Hyperplastic, Premalignant and Malignant Lesions of the Prostate Gland

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1 Jehoram Tei Anim, md, FRCPath; Sitara Abdul Sathar, MB; Mohammed Ejaz Bhatti, MSc From the Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait. Address reprint requests and correspondence to Dr. Anim: Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat, Kuwait. Accepted for publication 12 April Received 15 November JT Anim, SA Sathar, M E Bhatti, Hyperplastic, Premalignant and Malignant Lesions of the Prostate Gland. 1999; 19(4): Some authors have pointed out certain similarities between benign prostatic hyperplasia (BPH) and prostatic cancer. 1 Moreover, most prostatic cancers arise within prostates showing BPH. Atypical adenomatous hyperplasia (AAH) and prostatic intraepithelial neoplasia (PIN) are now thought to be premalignant lesions, 2-4 the latter more so than the former. 5,6 Thus, while morphological studies have suggested strong association between high-grade PIN and prostatic carcinoma, 6,7 no such association has been found with low-grade PIN. 8 Similarly, the association between AAH and prostate carcinoma has been found to be weak, at best. 5,9 Application of modern technology to the study of prostatic diseases has yielded much valuable information. Among recently employed techniques are studies on DNA ploidy, 6,10 and the application of cell kinetics to study PIN and AAH, 5 quantitative methods such as machine vision system techniques for the study of premalignant and malignant lesions of the prostate, 11,12 and immunohistochemical demonstration of oncoproteins such as p53 protein. 13 Harvey 14 has recently advanced a hypothesis linking BPH with prostatic carcinoma through the intermediary of PIN. His views may not be shared by all, but it is worth pursuing the subject and taking a closer look at all the epithelial hyperplastic lesions that are commonly observed in BPH, in order to determine if there are significant associations either between any of them and the premalignant lesions, or between the premalignant lesions themselves and carcinoma. We have studied all prostatic specimens submitted over a seven-year period to the Mubarak Al-Kabeer Teaching Hospital, Kuwait, in an attempt to assess any relationships among benign, premalignant and malignant lesions. Materials and Methods All prostatic specimens submitted to the Department of Pathology of Mubarak Al-Kabeer Teaching Hospital, Kuwait, over the seven-year period from January 1988 to December 1994, were reviewed. Suprapubic and transurethral resection (TUR) specimens were included in the study. There were only three of the former, and for practical purposes, the material was considered as made up entirely of TUR specimens. Needle biopsy specimens were considered unrepresentative for the purposes of the study and were excluded. Hematoxylin and eosin-stained slides of paraffin sections were examined independently by two pathologists and a consensus arrived at where there was a difference of opinion. Where necessary, extra sections were cut for further study. A total of 606 specimens were examined over the seven-year period, and an average of six sections (3-20) were reviewed per case. The specimens were separated histologically into BPH and carcinoma. The parameters looked for in the benign group included basal cell hyperplasia (Figure 1), papillary hyperplasia (Figure 2), cribriform hyperplasia (Figure 3), atypical adenomatous hyperplasia (Figure 4), and prostatic intraepithelial hyperplasia (Figure 5). These entities have been defined by various authors. 3,5,8,9

2 Table 1. Relationship between prostatic intraepithelial neoplasia (PIN) and cribriform hyperplasia, papillary hyperplasia and basal cell hyperplasia. Cribriform hyperplasia Papillary hyperplasia Basal cell (%) * (%) * hyperplasia (%) ** PIN grades Absent Present Absent Present Absent Present (94) 22 (6) 276 (74) 96 (24) 199 (54) 173 (46) 1 98 (81) 23 (19) 83 (69) 38 (31) 38 (31) 83 (69) 2 43 (74) 15 (26) 32 (55) 26 (45) 25 (43) 33 (57) 3 8 (50) 8 (50) 6 (38) 10 (62) 4 (25) 12 (75) Total 499 (88) 68 (12) 397 (70) 170 (30) 266 (47) 301 (53) * P<0.001; ** P< Table 2. Relationship between carcinoma of the prostate and atypical adenomatous hyperplasia (AAH) and prostatic intraepithelial neoplasia (PIN) in 606 specimens. AAH (%) * PIN (%) ** Carcinoma Present Absent Absent Grade 1 Grade (82) 105 (18) 372 (66) 121 (22) 74 (13) 28 (72) 11 (28) 8 (21) 21 (54) 10 (26) Total 490 (81) 116 (19) 380 (63) 142 (23) 84 (14) * P<0.2; ** P< Figure 1. Photomicrograph of prostate glands showing grade 2 basal cell hyperplasia (arrows) (H&E, 250x). Parameters examined in the carcinoma group included type of carcinoma, modified Gleason's grade, estimation of percentage of tissue involved by carcinoma and the presence of PIN and AAH. The SPSS program (version 6.1) was used in the statistical analysis of the data. Pearson's test was used to assess correlation between the observed parameters. Results Of the 606 specimens reviewed, 39 (6.4%) were carcinoma and 567 (93.6%) were BPH. Ages ranged between 33 and 98 years (mean 63 years) for BPH and between 45 and 84 years (mean 67 years) for carcinoma. Table 1 summarizes the occurrence of the various proliferative lesions in 567 cases of BPH. Using Pearson's chi-square test to determine relationships between the various proliferative lesions and the putative premalignant lesions, AAH showed significant association with only cribriform hyperplasia (P<0.005). On the other hand, there was significant association between grades 2 and 3 PIN and all three hyperplastic lesions (basal cell hyperplasia, P<0.001; papillary hyperplasia, P<0.001; cribriform hyperplasia, P<0.002).

3 AAH was observed in 11 carcinomas, but there was no significant association between the two parameters (P<0.2). However, PIN was observed in 31 of the 39 carcinomas, of which 10 were grades 2 and 3 (Table 2), and there was strong association between carcinoma and high-grade PIN (P<0.0001). No useful information could be obtained from the other parameters (age, grade, etc.) observed in the carcinoma group, on account of the small numbers. Discussion The results of this study show that whereas there is an association between only cribriform hyperplasia and AAH, the latter itself shows no significant association with carcinoma. Many workers have examined the malignant potential of AAH in prostatic specimens, and opinions at this point remain divided. 5,9 The majority accept the view that even if it exists, the malignant potential of AAH is small. 1,16 Figure 2. Photomicrograph of dilated prostatic glands showing papillary hyperplasia of glandular epithelium (H&E, 250x). Figure 3. Photomicrograph of prostatic glands showing cribriform hyperplasia (H&E, 250x). The incidence of PIN in prostatic malignancy, as quoted in the literature, varies from 33% to 100%, depending on the author In our study, we demonstrated PIN in 79% of the carcinomas. There was a statistically significant correlation between PIN and all three epithelial hyperplastic lesions observed in our BPH cases. Moreover, there is a strong association between high-grade PIN and carcinoma, as already established by other workers. The statistical results in our study need to be interpreted with caution because of the small number of carcinomas. We suggest, however, that the stimuli which provoke the different forms of epithelial hyperplasia are also responsible for the changes that are commonly observed in PIN. The same or different stimuli then act on PIN, causing the progressive

4 changes that ultimately lead to frank carcinoma. In this connection, Harvey 14 has proposed a unifying hypothesis that links benign prostatic hyperplasia and PIN with prostate cancer. He points out that new growth in the adult prostate is abnormal because epithelial cells tend to grow into ducts. This pattern of growth may be responsible for papillary and cribriform types of hyperplasia commonly demonstrated in BPH, as evident in this study. He further suggests that such epithelial proliferations are inaccessible to growth inhibitory signals and, therefore, continue to grow, resulting in AAH. This may explain the positive association between AAH and cribriform hyperplasia in this study. In Harvey's scheme, AAH is followed by blockage of ducts, formation of cysts and, ultimately, PIN and carcinoma. Figure 4. Photomicrograph of prostate showing crowded microglandular proliferation, typical of AAH (H&E, 100x). Figure 5. Photomicrograph of prostatic glands showing grade 3 PIN. Note large nuclei with large prominent nucleoli (H&E, 250x). In an earlier study, we found an association between basal cell hyperplasia and glandular necrosis, and suggested that basal cell hyperplasia is an early response in the partially destroyed gland. We believe that the initial stimulus that may be responsible for the series of events outlined above is the stimulus for glandular repair following necrosis, which starts with proliferation of basal cells followed by the other types of epithelial hyperplasia. Whether the hypothesis of Harvey is accepted or not, there is a significant association between the various hyperplastic lesions and PIN, as shown in this study. It is now well established that high-grade PIN is a premalignant lesion, and since the hyperplastic lesions form part of BPH, it is not surprising that most cancers (83.3%) arise in prostates with concomitant BPH. 1 The difficulty in establishing AAH as a premalignant lesion is perhaps because it occurs earlier in the sequence of events proposed by Harvey. 14 Recent application of molecular techniques to study relationships among these lesions may provide better evidence for the progression from one lesion to another, and may also help to resolve, once and for all, the role of

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