Editorial The Puzzle of Prostatic Carcinoma Carcinoma of the prostate is the most common malignant tumor in elderly men. Data from autopsy studies based on routine tissue sections indicate that the rate of occurrence of prostatic carcinoma increases sharply in persons older than 50 years of age. In the eighth decade of life, a mean of 34% of men (range, 20 to 52%) living in the Western hemisphere will harbor occult foci of this tumor. If histologic step sections are used, the rate of occurrence of occult cancer in persons of the same age group increases to a mean of 53% (range, 18 to 100%). 1 Thus, autopsy data strongly suggest that the clinically obvious cases represent only a fraction of all prostatic cancers. Nonetheless, cancer of the prostate as a clinical disease is the second most common cancer in American men, second only to lung cancer but with an exceedingly different behavior pattern, inasmuch as the course of the disease is often slow and the behavior of the tumor can be manipulated by hormonal therapy. 2 The issue is complicated further because of an apparent racial and geographic diversity associated with prostatic carcinoma. For example, the disease is more common and seems to behave more aggressively in American Blacks than in Whites. 3 Furthermore, overt prostatic carcinoma is rare in Japan, even though the rate of occult cancer in that country is similar to that in the United States. 3,4 Thus, the progression of occult carcinoma to overt clinical cancer is obviously not a simple cause-and-effect event. The reasons for these behavioral and biologic variables are totally obscure at this time. From the purely practical standpoint, cancer of the prostate poses two major diagnostic and therapeutic dilemmas. The first dilemma pertains Personal work cited in this editorial is supported by Grant CA1 34790 from the National Cancer Institute, National Institutes of Health. Address reprint requests to Dr. L. G. Koss, Department of Pathology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. Mayo Clin Proc 63:193-197,1988 193 to occult prostatic cancers that are disclosed as an incidental finding as a consequence of a transurethral resection or prostatectomy for benign disease or as a result of the increasingly used and effective thin-needle aspiration biopsy. 5 Whether to treat or not to treat patients with these lesions is the question. The second dilemma, which is at the other end of the diagnostic spectrum, is the problem of assessment of the effects of treatment and hence prognosis on clinically overt carcinomas, inasmuch as the behavior of these tumors is so capricious. The puzzle of occult prostatic carcinoma has been approached from many different points of view. Biochemical factors, such as elevation of the specific prostatic acid phosphatase and, more recently, specific prostatic antigen, have been proposed to identify men at risk for occult prostatic cancer or to follow the progression of the disease. 6-8 The question of what proportion of occult carcinomas, still confined to the prostate, will progress to metastatic disease has not been answered on prospective bases, in the absence of a long-term follow-up on a large group of patients, which is necessary for determining whether and to what extent the biochemical or microscopic abnormalities translate into clinical disease. The existing information is anecdotal. Thus, in a study of 117 patients with stage A prostatic cancer followed up without treatment, Cantrell and associates 9 reported progression of the disease in 32% of the patients. The progression was correlated to some extent with size and histologic grade of the tumor. Reciprocally, 68% of these patients apparently remained free of disease, a suggestion that most of the incidentally discovered prostatic carcinomas are not lifethreatening. Nevertheless, the urologist confronted with the dilemma and unable to predict the natural course of the disease will often choose to treat the patient, sometimes by orchiectomy with or without hormonal therapy and sometimes "for cure" by a prostatectomy. The results of treatment for stages A and B prostatic cancer in the absence of metastatic lesions seem to be excellent. 10-14 Hence, the iconoclastic question: Was the treatment necessary in the first place, and did it, in fact, contribute to the patient's survival and quality of life?
194 EDITORIAL Mayo Clin Proc, February 1988, Vol 63 The question is complicated by the fact that even patients with advanced stages of prostatic carcinoma who have no skeletal metastatic lesions may experience good survival. In some of these patients, the disease is arrested or perhaps even cured by surgical treatment, as reported by Winkler and associates in a study of patients with stage Dl prostatic carcinoma in this issue of the Proceedings (pages 103 to 112). Can the puzzle of occult prostatic carcinoma be solved? A common approach to the prognosis of patients with cancer has been histologic grading, pioneered by Broders at the Mayo Clinic in the 1920s. The application of this concept to the prostate, most notably the grading system suggested by Gleason and colleagues, 15 Utz and Farrow, 16 and Mostofi, 17 had as its purpose a correlation of histologic patterns with prognosis. Briefly, tumors that formed glands similar to normal prostatic glandular architecture were thought to be of low grade and hence associated with a better prognosis than tumors with growth patterns that showed various degrees of deviation from normal. Some problems with grading are that it often lacks reproducibility 18 and that the tumor patterns may vary from one histologic site to another, as noted by Gleason and coworkers, 15 who introduced a numerical grading system based on a combination of patterns. A grading of prostatic tumors into three groups based on Cytologie patterns in aspiration biopsy specimens was proposed by Esposti. 19 Usually, very well differentiated tumors have a protracted course, whereas poorly differentiated tumors, regardless of grading system, are associated with a poor prognosis and behave aggressively, the end result of which is rapid dissemination of the disease and death. For the bulk of prostatic carcinomas that have an intermediate grade of differentiation, the histologic or Cytologie grading sheds limited light on tumor behavior and thus on the potential for survival of the individual patient. The recognition that the prognostic value of histologic or Cytologie patterns of human cancer has severe limitations can be traced to the 1930s, when several German pathologists began to measure components of tumor cells in histologic sections in an attempt to extract objective useful data not immediately evident to the human eye. 20 These efforts were superseded by the developments in cytochemistry that led to measurement of specific cell components in Cytologie preparations, by using either ultraviolet light or the DNA-specific Feulgen stain, in a static laboratory procedure known as cytophotometry. 20 Further technical developments resulted in the construction of machines known as flow cytometers, which facilitate rapid measurement of DNA and other cell components in a large number of cells. 21 Fundamentally, flow cytometers are instruments that measure fluorescence; hence, the measurements must be based on the binding of the cell component to be measured (such as DNA in the cell nucleus) with an appropriate fluorescent dye for example, propidium iodide, as used by Winkler and associates in their current study. A method developed by Hedley and colleagues 22,23 allowed application of flow cytometry and cytophotometry to archival, paraffin-embedded tissue samples; thus, the scope of these measurements was extended substantially to include patients with a known clinical outcome. The concept that measuring DNA in human tumors may be of prognostic value was summarized in a recent editorial that addressed the issue of colonic cancer. 24 With the increasing availability of instrumentation, the search for objective prognostic measurements in patients with prostatic carcinoma continues. Prior studies, such as those by Auer and Zetterberg 25 who used cytophotometry on archival smears of prostatic aspirates and by Tribukait 26 who used flow cytometry of fresh cell and tissue samples, suggested that prostatic carcinomas with a dominant DNA content in the diploid range are associated with a better clinical outcome than are tumors with DNA values outside the normal range (that is, tetraploid and aneuploid). Furthermore, data presented by Tribukait 27 indicated that 80% of carcinomas still confined to the prostate were in the diploid range, whereas tumors that spread beyond the prostate were, for the most part, either aneuploidtetraploid or outright aneuploid. These data strongly suggested that DNA ploidy measurements may be of prognostic value. The current article by Winkler and co-workers, based on archival material, extends this concept still further namely, to stage Dl prostatic carcinomas treated surgically: those patients with tumors in the diploid range had a statistically significant better survival than patients with tumors that were either aneuploid-tetraploid or aneuploid. Somewhat similar although not quite
Mayo Clin Proc, February 1988, Vol 63 EDITORIAL 195 as optimistic information was reported by Stephenson and co-workers, 28 who measured DNA in metastatic lesions of prostatic cancer and who pointed out that patients with diploid-range tumors lived longer than patients with nondiploid tumors. Although retrospective studies have severe limitations for several technical reasons such as problems with preparation of samples and interpretation of histograms the broad canvas of this information is obviously encouraging and promises that measurement of DNA in prostatic cancer may be the flickering light in the prognostic darkness that ultimately may guide urologists in selecting optimal treatment for their patients. Unfortunately, stages C and D prostatic carcinomas with diploid-range DNA content are relatively few. Although Winkler and associates do not report what proportion of all advanced prostatic cancers seen at the Mayo Clinic had diploidrange histograms, experience from other sources suggests that only a relatively small group of patients have such cancers. Tribukait's data suggest that only 12% of T3 tumors (corresponding to stage C) and 2% of T4 tumors (corresponding to stage D) had DNA histograms in the diploid 26 27 range. ' Tribukait's data are in agreement with results of studies being conducted by my colleagues and me, which consist of a prospective and a retrospective arm. 29 In the prospective study, we attempt to measure DNA in fresh tissue and cell samples from carcinomas still confined to the prostate (stages A and B), whereas in the retrospective study (based on archival, paraffinembedded tissues and archival prostatic aspiration smears), the emphasis is on stages C and D prostatic carcinomas. Although the results are not final and the numbers of patients are still small (63 patients in the prospective study and 67 in the retrospective study), a trend seems to emerge that has not changed significantly with accrual of additional patients most prostatic carcinomas of stages A and B have a diploid DNA pattern (diploid:aneuploid ratio, 4:1), whereas most carcinomas of stages C and D are nondiploid (diploid:aneuploid ratio, 1:4). The correlation of ploidy patterns with histologic grading by Gleason's system was satisfactory only in poorly differentiated tumors (numerical values 5 to 9) that were, for the most part, aneuploid. In the prospective study, almost all patients who underwent prostatectomy for treatment of stage A or B carcinoma have had diploid-range tumors and excellent survival to date. What do these findings mean? Why do tumors in the diploid range behave differently from tumors that are not diploid? Do the immune defense mechanisms of the host recognize and hence provide better control of the proliferation of tumor cells that resemble normal than cells that have lost their identity? Could "diploid" tumors become aneuploid? The available evidence suggests that such an evolution usually does not occur. Could diploid tumors have a small, undetectable subpopulation of aneuploid tumor cells capable of overgrowing the diploid component and changing the behavior of the tumor? It has been shown that some tumors, such as some malignant lymphomas with an aggressive behavior pattern, may have a normal DNA content. In such tumors, substantial chromosomal abnormalities may occur in the form of balanced translocations, which may lead to activation of oncogenes. 30 The information on chromosomal makeup of prostatic carcinoma is scanty and does not shed light on this question. Nevertheless, an increased expression of ras oncogene p21 protein in prostatic cancer was recently correlated with the degree of tumor differentiation but unfortunately not with DNA content. 31 The changes in leukemias and lymphomas, however, may have little in common with carcinomas. The answers to these and many other questions about tumor behavior and host response to prostatic carcinoma are currently unknown. Because of the relatively scanty data available to date, a definitive conclusion in reference to the prognostic value of DNA measurements in prostatic cancer would be premature, but perhaps a hypothesis could be proposed based on our studies, Tribukait's data, and the current contribution by Winkler and co-workers. It seems reasonable to assume that most cancers still confined to the prostate are diploid; most of these tumors, possibly 80%, are unlikely to progress beyond the prostate during the lifetime of the patient. The relatively small proportion of early stage prostatic cancers that are nondiploid ab initio are likely to progress and spread beyond the prostate. Therefore, prostatic carcinomas in clinically advanced stages are generally nondiploid. Even in patients with clinically advanced stages of pros-
196 EDITORIAL Mayo Clin Proc, February 1988, Vol 63 tatic carcinoma, the minority with diploid-range tumors will have a considerably greater chance of either long-term survival or cure. This hypothesis is in agreement with the autopsy data cited at the onset, with the clinical data pertaining to the excellent results of treatment of stages A and B prostatic carcinomas, and with the data presented by Winkler and colleagues. Are we currently able to answer the hypothetical question raised before in reference to the need for treatment of stage A and possibly B prostatic carcinomas? Should the DNA content in these tumors be considered a dependable guide to the dilemma of whether to treat or not to treat the patient? Although it is entirely premature to offer definitive conclusions at this time, it may be safely stated that all tumors that are clearly not diploid must be treated. How to manage the diploid-range tumors is uncertain at this time because at least some of them will progress beyond the prostate. Distinguishing those diploid tumors that will progress from those that will not is an obvious task that lies ahead. In the interim, if an occult, incidentally discovered prostatic carcinoma has an unequivocal, clearly diploid DNA pattern, the decision "not to treat" may be somewhat easier to make under suitable clinical circumstances. Acknowledgment. I thank Dr. Selwyn Z. Freed, Chairman of the Department of Urology at Montefiore Medical Center, Albert Einstein College of Medicine, and his faculty for their participation in the project on prostatic carcinoma. Drs. Robert Wersto and Daniel Deitch assist with the prospective arm of this study. Dr. James B. Amberson, formerly an American Cancer Society Fellow at our institution and now in the Department of Pathology, Cornell University Medical School, is in charge of the retrospective arm of the study. 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