Monday, June 27, 1994

Pathology I - Premalignancy

ADVANCES IN THE DETECTION OF PRENEOPLASIA AND EARLY CARCINOMA: OPENING REMARKS TO MINI-SYMPOSIA Walter N. Hittelman, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

While modest advances in the treatment of lung cancer have occurred in recent years, disease- associated mortality remains a major problem. One strategy to decrease lung cancer mortality is to prevent the onset of the disease by either limiting carcinogenic exposure or through chemopreventive intervention. The development of interventive strategies requires a better understanding of the disease process. The clinical and pathological findings of multifocal lesions in a carcinogen-exposed tissue field suggest that lung tumorigenesis involves a field cancerization process (1). The findings of premalignant lesions in the field at risk as well as the presence synchronous and metachronous tumors suggest a multistep process whereby genetic changes accumulate in the tissue at risk and eventually culminate in malignant lesions (2). Studies presented in this mini-symposium as well as work from our own laboratory provide molecular and immunocytochemical evidence for these hypotheses. For example, premature chromosome condensation studies of histologically normal lung tissue obtained at the time of lung tumor resection demonstrate the presence of significant amounts of chromosome alterations. In some cases, specific alterations were detected that were held in common with the tumor. However the normal tissue also harbored random karyotypic changes which differed from those found in the tumor (3). These findings suggested that genetic changes are accumulating throughout the carcinogen-exposed tissue and tumors arise in those sites where specific genetic changes occur that allow preferential cell outgrowth and dysregulation of differentiation, cell loss, and invasive properties. The notion that genetic alterations are occurring throughout a field at risk is supported by our recent chromosome in situ analyses of endobronchial biopsies and brushings obtained from heavy smokers where both random and clonal genetic alterations could be detected. Immunocytochemical analysis of these same tissues with markers for proliferation (PCNA), growth regulation (EGFR, p53), differentiation, and cell loss indicate that the generalized genetic changes occurring in cells in the exposed field are accompanied by phenotypic changes. The findings of generalized changes occurring throughout the tissue at risk for lung cancer emphasize the need to develop quantitative markers of both generalized change as well as specific changes necessary for lung tumor development (4). Such markers would be extremely helpful as indicators of tumor risk in exposed individuals and might be used to select suitable subjects who would best benefit from chemopreventive intervention. In addition, many of these markers might be useful as intermediate markers of response to chemopreventive strategies. The speakers in this mini-symposium will describe recent advances in the identification of specific changes that occur in lung preneoplasia and tumors that can be useful for identifying high risk individuals who may benefit from preventive intervention as well as individuals with occult lesions that would benefit by early therapeutic intervention. References 1. Gluckman, J.O., Crissman, J.D., and Donegan, J.O. Multientric squamous-cell carcinoma of

the upper aerodigestive tract. Head Neck Surg. 4:90-96, 1980. 2. Farber, E. The multistep nature of cancer development. Cancer Res., 44:4217-4223, 1984. 3. Hittelman, W.N., Lee, J.S., Cheong, N., Shin, D., and Hong, W.K. The chromosome view

of “Field Cancerization” and multistep carcinogenesis. Implications for chemopreventive approaches in chemoimmunoprevention of cancer. (Eds. U. Pastorino and W.K. Hong) pp. 41-47, 1991.

4. Benner, S.E., Hong, W.K., Lippman, S.M., Lee, J.S., and Hittelman, W.N. Intermediate biomarkers in upper aerodigestive tract and lung chemoprevention trials. J. Cell Biochem., Suppl. 16G:33-38, 1992.

THE NC1 EARLY LUNG CANCER DETECTION PROGRAM

Dr. Myron R. Melamed, Professor & Chairman, Department of Pathology, New York Medical College/Westchester Medical Center, Valhalla, New York 10595

Anecdotal reports of roentgenologically occult, early lung cancer detected by sputum cytology(Rere published in the 1950's and 1960:s (see Melamed et al for references) raising hopes of earlier detection and better cure rates with what was then a new technique. The flexible bronchoscope introduced at that same time"', and bronchial brush cytology, made it possible to localize the source of exfoliated cancer cells. Thus, in 1971 a lung cancer detection program was undertaken by the National Cancer Institute to determine whether periodic sputum c@c$ogy examinations, supplementing the chest x-ray, couldr detect lung cancer at an earlier stage, increase resectability and improve the cure rate. Three institutions collaborated in the program: Johns Hopkins Medical Institutions (JH), the Mayo Clinic (MC) and Memorial Sloan-Kettering Cancer Center (MSK). In toto, approximately 30,000 asymptomatic cigarette-smoking men, considered at high risk, were entered into the program and followed with periodic examinations for up to 10 years. At JH and MSK, participants were randomly assigned to dual screen examinations (cytology and annual chest x-rays) or annual chest x-rays only. At MC all participants had initial dual screening and were then randomly allocated into continued dual screening or control (no screening) groups.

On initial examination'3' lung cancer was detected and confirmed in 223 men or about 7 per thousand. Of those who had dual screening, approximately 25% were detected by cytology alone, and 80% of these cancers were in Stage I; 40% of the cancers detected by x-ray were Stage I. During

~~~e~~q~$ ~~?n~~." of screening an additional 1072 men

. Interestingly, earlier detection by sputum cytology did not provide a survival advantage over x-ray detection. The cases detected by cytology proved to be selectively slow growing squamous carcinomas that were still resectable and curable when discovered at a later time by chest x-ray.

The chest x-ray was most effective in detecting small peripheral adenocarcinomas of lung, which are now the most common type of lung cancer. A ma&pematical model of the progression kinetics of this cancer , derived from the lung

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cancer program data, yields estimates of upwards from 4 years for'mean duration in early stage. However, the probability of detection during this period by a single, screening radiologic examination is less than 20%, and estimates of curability overall are less than 50%. While more sensitive (and specific) methods of detection may be required to justify the cost of a lung cancer screening program, but the importance of diagnosing lung cancer while still early and asymptomatic is beyond doubt. Patients with lung cancer detected by screening in this program, in all stages, had an estimated survival of 45% at seven years, and survival from Stage 1 lung cancer which constituted 40% of all cases was 65% to 75%. In contrast, patients with lung cancer found as a result of symptoms have an estimat@E 53% survival at seven years. Thus, though the chest z?-gay is not an efficient detection technique it is the most effective, least expensive technique presently available, and provides the best hope for long survival and cure of those who develop lung cancer.

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Melamed MR, Koss LG, Cliffton EE: Roentgenologically occult lung cancer diagnosed by cytology. Cancer l6, 1537-1551, 1963.

Ikeda S, Yanai H, Ishikawa S: Flexible bronchofiberscope. Keio J Med 17, 16-18, 1968.

Members of the Early Lung Cancer Co-operative study: Early Lung Cancer Detection. Summary and Conclusions. Am Rev Resp Dis 130, 565-570, 1984.

Melamed MR, Flehinger BJ: Early lung cancer as a potential target for chemoprevention. J Cell Biochem Supp 17F, 57-65, 1993.

Flehinger BJ, Kimmel M, Melamed MR: Natural History of adenocarcinoma-large cell carcinoma of the lung. Conclusions from screening programs in New York and Baltimore. JNCI, 80, 337-344, 1988.