Hypothesis / aims of study
In a previous study, benign prostatic hyperplasia (BPH) was reported to show a histological transition from smooth muscle-dominant type to fibrous-dominant type as it becomes more severe. Severe BPH patients with fibrous-dominant type could have the resistance to oral medication. However, the mechanism of BPH fibrosis and the influence on lower urinary tract symptoms (LUTS) by tissue fibrosis remained unresolved. On the other hands, we reported that complement activation by an autoimmune reaction was associated with the growth process of BPH. Therefore, we hypothesized that activation of complement pathways might be also associated with the fibrous process of BPH with progression. In this study, to clarify the mechanism of BPH fibrosis with progression and the influence on LUTS by tissue fibrosis, we analyzed the histological severity and the expression of complement components using human fibrous BPH tissues.
Study design, materials and methods
The subjects were 56 histological BPH patients who underwent prostate needle biopsy due to high PSA levels in our institutions (mean age 68.6 ± 6.5 years). BPH patients were divided into two histological groups, fibromuscular type and fibrous type, by hematoxylin-eosin and elastica-Masson staining. Complement expression function analysis was performed by immunohistochemical staining using C3, factor B, and C5b-9 antibody, and the occupancy ratio of the stained region was calculated. In addition, the correlation between these histological changes of BPH and IPSS scores was analyzed.
Results
Twenty-seven cases (48.2%) were classified as fibromuscular type, and 29 cases (51.8%) were classified as fibrous type. The proportion of fibrous components was significantly lower in the fibromuscular type than in the fibrous type (fibromuscular type 36.0 ± 12.9%, fibrous type 61.1 ± 11.7% (p<0.01)). Abundant infiltration of inflammatory cells was observed in the fibromuscular type (p=0.03). In the expression analyses of complement components, factor B was not significantly different between the two groups, whereas C3 (fibromuscular type 10.7 ± 8.2%, fibrous type 16.4 ± 12.7%) and C5b-9 (fibromuscular type 15.9 ± 6.2%, fibrous type 17.6 ± 9.2%) were significantly upregulated in the fibrous type compared to the fibromuscular type (p = 0.04, p = 0.04). The IPSS-3 score in the fibrous type was significantly higher compared to that in the fibromuscular type (p=0.04).
Interpretation of results
Generally, the histological findings of BPH shows a histological transition from the fibromuscular type to the fibrous type during the fibrous process of BPH. In this study, we analyzed the time-dependent change of the expression of complement components and LUTS including voiding and storage symptoms using human fibrous BPH tissues. In these analyses could clarify the mechanism of BPH fibrosis by the complement pathway activation. First, as the histological findings of BPH show a histological transition to fibromuscular type, the activated complement pathway made the shift change to complement alternative pathway activation with the abundant infiltration of inflammatory cells. Secondly, as the histological findings of BPH show a transition from fibromuscular type to fibrous type, the activated complement pathway made the shift change to the complement late pathway. These results suggested that shift change to complement late pathway activation was involved in the progression of fibrous BPH. Furthermore, the deterioration of LUTS associated with the progression of BPH fibrosis was predominant in voiding symptoms, suggesting that the complement pathway might be a therapeutic target for voiding symptoms.