification of urothelial neoplasms, building upon earlier works and classification systems. It is meant to serve as a springboard for future studies that will help refine this classification, thus enabling us to provide better correlation of these lesions with their biologic behavior using uniform terminology.

Background: Epidemiologic studies have suggested that vitamin E and ␤-carotene may each influence the development of prostate cancer. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a controlled trial, we studied the effect of ␣-tocopherol (a form of vitamin E) and ␤-carotene supplementation, separately or together, on prostate cancer in male smokers. Methods: A total of 29 133 male smokers aged 50-69 years from southwestern Finland were randomly assigned to receive ␣-tocopherol (50 mg), ␤-carotene (20 mg), both agents, or placebo daily for 5-8 years (median, 6.1 years). The supplementation effects were estimated by a proportional hazards model, and two-sided P values were calculated. Results: We found 246 new cases of and 62 deaths from prostate cancer during the follow-up period. A 32% decrease (95% confidence interval [CI] = −47% to −12%) in the incidence of prostate cancer was observed among the subjects receiving ␣-tocopherol (n = 14 564) compared with those not receiving it (n = 14 569). The reduction was evident in clinical prostate cancer but not in latent cancer. Mortality from prostate cancer was 41% lower (95% CI = −65% to −1%) among men receiving ␣-tocopherol. Among subjects receiving ␤-carotene (n = 14 560), prostate cancer incidence was 23% higher (95% CI = −4%-59%) and mortality was 15% higher (95% CI = −30%-89%) compared with those not receiving it (n = 14 573). Neither agent had any effect on the time interval between diagnosis and death. Conclusions: Long-term supplementation with ␣-tocopherol substantially reduced prostate cancer incidence and mortality in male smokers. Other controlled trials are required to confirm the findings. [J Natl Cancer Inst 1998;90:440-6]

No abstract

This article reports the historic background leading to the introduction of cervical smears as a tool in the detection of precancerous changes in the uterine cervix. The false-negative error rate in the primary screening process is discussed and illustrated by data recently compiled from this laboratory. Rescreening of approximately 25% of cervical smears yielded an error screening rate of approximately 5% of precancerous lesions and cancer of the uterine cervix. The total false-negative screening error rate was much higher but was unknown and should be determined by additional studies. The reasons for the false-negative screening errors are discussed. Some of the proposed remedies, particularly screening of the entire population for human papillomavirus infection, are judged to be unacceptable because of the high prevalence of this virus in well women and because the biologic events linking the presence of viral DNA with the development of precancerous lesions are unknown. Screening assistance with the help of a newly developed interactive machine, combining image analysis with a neural net was promising as a tool in quality control. tended by approximately 90 interested gynecologists and pathologists. I wish that I could say that this conference offered an unequivocal endorsement of the smear as a tool for cancer prevention, but this was not the case. In fact, the senior pathologists of the day attending the conference expressed significant reservations about the cytologic approach to the diagnosis of cancer. It is reliably reported that my former chief, the late Dr. Fred W. Stewart, then the head of Pathology at the Memorial Hospital for Cancer and Allied Diseases (the Sloan Kettering Institute was still in the planning stage at that time), declared that "a biopsy was better." With the passage of time, Stewart' changed his opinion about the value of the smear and, in his last article published in 1971, and characteristically entitled "Retirement in New York: Prognosis and Reminiscences of a Nonoptimist," he had this to say, "I suspect that in the field of service-to-the-patient pathology-if we leave out the great contribution of cytology toward early diagnosis (italics, L.G.K.)-about all the progress we have made involves the correction of old errors."Papanicolaou's sampling technique, initially developed to study the hormonal status of mice, was a vaginal pool smear, and this was the method originally used in clinical observations on ~o m e n .~,~ Microscopic examination of the vaginal smear was tedious, time consuming, and required the most careful screening of the material, searching for a few abnormal cells as evidence of cervical cancer or precancerous states. It was not surprising, therefore, that when the Canadian gynecologist and ardent follower of Papanicolaou, J. Ernest Ayre,' proposed that a wooden tongue depressor, cut to fit the contour of the uterine cervix, would allow a direct sampling of this organ under visual control the method was endorsed enthusiastically. The direct cervical smear was eas...

Much of the fascination of the study of exfoliative cytology of the uterine cervix results from the fact that one can observe cellular abnormalities that are not obvious on histologic examination of tissues. The insistence of cytologists on correlating morphologic cellular changes with tissue patterns has undoubtedly been a factor in directing the attention of pathologists toward low-grade alterations of cervix epithelium that were hitherto little known and either passed unnoticed or were labeled, without due consideration, chronic cervicitis, and thus thrown into the diagnostic waste basket of gynecologic pathology. The difficulty of correct classification of such tissue changes has been well known for years. It was frequently circumvented by the creation of special diagnostic classifications such as the famous "rubrics" of Hinselrnanne7 On many occasions, new names have been created for groups of lesions of unknown standing. Thus the terms anapla~ia,'~ atypical hyperplasia,'* dysplasia,+ precancerous metaplasia? restless epithelium,6 to name a few, were attached to poorly defined cervix lesions.Inevitably, over a period of years, we have encountered a number of cases difficult, if not impossible, to classify on histologic grounds..4s a result of long-term study, it appears that one and, possibly, a second tissue pattern of disorderly epithelium can be isolated among these lesions. The first one is characterized essentially by the presence in histologic sections of large cells with relatively small but irregular and hyperchromatic nuclei surrounded by clear and transparent cytoplasm. Thus, the nucleus seems to be suspended in an empty space. For descriptive purposes, we have coined the term koilocytotic atypia, from the Greek word "koilos," meaning hollow or cavity, to designate this lesion. Many of these lesions were recognized primarily in smears before their recognition in tissues. The term "warty dyskeratosis" was commonly used in the pathology laboratory when referring to this type of epithelial change.The second atypical pattern, which will be mentioned only briefly in the present paper, is not well defined and is characterized by the presence of abnormally elongated, spindly cells. Therefore, the term spiizdly atypia will be used to describe it. Review of the literature reveals that the koilocytotic atypia has been noticed and illustrated by others, without any attempt, however, to isolate it as a pathologic entity. Thus, Ayrel uses photographs of several of these lesions to illustrate his precancer cell complex. Wespi14 calls it irregular epithelium. Lapid and Goldbergerg call it atypical cervix lesion. Reagan et al.'? call it atypical hyperplasia or dysplasia of slight degree. Yon Haam4 calls it dys-1245

The PAPNET system is an automated interactive instrument for analysis of conventional (Papanicolaou) cervical smears. The instrument, described in this paper, introduces several important innovations to cytology automation. The cell selection system is composed of two stages: an algorithmic classifier, followed by a trained neural network allowing for great flexibility and precision in recognition of abnormal cell images. Contrary to other attempts at cytology automation, this machine does not attempt to diagnose cell abnormalities. Instead, it is interactive, leaving the assessment of the cells displayed on a high-resolution video screen to trained human observers. The slides judged to contain abnormal cells or to be inadequate are referred for a second microscopic review. Two versions of the instrument (Alpha and Beta) were evaluated in several modes. Initial testing was performed on archival smears with known, histologically confirmed neoplastic lesions of the uterine cervix. These lesions comprised the entire spectrum of abnormalities, from low-grade lesions to invasive cancers of several types. The Alpha machine displayed recognizable abnormal cells in 97% of the 201 cases, and the Beta machine displayed such cells in 97.2% of 176 cases. The Beta instrument was subsequently tested on 500 sequential archival cervical smears that had been previously subjected to a rigorous quality control. One hundred forty smears (28%), which either displayed atypical cells or were considered "inadequate," were referred for further rescreening. Fifteen of 16 previously diagnosed neoplastic smears were appropriately identified with the help of the machine. The one missed case contained a single cluster of vacuolated cancer cells from an endometrial carcinoma. As a result of PAPNET-triggered review, three new cases of low-grade squamous intraepithelial lesions view, three new cases of low-grade squamous intraepithelial lesions (SIL) came to light in previously negative smears; three additional cases, previously classified as atypical, were also reclassified as SIL, for a net gain of six neoplastic abnormalities. In two additional atypical cases, colposcopic follow-up was recommended, even though the diagnosis was not modified. Two cases of cervical intraepithelial neoplasia, represented by tiny single clusters of abnormal cells missed on original screening, quality control, and on machine rescreening, came to light on second review of the residual 360 cases. The initial experience with the PAPNET system suggests that the instrument may be valuable in quality control and may assist in significantly reducing false-negative cervical smears in an efficient and timely manner. Further testing of the instrument on a much larger number of cervical smears is in progress.

No abstract

Fourteen anaplastic, small cell cancers of minor salivary glands, histologically akin to oat cell carcinoma of the bronchus, were presented. Half of the patients had neck node metastases; four patients survived 5 years or longer. The possibility of minor salivary gland primaries must be kept in mind whenever small cell carcinomas are found in neck nodes. A speculative comment on the possible common cellular origin of these minor salivary gland tumors and oat cell carcinoma of the lung is offered.