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Modern Considerations and Investigations in Benign Prostatic Hyperplasia (BPH)

J. Vogel, E. Bierhoff, U. Pfeiffer, W. Vahlensie

Fig. 1 Section of a BPH specimen with glandular and stromal nodules of different size (H&E, loop magnification).

Fig. 2a Border of a mixed stromal nodule (H&E).

Fig. 2b Section of a mixed nodule with smooth muscle stain (Masson trichrome stain).

Fig. 3 Vimentin reaction in fibrous type nodule.

Fig. 4   Actin reaction in smooth muscle type nodule.

Fig. 5   Actin stain in the three different types of nodules.

Fig. 5a Immature mesenchymal nodule with few fibers; actin stain only positive in blood vessel

Fig. 5b Mixednodulewith actin stain of fibers and blood vessels.

Fig. 5c Almost pure smooth muscle nodule with positive actin stain in the majority of fibers.

Fig. 6 Section of a fibrous nodule with many rather thickwalled blood vessels.

Fig. 7a Demonstration ofT-lymphocytes in stroma and

Fig. 7b  in the walls of blood vessels (UCHL-1 and H&E).

Introduction

Etiology, pathogenesis, endocrinology, functional pathology, and clinical aspects of no other benign lesion have interested urologists, endocrinologists, and pathologists as much as benign prostatic hyperplasia (BPH). The importance of the interaction between stroma and glandular epithelium is already sufficiently well known. The differentiation of glandular elements and stroma depends on the concentration of circulating male sex hormones and their metabolites (1,3,6,15). The possible etiological role of estrogens, and the exact molecular mechanisms of BPH development are as of yet unknown.

The importance of the nodular and diffuse glandular areas in BPH is well documented (4,5,8,9,10,11). Nodular changes in the stroma have received less attention up to this point. Their histological structure, cellular composition, size, number, and distribution in the prostate gland have so far not been investigated in a systematic fashion.

Materials and Methods

The material from 260 transurethral resections of the prostate done for BPH were examined for the presence of pure fibromuscular stromal nodules. Besides a diffuse stromal hyperplasia, purely stromal nodules were identified in 118 cases. Up to four stromal nodules ranging in size from 0.3 to 1.2cm were seen per case.

More detailed studies concerning the composition of the nodules were performed in 35 selected cases. The specimens were stained using H&E stain, Sirius red stain, and trichrome stain. Furthermore, immunohistochemical staining was performed using antibodies against vimentin, desmin, smooth muscle a-actin, myosin, factor VIII, and macrophages. In an effort to further characterize the lymphocytes, antibodies against T-lymphocytes (UCHL-1) and B-lymphocytes (L-26) were used (all antibodies were purchased from Dakopatts GmbH, Hamburg, Germany).

Results

Considering the predominant component in the stromal nodules, 22 nodules consisted mainly of fibrous tissue, while 13 consisted mainly of smooth muscle fibers. In the H&E stain the fiber structures cannot be clearly differentiated (Fig. 1). The Masson trichrome stain intensely stains the smooth muscle fibers (Figs. 2 a and b). The fibrous nodules all react positive to staining with vimentin antibodies (Fig. 3), while the smooth muscle components are stained with the desn-dn and partially with the a-actin antibodies (Fig. 4). However, 9 of 22 fibrous nodules also stained positive with anti-desmin antibodies, 3 of 5 were actin positive, and 5 of 13 smooth muscle nodules stained positive with anti-vimentin antibodies (Table 1). Individual loosely structured nodules were negative for actin except for the wall of small blood vessels. These nodules represent the first of the three different types of nodules. In the mixed nodules both fibroblasts and smooth muscle cells were found, while in the third type exclusively smooth muscle elements were found (Figs. 5 a-c).

When the intensity of the immunohistochemical staining was evaluated, fibrous nodules stained predominantly strong with anti-vimentin antibodies, while smooth muscle nodules showed only a weak staining pattern against this antibody. The opposite pattern was found for staining with anti-desmin antibodies (Table 1).

Tab. 1 Comparison of the immunohistochemical staining pattern with antibodies against vimentin, desmin, and actin in stromal nodules and grading of the intensity of staining.

Antibody Fibrous type n=22 Smooth muscle type n=13

ø + ++ +++ ø + ++ +++

Vimentin
n=35 0 0 9 13 8 4 1 0

Desmin
n=35 13 4 5 0 0 0 4 9

Actin
n=9 2 3 0 0 0 0 0 4

The nodules richer in fibrous tissue had a higher incidence of blood vessels when compared to the mainly smooth muscle nodules. Furthermore, these blood vessels were rather thick-walled, more eccentric, immature, and the endothelium did not stain with anti-factor-VIII antibody (Fig. 6 and Table 2).

Tab. 2 Analysis of the blood vessels in stromal nodules

Fibrous type (n=22) Smooth muscle type (n=13)

34 per 10 HPF 18 per 10 HPF

Thick-walled Thin-walled

(Compact and concentric) (eccentric-branched)

Immature Mature

Negative for factor VIII Partially positive for factor VIII

The lymphocytes present in various amounts were predominantly T-lymphocytes (Figs. 7a and b). They were partially located diffusely throughout the nodules, and partially in the wall of blood vessels or in the perivascular space. Macrophages were only rarely seen.

Discussion

Comprehensive and detailed anatomical studies of the prostate have demonstrated that benign prostatic hyperplasia (BPH) develops mainly in the proximal periurethral structures (10-13). An interpretation of pathological findings requires a detailed understanding of the complex anatomy of the organ. In general a stromal-epithelial interaction is assumed to be responsible for the development of BPH. Other authors maintain that the glandular components are not involved in the maturing of the nodules to purely smooth muscle-tissue-containing nodules (7). According to McNeal two different types of nodules have to be separated: (1) the periurethrally located stromal nodule, and (2) the purely glandular nodule located in the transition zone (8,10). Based on the presented histological and immunohistochemical studies we suggest distinguishing three different types of these stromal nodules:

Immature mesenchymal fibrous nodules with few vimentin-positive fibers but no smooth muscle components,
mixed nodules with fibroblasts and smooth muscle fibers and
pure smooth muscle nodules.

The various types of fibers can be clearly distinguished using immunohistochemical staining techniques, most impressive with the anti-actin antibody. Whether these types of stromal nodules represent different stages in a maturation process or indicate a focal embryonic reawakening as postulated by McNeal remains to be determined.

The central role of the smooth muscle cell for the proliferative process of the stroma. has been pointed out by many investigators (2, 14). A large number of the analyzed nodules is rich in activated fibroblasts and therefore clearly different from the normal prostatic stroma. Nuclear steroid hormone receptors have been demonstrated in stromal cells. The importance of other factors is up to this point unknown. The three types of stromal nodules develop predon-dnantly in the periurethral region, but occur also in other parts of the gland.

The noticeably rich vascular supply of the nodules and the unusual blood vessel architecture have so far received little attention by researchers. Considering the fact that stromal nodules with a rich blood supply are distributed over the entire organ, this vascular component n-dght be of importance in the development of the so-called prostatic congestion associated with BPH in cases with a predominance of stromal tissue components.

Although it is known that in BPH the dihydrotestosterone concentration varies between stroma and epithelium, it is still unclear why the tissue composition is sometimes purely stromal and in other cases more or less purely epithelial.

Equally unknown is why the lymphocytic infiltrates contain mainly T-lymphocytes. This often rather obvious lymphocytic infiltration furthermore raises the question of whether, in addition to the already known endocrine factors, inflammatory or immunological changes are of importance in the development of mesenchymal proliferation. The presented results and considerations will form the basis for further investigations in the future.

Summary

Pure stromal proliferations are seen in benign prostatic hyperplasia (BPH) in various numbers and distribution, or even exclusively. These cases are investigated in more detail in a histological and immunohistochemical analysis. Three different types of stromal nodules are distinguished: immature mesenchymal nodules which are poor in fibers; mixed nodules containing fibroblasts and muscle fibers; and only smooth muscle containing nodules. These nodules are very vascular, which may be of importance in particular regarding the associated prostatic congestion. In the stromal nodules and in the associated blood vessels many T-lymphocytes are found. Their role in the development of BPH is as of yet undetermined. The presented morphological studies will be the subject of further investigations.

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