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Pathology of Benign Prostatic Hyperplasia (BPH)

B. Helpap

Introduction

Fig. 1  Hyperplasia of the lateral prostatic lobes with bladder trabeculation and hemorrhagic cystitis (left). Enlarged median lobe (right).

Fig. 2  Enucleated prostate gland with irregular, glandularstromal hyperplasia of both lateral lobes.

Fig. 3  Cut surface of nodular benign prostatic hyperplasia.

Fig. 4  Glandular-stromal hyperplasia of the transition zone. In the so-called prostatic capsule a dark blue stained focal carcinoma is identified. HematoxylinEosin (HE).

Fig. 5   Nodular, vascular, stromal hyperplasia (HE; x30).

Fig. 6   Glandular portion of benign prostatic hyperplasia (HE; x30) (10).

Fig.7  Cribriform prostatic hyperplasia (HE; x 30).

Fig. 8  Basal cell hyperplasia (HE; x 30).

Fig. 9  Labeling of the basal cell layer by the stratum corneum-keratin reaction (PAP method; x 63).

Fig. 10  Expression of prostatic specific antigen (PSA) in the secretory cells of the hyperplastic prostate gland. The basal cell layer is negative (ABC; x 30).

Fig. 11  Single chromogranin A-positive endocrine cells between the hyperplastic secretory glands (ABC; x 63).

Fig. 12   Patchy staining of the basal cells in atypical hyperplasia with stratum corneumkeratin (PAP; x 160) (31).

Fig. 13   Prostatic hyperplasia with stratum corneum-keratin labeled basal cell layer. Next to it a glandular carcinoma without basal cell layer (PAP; x 63).

Fig. 14   Estrogen receptors in an area of basal cell hyperplasia (APAAP; x 180). Prof. Dr. V. Loy, Institute for Pathology, University Medical School, Hospital Steglitz, Berlin, Germany).

Fig. 15  Demonstration of estrogen receptors in the stroma (periglandular region). (APAAP; x 190). Prof. Dr. V Loy, Institute for Pathology, University Medical School, Hospital Steglitz, Berlin, Germany).

Fig. 16  Stripping-film-autoradiograph with radioactively labeled cells in atrophic and postatrophic hyperplastic gland (HE; x 30).

Fig. 17  Cystic atrophy of the prostate (HE; x30) (10).

Fig. 18  Post-atrophic hyperplasia (HE; x 30).

Fig. 19  Periglandular nonspecific round cell reaction in prostatic hyperplasia (HE; x30)

Fig.20   Lymph follicle formation in BPH with glandular destruction by chronic prostatitis (HE; x 30).

Fig. 21  Congestive prostatitis with large amounts of macrophages in a hyperplastic prostate (HE; x 63) (10).

Fig. 22  Highly differentiated glandular prostatic carcinoma between hyperplastic glands (HE; x 63).

Fig. 23  Atypical glandular-adenomatous "central" hyperplasia (HE; x 30).

Fig. 24  Severe prostatic intraepithelial neoplasia (ductal cribriform atypia) PIN neighboring a microglandular prostatic carcinoma (HE; x 30).

Benign, nodular, paraurethral hyperplasia. of the prostate (BPH) is one of the most common diseases in elderly men. Eighty percent of all men above the age of 40 years suffer from urodynamic consequences of BPH. The usual therapy in advanced stages with obstructive voiding symptoms is surgical treatment, most commonly the transurethral resection of the prostate. More recently conservative drug therapies are also discussed based on certain considerations regarding etiology and pathogenesis of BPH. Based on the idea that a prostatitis might induce the process or occur as a complicating associated phenomenon, treatments directed at influencing inflammatory processes have also been discussed. In this context histopathological and anatomical findings, newer immunohistochemical studies, and complicating associated phenomena in patients with typical BPH are discussed.

Anatomy

The peripheral and central zone of the prostate are divided according to newer anatomical studies in:

1. A dorsocranially located central zone with wide lumina and a high cylindrical epithelium. The glands show papillary folding. The cellular cytoplasm is light and granular. The stroma is loose.
2. A transition zone, located mediolateral of the urethra. This zone is characterized by narrow glands and a very tight stroma.
3. A peripheral zone with loose stroma and glands such as are seen in the transition zone (23).

In all three zones glandular acini and ducts with basal and secretory cells are found, interspersed endocrine cellular elements, which show clearly chromogranin and Grimelius-positive staining.

Prostatic hyperplasia develops in the transition zone, while prostatic carcinoma develops in 70 % of cases in the peripheral zone. Only 20 % of all carcinoma are found in the transition zone, and these are usually highly differentiated incidental carcinoma. Carcinoma are also found in 10 % of the cases in the central zone (23).

Pathology

Formal Pathogenesis

Nodular hyperplasia of the prostate is initiated by a proliferation of the mesenchymal-stromal or the glandular-epithelial portion of the gland. Most likely the proliferation begins primarily in the stroma, while the proliferation of the glandular epithelium is secondarily induced. In comparison to the normal prostate the secretory activity of the glands in the hyperplastic prostate is somewhat reduced. In relation to the cytoplasmic volume an increase in the cellular organelles of the smooth muscle cells is seen. In fully developed hyperplasia the stromal portion of the parenchyma predominates (1). In the course of the hyperplastic proliferative process the peripheral prostate is compressed to the shape of a capsule. Pathomorphogenetically the stroma is therefore of greatest importance in benign prostatic hyperplasia.

Nodular hyperplasia develops from a regular but slowly developing proliferation of the glands with maintenance of the epithelial-stromal unit. If the epithelial proliferation is increased and in particular if the basal cells are activated, incompletely matured glands result. Immature (basal) cell hyperplasia is the end result of this process. If the epithelial - stromal unit is disturbed in the case of increased cellular proliferation, atypical glandular adenomatous; or intraglandular/ intraductal cribriform atypia may develop. If this occurs in the central part of the gland it is called atypical hyperplasia, while in the peripheral parts it is termed intraepithelial neoplasia with different grades of atypia (8,9,16).

Macroscopic Anatomy of BPH

The hyperplastic prostate is nodular and exhibits a partially solid, and partially micro- or macrocystic pattern. An exclusive hyperplasia. of the lateral lobes, or an isolated enlargement of the median lobe may result. In most cases a combination of both is present. The obstruction of the urine flow induces the development of a so-called bladder trabeculation, often combined with a chronic cystitis. The consistency of the hyperplastic prostate is influenced by the predominance of either the glandular-cystic or the fibromuscular portion (Fig. 1).

In a macro- or micronodular hyperplastic prostate, small focal carcinoma, in particular in the median or central areas, cannot be detected with the naked eye. Exact histomorphological examination of enucleated glands or TURP specimens is therefore mandatory (Figs. 2,3,4).

Microscopic Anatomy of BPH

The hyperplastic prostate may consist purely of fibroleiomyomatous nodules, or of purely glandular or glandular-cystic areas. The fibromatous nodules are more vascularized than the purely leiomyomatous nodules (35).

Often, however, these structures are intertwined. The content of smooth muscle fibers changes in particular when concomitant chronic inflammatory processes are present. If after transurethral resection in a recurrent hyperplastic gland a chronic TUR-prostatitis has developed, the fibromatous portion increases with little or no nodule formation. Vascularization and cellular content also change. Mitotic activity is often non-measurable (Fig. 5).

The glandular hyperplastic part shows a histological picture which resembles the normal gland (Fig. 6). The fibromuscular stroma is located on top of a basal cell layer and the zone of the secretory epithelial cells. Depending on the grade of hyperplasia, intraglandular papillae form with a narrow stromal center with capillary blood supplies. The epithelium, however, may also flatten or form cribriform patterns (Fig. 7). The mitotic activity of the glandular epithelium is very low. Usually 1 to 2 mitotic figures are found per 5000-10000 cells. The same holds true for the basal cell layer. In cases of a juvenile basal cell hyperplasia of the prostate, occasionally slightly increased numbers of mitotic figures are observed (Fig. 8) (10).

Immunohistochemistry

The fibroleiomyomatous parts of BPH show a strong reaction with antibodies against vimentin, desmin and actin (35). The basal cell layer can be delineated by the stratum-corneum keratin reaction (cytokeratin M 903) (Fig. 9). The expression of prostatic specific antigen (PSA) and prostatic specific acid phosphatase (PAP) is negative in the basal cell layer. The secretory cells show an inverse pattern. PSA and PAP show strong staining (Fig. 10). Occasionally chromogranin A-positive endocrine cells are detected between the hyperplastic secretory glandular epithelium (Fig. 1:0. The reaction for stratum corneumkeratin (M 903) is negative.

The staining of the basal cell layer by the stratum corneum-keratin reaction has been found to be an important differential diagnostic index between typical and atypical hyperplasia and prostatic intraepithelial neoplasia (PIN) of a moderate and severe grade, and between a glandular prostate carcinoma (2,5,28,34). The expression pattern of stratum corneum-keratin becomes more and more patchy with increasing atypia and finally disappears, corresponding to the dissolution of the basal cell layer and the loss of this layer in the case of a carcinoma (Figs. 12, 13). The basal cell prostatic hyperplasia is characterized by strong stratum corneumkeratin expression (M 903) with a lack of PSA or PAP staining (8,9,10).

Intranuclear estrogen (ER) and progesterone (PR) receptors are not found in the secretory cells. However, the basal cells in hyperplastic prostate may express these receptors. The receptors are mainly found in the periglandular stromal cells (19; Wernert and Dhom 1988; Wernert et al. 1988) (Figs. 14,15). According to newest results the androgen receptor is found in the secretory cells (29). The immunohistochemical pattern of the hyperplastic, stromal, and glandular parts of the hyperplastic prostates do not differ from that of the normal prostate. In basal cell hyperplasia, almost all basal cells expressed the estrogen receptor in the nucleus (Wernert et al. 1988). The single-layer secretory epithelium, located towards the lumen of the gland, is, however, negative. By utilizing the proliferation marker Ki 67, proliferatively active cells can be demonstrated in basal cell hyperplasia (19). The fibrous and smooth muscle cells in the stroma can be characterized by the intermediate filaments vimentin and desmin.

In immature cell-rich stromal nodules, few labeled cells can be demonstrated by Ki 67 immunohistochemistry. In quiescent stroma no cells are labeled by the antibody Ki 67 (18). This correlates well with cell kinetic-autoradiographical studies with 3H-thymidan. Radioactively labeled stromal cells are very rarely seen. The index of labeled cells is under .01 %. This pattern does not change significantly in the so-called florid mesenchymal nodule formation. In cases of basal cell hyperplasia and in particular in the postatrophic hyperplasia, the index may rise to 1.6 % labeled cells (8,9,10) (Fig. 16).

Regressive Changes in the Hyperplastic Prostate

Regression of the prostate is regularly observed next to progression. Atrophic glandular complexes form, with smaller or larger cysts lined by a single-layer epithelium which has a cubic character (Fig. 17). The mitotic and cell kinetic or immunohistochemical proliferative activity is again very low. In the case of a secondary hyperplasia (so-called post-atrophic hyperplasia), in which activated basal cells and secretory cells, often with eosinophilic cytoplasm, occur, the pro-liferative activity can increase significantly (Fig. 18). The surrounding stroma, however, shows no such changes. PSA and PAP may be demonstrated immunohistochemically in the atrophic and post-atrophic hyperplastic glands.

Cytokeratin (M 903) regularly stains the basal cells (10). Immature metaplasia induced by a significant proliferation of basal cells or mature squamous epithelial metaplasia results in an increase in the proliferative activity with indices up to 4 % labeled cells. PSA and PAP are not expressed; however, the staining with cyto-keratins is clearly positive. The estrogen receptor is immunohistochemically demonstrable in metaplastic squamous epithelium and hyperplastic basal cell epithelium (30).

Inflammation and BPH

In 30-50% of histologically examined, hyperplastic prostatic tissue, periglandular round cell infiltrates of varying density are found (Fig. 19). Occasionally lymph follicles have formed (Fig. 20). Not rarely, evidence is found for a so-called congestion prostatitis in discrete hyperplastic areas. In the glandular lumen macrophages mixed with round cells and single polymorphonuclear leukocytes are found. The hyperplastic glandular epithelium is flattened or destroyed. In the periglandular area round cell infiltrations of varying densities are found again (Fig. 21). These loose periglandular round cell infiltrates can, however, be at best considered an inflammatory concomitant reaction. The cellular changes are not sufficient to allow the diagnosis of a classic prostatitis (10).

Stroma and epithelium are not activated in the hyperplastic prostate in cases of a reactive periglandular round cell infiltration. In cases of chronic granulomatous, non-specific prostatitis with hyperplasia proliferative indices are found like those seen in cases of chronic prostatitis without hyperplasia (10).

The number of Ki-67-positive proliferative epithelial cells is increased. These are predominantly basal cells which result in a hyperplastic basal cell or squamous epithelial process (19). The inflammatory infiltrate initially consists of the typical mixture of T- and B-lymphocytes. In advanced stages the T-lymphocytes predominate, however (11,19) (see also chapter, "Prostatitis").

BPH and Prostatic Carcinoma

If an advanced peripherally located glandular prostatic carcinoma grows into the hyperplastic inner aspects of the prostate, carcinomatous and hyperplastic glands are seen in close relationship. The prostatic carcinoma growing peripherally can usually clearly be separated from the hyperplastic glands by the usual histological staining methods (Fig. 22). This differential diagnosis, however, may be difficult in the case of the rare so-called central, very highly differentiated, glandular prostatic carcinoma.

The demonstration of a basal cell layer in the hyperplastic glands by the stratum corneum-keratin reaction, and vice versa, the lack of this reaction in the highly differentiated, glandular prostatic carcinoma allows a clear separation (Fig. 13). The expression of estrogen and progesterone in the stroma neighboring of the prostatic carcinoma is increased (20).

Atypical Hyperplasia and Prostatic Intraepithelial Neoplasia (PIN)

These changes represent proliferative processes of the glandular epithelium. In the central parts of the prostate, glandular-adenomatous epithelial proliferation occurs, while in the peripheral prostatic regions, intraductal cribriform epithelial proliferations are observed leading to a cellular atypia of varying intensity In the course of the increasing cellular atypia, a loss of basal cells may occur (Figs. 23,24). The immunohistochemical PSA expression becomes heterogeneous. The basal cell layer staining by the stratum corneum-keratin (M 903) decreases with increasing atypia (Fig. 12). DNA cytometry reveals in lower grades of atypia exclusively diploid DNA patterns. In cases of severe atypia or intraepithelial neoplasia (PIN), aneuploid patterns may be found. Those changes in their severe expression are considered as a preneoplastic lesion. The central atypical hyperplasia is the precursor of the incidental prostatic carcinoma, while the prostatic intraepithelial neoplasia (PIN) is the precursor of the clinical carcinoma (2,12,16,17,22,27).

Classification and Nomenclature of Prostatic Hyperplasia

The diagnosis of prostatic hyperplasia can be established by clinical tests relatively clearly. However, the morphology may reveal surprises. Atypical formations in the hyperplastic prostate gland and incidental carcinoma are found with a frequency between 8 and 10%. The importance of proliferative processes led to a number of different names. The terms "hypertrophy" and "adenoma" are commonly utilized in clinical context. Since the hyperplastic process, however, is morphologically, by means of cell kinetics, by DNA-cytometry, and immunohistochemically documented, the terms "hypertrophy" and "adenoma" should not be used any longer (7,8).

Kastendieck (14) divided primary hyperplasia in several subgroups, namely immature, mature, nodular, and diffuse forms, and separated the subgroups from a primary atypical hyperplasia and from the secondary (post-atrophic) hyperplasia. Special entities are the dysplasia and the "borderline-lesion" (15).

The classification according to Elbadawi is based on extensive histological studies (4). He separates the nodular paraurethral stromal-glandular hyperplasia from the ductal hyperplasia; furthermore, secondary postatrophic hyperplasia and metaplasia are distinguished. In his staging system, the atypia in the stromal and the glandular parts of the gland in juvenile hyperplasia, after prostatic infarction, inflammation, and basal cell reaction are listed separately, as is the atypia in the case of the cribriform median lobe hyperplasia.

The WHO classification (26) differentiates nodular hyperplasia and other hyperplasia forms in post-atrophic, secondary and basal cell hyperplasia. In an earlier categorization (25) primary atypical hyperplasia was listed together with primary prostatic glandularstromal hyperplasia.

Dhom (3) distinguishes between primary hyperplasia, atrophy, and metaplasia. Under the term "primary hyperplasia," simple hyperplasia, adenomatous small-glandular, cribriform, and papillary hyperplasia are summarized. Under the grouping "atrophy," simple atrophy, cystic atrophy, as well as post-atrophic nodular hyperplasia and postsclerotic hyperplasia are listed.

For clinical pathological purposes the following grouping taken from the staging system according to Mostofi and Price (25) and Mostofi et al. (26) (VVHO) has been found valuable (6,7,8,16):

1. Primary typical nodular hyperplasia, glandular-stromal, mature/ immature (BPH).
2. Primary atypical glandular adenomatous hyperplasia in the central organ (AH) and prostatic intraepithelial neoplasia in the peripheral gland (PIN) with mild, moderate, or severe atypia.
3. Secondary post-atrophic hyperplasia.

Conclusions

Benign prostatic hyperplasia is a partially nodular, partially diffuse, stromal and glandular process which develops on the basis of a cell proliferation. A fibrous capsule like that seen in other adenomata, or a hypertrophy with increase in tissue mass and no increase in cell number does not occur. Therefore, the term prostatic hyperplasia should be used exclusively.

The demonstration of estrogen and progesterone receptors in the periglandular stroma supports the concept of an estrogeninduced stromal hyperplasia. However, the same pattern of expression has also been found in the peripheral aspect of the prostate such that the histogenetic difference of the three prostatic zones as proposed by McNeal (23,24) cannot be reconciled with the expression pattern of the estrogen receptors (20).

The biochemically documented synergism between androgens (dihydrotestosterone), their metabolic products, and estrogens continues to remain an etiologic and pathogenetical postulate for the development of benign prostatic hyperplasia. A clear morphological cause and effect relationship for an exclusive estrogen induction of hyperplasia, however, is lacking (8,9). An active proliferative process in the stroma and the glandular part of the hyperplastic prostate cannot be documented. This has been shown using DNA cytometry, autoradiography, and immunohistochemistry. The question has been raised whether BPH may be not a problem of an increased growth rate but ratherthe consequence of an androgen-mediated over-aging of the tissue with inappropriately low cellular turnover (Loy et al. 1988). The rate of apoptosis in the hyperplastic prostatic tissue, however, does not differ from the rate observed in normal prostatic tissue (31,32, 33).

Furthermore morphologic and immunohistochemical studies do not indicate the cause exclusively in a proliferation of basal cells. The percentage of active nodular formation with exclusively hyperplastic and activated basal cells like those seen in juvenile basal cell hyperplasia is very small in the common type of BPH. A stromal proliferation in these areas cannot be detected in comparison with the reactions seen in mature, hyperplastic areas. Nevertheless, on the basis of biochemical analyses, it remains undisputed that the stroma plays an important role in the induction of BPH.

The idea that recurrent prostatitis might induce the development of BPH is still being debated, but has not been confirmed up to now. The loose, periglandular, round cell inflammations in the stroma are a morphological finding without correlating clinical relevance. The term "BPH concomitant prostatitis" should not be utilized in the morphological BPH diagnosis in the face of a very modest cellular periglandular stromal reaction.

Periodically occurring cell proliferations in the stroma or glandular epithelium in areas in which these loose periglandular round cell infiltrates exist cannot be documented using immunohistochemical techniques or studies of cell kinetics. Extensive prostatitis, which leads to destruction of the glandular epithelium and a dense inflammatory stromal reaction, induces a proliferative reaction. This reaction, however, has an exlusively reparative character in the area of the destroyed epithelial cells or the destroyed stroma. The fact that in prostatectomy or autopsy specimens in young men without matured hyperplasia, no significant classical inflammatory infiltrates are found in the prostate argues against an inflammatory induction of BPH which would assume that hyperplasia is preceeded by prostatitis. Furthermore, if prostatitis exists, it is located in the peripheral gland. Significant chronic recurrent prostatitis in hyperplasia as it is almost exclusively seen in patients over 50 years of age has the potential to influence the hyperplastic process, e.g., to congestive prostatitis. For the development of benign prostatic hyperplasia, however, prostatitis does not play an inductive role according to our current knowledge.

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