Begin Disorders of the Prostate: A Histopathological Study
1998; King Faisal Specialist Hospital and Research Centre; Volume: 18; Issue: 1 Linguagem: Inglês
10.5144/0256-4947.1998.22
ISSN0975-4466
AutoresJ.T. Anim, Bader Ebrahim, Sitara A. Sathar,
Tópico(s)Genital Health and Disease
ResumoOriginal ArticlesBegin Disorders of the Prostate: A Histopathological Study J.T. Anim, MD, FRCPath B.H. Ebrahim, and MB S. Abdul SatharMB J.T. Anim Address reprint requests and correspondence to Dr. Anim: Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. From the Department of Pathology, Faculty of Medicine, Kuwait University Safat, Kuwait. Search for more papers by this author , B.H. Ebrahim From the Department of Pathology, Faculty of Medicine, Kuwait University Safat, Kuwait. Search for more papers by this author , and S. Abdul Sathar From the Department of Pathology, Faculty of Medicine, Kuwait University Safat, Kuwait. Search for more papers by this author Published Online:1 Jan 1998https://doi.org/10.5144/0256-4947.1998.22SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractAlthough the medical literature contains adequate accounts of the pathophysiology of various benign prostatic disorders, it is often necessary to revisit these lesions, to reexamine the relationships between known benign lesions and more sinister, malignant disorders, in the light of new advances in our understanding of the processes. We carried out a histopathological review of prostatic surgical pathology material seen over a seven-year period in our hospital. Our findings show that benign enlargement of the prostate or benign prostatic hyperplasia (BPH) is initially fibromuscular in many cases, becoming glandulostromal with advancing age. While we found no relationship between prostatitis and age, individual gland necrosis tended to occur relatively early and correlated well with stromal repair, which we believe forms the basis of fibromuscular hyperplasia. Epithelial hyperplasia may result from glandular regeneration, and basal cell hyperplasia, papillary hyperplasia and cribriform hyperplasia all showed significant correlation with prostatic intraepithelial neoplasia (PIN). On the other hand, only cribriform hyperplasia showed correlation with atypical adenomatous hyperplasia (AAH), and also demonstrated an increase in incidence with advancing age. Our findings underline the positive relationships between benign events such as glandular necrosis with repair and epithelial hyperplasia, which may itself predispose to recognized premalignant lesions such as PIN.IntroductionWithin the past decade or so, there has been a sudden increase of interest in diseases of the prostate. This is largely due to the recently perceived high incidence of prostatic carcinoma in different geographical and ethnic groupings.1–3 Attention has naturally focused on malignant, as well as premalignant, lesions of the prostate.4–8 Recently, these premalignant lesions have become better defined, largely as a result of advances in technology. Therefore, in the light of growing knowledge about prostatic lesions, it is necessary to periodically review known benign lesions in order to re-assess any relationships or impact they may have on malignant or premalignant prostatic disease. We have thus reviewed all prostatic specimens diagnosed as benign prostatic hyperplasia (BPH) in the Pathology Department of Mubarak Al-Kabeer Teaching Hospital, Kuwait, over a seven-year period, in an attempt to analyze the significance of various histopathological changes in the prostate and to determine any correlation among these changes.MATERIALS AND METHODSProstatic specimens received in the Pathology Department of Mubarak Al-Kabeer Teaching Hospital, Kuwait, during the seven-year period from January 1988 through December 1994 were included in the study. These were transurethral resections (TUR), as well as suprapubic prostatectomy specimens diagnosed as benign prostatic hyperplasia (BPH). Needle biopsy specimens were excluded from the study because they were considered unrepresentative. Sections stained with hematoxylin and eosin were reviewed independently by two histopathologists and a consensus arrived at where there was a difference of opinion. Where necessary, extra sections were cut for further study. The following parameters were specifically examined:Histological pattern of prostatic enlargement (BPH): This was categorized as “glandulostromal” where there was excess glandular proliferation over stromal, or where proliferating glands and fibromuscular stroma were qualitatively assessed to be in roughly equal proportions. Where the sections showed more stromal elements than glands or were made up almost entirely or entirely of stromal elements, this was designated as “stromal.”Prostatitis: Inflammatory changes within the prostate gland (excluding prostatic urethral mucosa) were separated into acute and chronic and graded individually as follows: Chronic: grade 1 (mild): scattered foci of largely mononuclear infiltrate; grade 2 (moderate): several foci of mononuclear infiltrate or light diffuse infiltrate with or without a few lymphoid aggregates; grade 3 (severe): heavy, diffuse mononuclear infiltrate, usually with lymphoid aggregates. Acute: grade 1 (mild): neutrophils within a few glands; grade 2 (moderate): neutrophils within many glands; grade 3 (severe): neutrophils within glands and stroma.Necrotic glands: The presence or absence of individually necrotic glands as well as confluent necrotic glands was noted. These glands were almost invariably surrounded or replaced by a localized inflammatory infiltrate.Stromal reparative changes: Reparative changes within the prostate gland were documented. These were commonly found around necrotic glands or areas of infarction.Types of epithelial hyperplasia: Various hyperplastic lesions were examined and some graded. The presence of cribriform hyperplasia was recorded while basal cell hyperplasia and papillary hyperplasia were graded into: grade 1: changes affecting a tew glands; grade 2: changes affecting glands in multiple foci, and grade 3: changes affecting glands in a diffuse pattern.Atypical adenomatous hyperplasia (AAH): The presence of atypical hyperplasia was defined using the criteria of Epstein.9 Briefly, it is a nodular focus of proliferating, newly formed acini or alveoli about a duct branch. It consists of a proliferation of small acini within a duct-acinar unit. The cells are cuboidal to columnar secretory epithelial cells, often with clear cytoplasm and little or no nuclear pleomorphism.Prostatic intraepithelial neoplasia (PIN): This was defined according to the criteria of McNeal and Bostwick10 and Jones and Young,5 into the conventionally accepted three grades (1 to 3).Miscellaneous: The presence of other lesions was also recorded. These included sclerosing adenosis, recent infarcts and squamous metaplasia.Simple statistical methods such as chi-square were used to determine significance between various observed parameters. A P-value of <0.05 was accepted as significant.RESULTSA total of 567 BPH cases were reviewed. The number of slides reviewed in each case ranged between 1 and 24, with an average of six slides per case. Apart from three suprapubic prostatectomies, all were transurethral resection specimens. The ages for 537 of the cases ranged between 33 and 98 years (mean = 63). Information on the ethnicity of the subjects was available for 285 cases, of which Kuwaitis accounted for 51.9%. Other non-Kuwaiti Arabs constituted 39.6% and the remaining were made up of a mixture of Caucasians, Asians and Africans.A glandulostromal pattern of prostatic hyperplasia was the most frequent histological pattern which occurred, and this also showed a progressive increase with age (Figure 1). A stromal pattern of hyperplasia was less common, but the proportions appeared slightly higher in the younger age groups.Figure 1. Age group distribution of histological patterns of BPH. Comparison of glandulostromal and stromal patterns.Download FigureChronic prostatitis was observed in 539 (95.1%) of all the biopsies reviewed. While the majority (401) showed only mild chronic prostatitis, only 19 showed severe (grade 3) chronic prostatitis, often accompanying healing infarctions. Most foci of chronic prostatitis were within the vicinity of individually necrotic glands, or glands in a state of repair following necrosis. Acute prostatitis was present in 282 (49.7%), while in 279 (49.2%) both acute and chronic prostatitis coexisted. Severe acute inflammation was only associated with recent glandular necrosis or a recent infarct. There was no significant variation in the occurrence of acute or chronic prostatitis with age.Scattered necrotic glands were present in 295 (52%) cases. In these glands, the epithelium was in varying stages of necrosis, some showing reparative changes, with or without squamous metaplasia. Periglandular lymphoid aggregation was a frequent finding in these necrotic glands, ranging in intensity from scattered lymphocytes to well-formed lymphoid follicles, some with what appeared to be well-formed germinal centers. In a few cases the necrotic glands were confluent. Recent necrosis was accompanied by acute inflammatory changes, while old necrotic glands showed periglandular fibrosis in addition to lymphoid infiltration. Some necrotic glands were intimately associated with the presence of corpora amylaceae and in some cases, “naked” corpora amylaceae were found in areas where glandular epithelium had disappeared and the area contained a heavy infiltrate of lymphoid cells. This raises the likelihood that glandular necrosis may be related to obstruction by concreted secretory material within the gland. Figure 2 illustrates the incidence of glandular necrosis in various age groups and shows a higher occurrence in the lower age groups, with a peak in the 51-60-year age group, followed by progressive decrease with age.Figure 2. Comparison of necrosis and stromal repair in different age groups.Download FigureStromal reparative changes ranged from granulation tissue formation shortly following an infarct or confluent glandular necrosis, through active proliferation of myofibroblasts, to formation of young fibromuscular nodules, some with prominent storiform areas resembling fibrohistiocytic lesions. The peak incidence of these nodules was in the 61-70-year age group, a decade older than that for glandular necrosis, but they showed less decline in incidence in the older age groups compared to necrosis (Figure 2). In the younger age groups (<50 years), the nodules tended to be less cellular and contained more connective tissue mucin. These were more commonly located within the zone surrounding the periurethral tissues, i.e., inner zone. There was significant correlation (Table 1) between glandular necrosis and the presence of stromal reparative changes in 241 BPH cases reviewed for 1988 and 1989 (P<0.005), but no significant relationship was found between stromal repair and the presence of recent infarcts.Table 1. Correlation between glandular necrosis and stromal repair in 241 cases of BPH.The frequencies of basal cell hyperplasia, papillary hyperplasia and cribriform hyperplasia were 301 (53.1%), 170 (30%) and 68 (12%), respectively. While cribriform hyperplasia showed increase in incidence with age, both basal cell hyperplasia and papillary hyperplasia showed no such trend (Figure 3). Among themselves, significant correlation was only found between cribriform hyperplasia and papillary hyperplasia (P<0.01), both of which involve proliferation of the secretory epithelium (Table 2). There was also significant correlation between basal cell hyperplasia and glandular necrosis (P<0.05). AAH was observed in 105 (18.5%) cases and showed a statistically significant increase in incidence with advancing age (Figure 4). There was also positive correlation (Table 3) between AAH and cribriform hyperplasia (P<0.005), but not with the other observed forms of hyperplasia.Figure 3. Comparison of basal cell, papillary and cribriform types of hyperplasia within BPH in different age groups.Download FigureFigure 4. Distribution of AAH, low-grade and high-grade PIN in different age groups.Download FigureTable 2. Correlation between papillary and cribriform hyperplasia of prostatic glands in 567 cases of BPH.Table 3. Correlation between atypical adenomatous hyperplasia (AAH) and cribriform hyperplasia.PIN was present in 195 (34.3%) cases. These were graded into the three conventionally accepted grades. However, as most workers now regard PIN-1 as of little prognostic significance with respect to malignant potential,9,10 the incidence of significant PIN in this study may be taken as that represented by PIN-2 and PIN-3, i.e., 74 (13%). PIN showed statistically significant correlation with all three observed forms of hyperplasia in this study (Table 4). There was also an increase in the incidence of high-grade PIN (2 and 3) with advancing age, as illustrated in Figure 4.Table 4. Correlation between prostatic intraepithelial neoplasia (PIN) and cribriform hyperplasia, papillary hyperplasia and basal cell hyperplasia.Recent infarcts were recorded in 76 cases, and squamous metaplasia in 168 cases (Table 5). There was a statistically significant association between the two lesions (P<0.001).Table 5. Correlation between infarcts and squamous metaplasia.DISCUSSIONThis study shows interesting associations and relationships among various observed parameters in BPH that bear reiteration. Thus, the onset of prostatic enlargement appears to be marked more by stromal hyperplasia than glandular, the latter predominating in later years (Figure 1). In addition, there is a significant relationship between glandular necrosis and stromal reparative changes, which in turn may be the beginnings of fibromuscular stromal hyperplasia. There is also evidence from this study to show that necrosis of glands provokes inflammatory response and stromal repair. The process of repair involves stimulation of proliferation of myofibroblasts, which ultimately may mature into the fibromuscular stromal tissue. The response is presumably mediated by cytokines released by the inflammatory cells that respond to glandular necrosis,11 and perhaps especially the lymphoid cells that collect around the damaged glands (Figures 2 and 3). This type of fibromuscular stromal repair is more liable to occur in the inner zone where glands tend to be fewer. The excess stromal proliferation over glandular in younger subjects in this study is confirmed in Figure 1.Necrosis itself may follow obstruction by inspissated secretory material within the glands, as shown by the presence of corpora amylaceae within many necrotic glands. Complete destruction of the gland is accompanied by intense inflammatory response, which has been called “microabscess” by some authors.12 We have, however, found that the cellular response is more mononuclear than polymorphonuclear, with excess macrophages in the early stages, later replaced by a cuff of lymphoid cells around the destroyed glands. The periglandular lymphoid aggregation, sometimes with the presence of germinal centers, may be due to response to material released from the damaged gland into the stroma, and the resulting inflammatory response further causes release of more cytokines.13,14There is a significant correlation between the presence of infarcts and squamous metaplasia (P<0.001), but there is no such correlation with individual gland necrosis. The glands showing squamous metaplasia are partially necrotic or injured glands commonly found at the edges of the infarcts and stimulation of squamous metaplasia may be due to the nature of the injury. Squamous metaplasia is less commonly associated with partial necrosis of individual glands, which more commonly show basal cell hyperplasia followed by regeneration of the glandular epithelium.15 Basal cell hyperplasia is the most common observed epithelial hyperplasia, followed by papillary and cribriform hyperplasia. Of the three, basal cell hyperplasia shows positive correlation with glandular necrosis (P<0.05). There is no direct correlation between glandular necrosis and papillary hyperplasia or cribriform hyperplasia, presumably because they are preceded by basal cell hyperplasia which, as noted earlier, is a response to glandular necrosis.15 The epithelial changes found in BPH have been described by several workers.16,17Cribriform hyperplasia shows an increase in incidence with advancing age, as do AAH and high-grade PIN. The latter two are believed to be premalignant lesions, PIN more so than AAH.5,7,18 Whereas our study shows an association between AAH and cribriform hyperplasia only, PIN shows a statistically significant association with all three forms of hyperplasia observed: basal cell, papillary and cribriform (P<0.001). On the basis of these findings, we can suggest that the presence of cribriform hyperplasia in a prostatic biopsy heralds or indicates one or other premalignant lesion, which should be searched for. Although the significance of cribriform hyperplasia remains unclear with reference to the development of adenocarcinoma, Petersen19 believes it may represent a stage in the morphological continuum from benign to malignant prostatic disease.The study serves to re-emphasize some basic concepts in the pathogenesis of various benign disorders of the prostate gland. Thus, prostatic hyperplasia (enlargement) is mainly stromal in younger individuals, becoming glandulostromal in older subjects. The presence of acute or chronic prostatitis is not related to age of the subjects, but glandular necrosis which appears early shows a peak occurrence in relatively younger age groups in the study population (51-60 years) and correlates positively with stromal reparative changes, which we believe lead to stromal hyperplasia. Epithelial hyperplasia which starts with basal cell hyperplasia may follow regeneration of glands, but cribriform hyperplasia is the only type of hyperplasia which increases with advancing age and correlates positively with both AAH and PIN. All forms of hyperplasia observed correlate well with high-grade PIN, a recognized premalignant lesion.5,6,20–25 On the other hand, the significance of AAH as a premalignant lesion has been questioned by some.9ARTICLE REFERENCES:1. Weidner N, Carroll PR, Flax J, Blumanfeld W, Folkman J. "Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma" . Am J Pathol. 1993; 143: 401–9. Google Scholar2. Ware JL. 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