The relationship between prostate inflammation and lower urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH) has raised the urological interest in the recent years, due to new evidence that support this potential link. Several different parameters, such as cytokines, lead to chronic prostatic inflammation and then to tissue damage, continuously in wound healing, contributing to the prostatic enlargement. Patients with chronic inflammation and BPH are proven to have larger prostate volumes, resulting in more severe LUTS or even acute urinary retention. Patients with metabolic diseases are considered to be affected by prostatic inflammation, following a possible pathway that connects their metabolic disorders with BPH. For the time being, the only sensitive diagnostic method for prostatic inflammation is prostate biopsy. Prostate calcifications, prostatic volume, or the severity of LUTS may only imply an underlying inflammatory pattern. The use of biomarkers is still limited, as an optimal and sensitive biomarker has not been yet established. As chronic inflammation may have a negative impact in the treatment of BPH, the identification of patients with both BPH and chronic inflammation is important in order to prevent LUTS progression.
KeywordsLower urinary tract symptoms, Benign prostatic hyperplasia, Prostate inflammation, Pathophysiology, Biomarkers, Metabolic syndrome, Calcifications
Lower urinary tract symptoms (LUTS) are common in men over 45 years of age [ ], and are divided into storage (urinary daytime frequency, nocturia, urinary urgency, incontinence), voiding (urinary hesitancy, slow stream, straining, splitting or spraying, intermittent stream, terminal dribbling), and postmicturition (feeling of incomplete emptying, postmicturition dribbling) symptoms [ , ]. In men, LUTS have been traditionally attributed to bladder outlet obstruction (BOO) as a result of benign prostatic obstruction (BPO), which is often associated with benign prostatic enlargement (BPE) resulting from the histologic condition of benign prostatic hyperplasia (BPH). The prostatic enlargement is age-related and seems to be androgen depended, while the whole process origins from a proliferation of epithelial and stromal benign cells. However, apart from those initial theories, other studies indicate a correlation of LUTS with other conditions responsible for voiding difficulties, such as decrease of detrusor activity or changes in the bladder neck and prostate smooth muscle. These conditions are not necessarily connected with the prostatic size [ ]. However, BPO/BPE has the dominant role in the development of male LUTS.
Additionally, more recent research focuses on the role of prostatic inflammation in the development of prostatic enlargement and consequently the severity of LUTS and the natural history of these symptoms. Several models and hypotheses have been suggested for the pathogenesis of this condition. Also, the relationship of the inflammation pattern with the progression of BPH is currently investigated through the molecular and metabolic pathways, which can be responsible for this connection.
Although all connective bridges between LUTS/BPH and prostatic inflammation are not yet well understood, there is evidence for their etiological relationship and interaction. As a result, clinical studies have already evaluated and underlined the important role of inflammation diagnosis in the urological practice.
Chronic histological inflammation of the prostate is a common finding in the results of the histopathological examinations after a prostate biopsy or a transurethral or open prostatectomy [ , ]. However, the model of the suggestive pathophysiological way connecting the inflammation pattern with LUTS and BPH is multiparametric and sometimes not absolutely clear.
The Immunochemical Pattern of BPH
The presence of activated T-cells in the hyperplastic prostate gland is known since the Theyer study at early 1990s [ ]. Peripheral blood T-cells express VEGF, a potent epithelial mitogen, while they secrete other growth factors, like HB-EGF and bFGF/FGF-2 [ ]. Therefore, the presence of T-cells in the prostate might have a potential role in the gland hyperplasia, affecting the local environment by producing stromal and epithelial factors, causing prostatic hyperplasia.
The immunological pattern of the inflammatory process in the prostate was the study object for several studies. In their investigation, Di Siverio et al. [ ] examined histologically 3942 patients’ biopsies, describing 43% cases with inflammation. Chronic type was the predominant (69% of them). Although the severity of the symptoms was characterized as mild in most of the cases, there has been a clear association with the age and prostate volume. In an older study, Irani and Robert [ , ] suggested a grading of prostatic inflammation, based on the hypothesis that the extension of the inflammatory cells could imply the whole histological grading of the inflammatory aggressiveness ( Table 3.1 ).
|0||No inflammatory cells|
|1||Scattered inflammatory cell infiltrate|
|2||Nonconfluent lymphoid nodules|
|3||Large inflammatory areas with confluence of infiltrate|
|0||No contact between inflammatory cells and glandular epithelium|
|1||Contact between inflammatory cell infiltrate and glandular epithelium|
|2||Clear but limited, that is less than 25% of the examined material, glandular epithelium disruption|
|3||Glandular epithelium disruption on more than 25% of the examined material|
|Cytological Grading||Immunohestochemical Grading|
Prostate is normally populated by a small number of inflammatory cells (leukocytes) that increase with age, consisting of scattered stromal and epithelial T and B lymphocytes, macrophages, and mast cells [ ]. The normal prostate gland is infiltrated around the periglandular area mainly by T lymphocytes and more particularly 70% CD8 cells. In the fibromuscular stroma, there are lymphoid aggregations, consisting of B lymphocytes, CD4 T lymphocytes over 50%, while CD8 cells are in a smaller ratio [ ]. However, in the prostate of adult men, the infiltration pattern is usually described as different, mainly because of the inflammatory process been present. Steiner et al. [ ] showed that the inflammatory infiltrates are mostly represented by CD3 T lymphocytes (70–80%), CD19 and CD20 B lymphocytes (10–15%), and macrophages (15%). There is, also, an interesting reverse of CD8 to CD4 T cells and finally the CD4 cells become prevalent in the inflammatory areas. Robert’s study [ ] came to be even more confirmative, as the investigation on 282 patients with BPH proved the presence of T lymphocytes in the 80% of cases, associated with 52% of antigen-presenting cells, such as B lymphocytes, and 82% of macrophages.
Another situation neighboring inflammation in the prostate is proliferative inflammatory atrophy, firstly described by De Marzo et al. [ ]. In this condition, the epithelium becomes atrophic or hyperplastic due to atrophy, something that also occurs in association with the chronic inflammation. The main characteristic is the presence of inflammatory cells in both epithelial and stromal areas, as well as stromal atrophy with variable amount of fibrosis.
The Inflammatory Pattern of BPH
The inflammatory pattern in BPH is based on the cytokine secretion from the inflammatory cells, hypoxia due to the increased oxygen demand by the cell proliferation, and eventually tissue damage. These cytokines are involved in the regulation of the immune response but may also interact with stromal and epithelial cells in the prostate [ ].
BPH tissue is populated by T-B lymphocytes and macrophages, which are responsible for the release of IL-2, IFN-γ, and TGF-β. This may support the fibromuscular growth in BPH [ ]. Moreover, some proinflammatory cytokines, such as IL-15 and IFN-γ in the stromal cells, IL-17 in the T-cells, and IL-8 in the epithelium, are upregulated in a BPH condition [ ].
T cells concentration is gradually increased, due to the action of the proinflammatory cytokines and when they reach a certain threshold, the surrounding cells are killed and replaced by fibromuscular nodules [ ]. The maintenance and progression of this immune inflammation process in the aging prostate is been regulated by the dendritic cells [ , ].
The Origin of Chronic Prostate Inflammation
Although the correlation of LUTS and BPH is well described in several studies, their accurate pathophysiological connection is not yet absolutely clear. A variety of pathogens are implicated, including bacterial infections, urine reflux with chemical inflammation, dietary factors, hormones, autoimmune response [ , ], and a combination of these factors.
Viruses, sexually transmitted organisms, and Gram-negative pathogens have been detected in the prostate and have been responsible for a chronic inflammatory situation leading to LUTS. Hence, chronic infections or colonization of human papilloma virus, human herpes simplex virus type 2, Neisseria gonorrhoea , Chlamydia trachomatis , Treponema pallidum , Trichomonas vaginalis , or even E. coli could imply a good connection between a chronic prostate inflammation and lower urinary tract symptoms [ , , ].
Chemical irritation due to urine reflux may be another etiological factor contributing to the development of prostate inflammation [ ]. In this case, the pathway begins from the crystalline urine, which can be realized by dying cells, engaging caspase-1-activating NALP3, a multiprotein complex presented in leukocytes mostly in macrophages [ ]. The next step is the stimulation for the production of cytokines and the incoming of more inflammatory cells.
Corpora amylacea in the prostate is considered as another possible source of inflammation [ , ]. In fact, corpora amylacea are frequently found adjacent to the damaged epithelium inducing focal inflammatory infiltration.
Prostate injury secondary to the earlier-mentioned etiologies can damage prostate epithelial cells and consequently provoke an immunological reaction, by releasing immunogenic antigens. This is based on the hypothesis that some prostatic proteins are not physiologically tolerated by the immune system and when they are released an autoimmune response is determined [ , ].
The interaction between gonadal sex hormones with the immune system is, also, well known and may be a key for the activation of lymphocytes in the prostate tissue. Estrogens are commonly considered proinflammatory hormones being involved in the susceptibility to inflammation by regulating the IFN-γ production in lymphocytes [ ]. They, additionally, induce the accumulation of CD 4 (Th1 type) T cells, responding to the antigen, and moreover they stimulate the production of the Th2 antiinflammatory cytokines (IL-4, TGF-β). Those substances are usually present in the BPH nodules. Also, IL-4 and IL-3 are overexpressed in advanced BPH and they are known to increase the production of 3b-hydroxydehydrogenase/isomerize type1 (3b-HSD) by prostate epithelial cells, an essential catalyst in the metabolism of androgens [ ]. The role of the diet factors, such as food wealthy in animal fat, has been investigated in animal models, showing variety of changes in the prostate tissue, with the role of mast cells and macrophage to be predominant inside the prostate [ , ].
The main hypothesis that all the above proposed mechanisms support is the development of a chronic epithelial injury in the prostate. Consequently, this may facilitate the growth of the inflammatory response, increasing the prostatic inflammatory infiltrates.
The Role of Inflammatory Cytokines
The proinflammatory cytokines are released by the inflammatory cells and may, in parallel, induce cyclooxygenase-2 (COX-2) expression in BPH, which is associated with the increased cell proliferation [ , ]. There is evidence supporting that IL-17, an upregulator of COX-2, is overexpressed in patients with BPH, mainly produced by T-cells, while this process requires additional factors, as IL-23 [ , ]. The pathway including IL-17 and IL-23 interaction is involved in promoting the inflammation response in BPH.
Penna et al. [ ] showed in tissue samples of men with BPH that stromal cells have an antigenic action, stimulating CD4 T-cells to produce IFN-γ and IL-17. Afterward, the production of IL-8 and IL-6 is induced and finally fibroblast growth factor 2 (FGF-2) is produced. This may be a connection of the stromal cell autoimmune response and the prostate proliferation [ ].
The possible role for TGF-β has also been investigated. TGF-β is an inflammatory cytokine regulating proliferation and differentiation in BPH. In the study of Descazeaud et al. [ ], the role of TGF-b receptor II protein (TGFBRII) was evaluated in 231 patients with BPH. The results showed a significant correlation between TGFBRII with prostatic volume and inflammation. Certainly, the expression of this protein was more evident in cases with CD4 T cells within the prostate.
Local hypoxia may also play a role in the prostate inflammation and furthermore in the development of BPH. Reactive oxygen species (ROS) seem to be released under hypoxia situations, leading to growth factor release, reaction with the epithelial and stromal cells, and finally gland enlargement [ ]. The main growth factors involved in this condition is FGF-7, TGF-b, FGF-2, and IL-8 [ ].
Taoka et al., in their investigations on hyperplastic prostatic tissues, proved significantly low levels of macrophage inhibitory cytokine-1 (MIC-1) in specimen with inflammation. This cytokine is expressed and/or increased in a normal prostate [ ].
It is rather obvious that a clear cause and effect relationship between prostate inflammation and BPH is not yet well understood. T-cells activity in the inflammation pattern may stimulate the proliferation of stromal and epithelial cells. Additionally, tissue damage and chronic, repetitive wound healing result in the development of BPH nodules.
Chronic Inflammation and LUTS
Several studies have investigated the potential association between chronic prostatic inflammation and the development of lower urinary tract symptoms ( Table 3.2 ).
|Study||Population||Evaluation of LUTS||Conclusion|
|Nickel et al. [ , ]||8224 patients from the REDUCE trial||IPSS||Chronic inflammation was associated with prostate volume and IPSS|
|Robert et al. [ ]||282 patients treated with surgery BPH||IPSS, prostate volume||Chronic inflammation was associated with higher prostate volumes, IPSS, and a higher frequency of open prostatectomy|
|Tuncel et al. [ ]||92 patients operated with TURP||AUR||AUR was higher in BPH patients with chronic inflammation|
|Roerhborn et al. [ ]||544 patients from the MTOPS study||AUR||Inflammation was associated with higher prostate volume and higher risk of AUR|
|Mishra et al. [ ]||374 operated with TURP||AUR||AUR was associated more with chronic inflammation, then with prostate volume|
|Torkko et al. [ ]||859 men from the MTOPS study||IPSS||Inflammation was correlated symptom progression and AUR|
|Nickel et al. [ ]||4109 men from the REDUCE study||IPSS||Chronic inflammation was associated with higher IPSS and higher risk of AUR|
|Kulac et al. [ ]||357 patients from PCPT||IPSS||Progression for IPSS < 8 did not differ between cases with inflammation and controls|
In a subgroup of men in the Medical Therapy of Prostate Symptoms (MTOPS) trial with baseline biopsies, the presence of chronic inflammation was found in 40% of baseline biopsy and in particular, in men with higher prostate-specific antigen (PSA) values and larger prostate volumes [ ]. Nickel et al. [ ] analyzed data from 8224 men, 50–75 years old included in the REduction by DUtasteride of prostate Cancer Events (REDUCE), who had a negative prostate biopsy within 6 mo prior to enrolment. At baseline 15.4% of the patients had acute inflammation, 77.6% had chronic inflammation, and 21.6% had no inflammation. Inside this selection, the 77.6% of the subjects presented with inflammation, either chronic or acute. The inflammation severity, for any subject, was assessed according to the pathology core findings with the following score: none (0), mild (1), moderate (2), or marked (3). Patients with chronic inflammation were found to have larger prostate volumes than those without relevant pathological findings (46.5 vs. 43.4 mL, respectively), resulting in a positive association between prostate volume and inflammation ( P < .001). The severity of LUTS was evaluated using the International Prostate Symptoms Score (IPSS). Older men and those with more severe inflammation found to score higher IPSS ( P < .001), while the chronic inflammation was statistically correlated with nocturia, frequency, urgency, and urge incontinence. Although these differences were statistical significant, their clinical significance seemed to be weak most probably due to the study inclusion criteria. Younger patients and patients with IPSS > 25 or those with IPSS > 20 under a-blocker treatment had been excluded.
Robert et al. [ ] moved one step further and evaluated prostatic inflammation by using cytological and immunohistochemical parameters. The study included 282 patients who were treated with surgery for complicated and/or symptomatic BPH. The evaluation of symptoms was based on the IPSS, while the inflammation grade was defined with the contribution of cytological and immuonohistochemical parameters. Cytological parameters were lymphocytes, macrophages, and polynuclear leukocyte infiltrates, and three glandular aspect modifications: glandular atrophy, glandular destruction, and tissue fibrosis, while immunohistochemistry markers included CD3, CD4, and CD8 decorating T-lymphocytes, CD20 decorating B-lymphocytes, and CD163 decorating macrophages. The median values of inflammation scores were used as thresholds to differentiate low- from high-grade inflammation patients. Patients with high-grade inflammation had higher IPSS score (21 vs. 12, respectively) and higher prostate volume (77 cc vs. 62 cc, respectively) than patients with low grade inflammation. In addition, patients with high-grade inflammation were also more likely to be operated by open prostatectomy (62% vs. 43%) probably as a result of their larger prostate volume. Finally, more patients with high-grade inflammation had a history of transrectal ultrasound (TRUS) guided biopsies than those with low-grade inflammation (37.6% vs. 23.9%, respectively). This may represent a possible limitation of the study since TRUS biopsies are known to be responsible for a bacteriological contamination of the prostatic gland that may result in a local immune response.
Despite the described limitations of these studies, they provide evidence to the hypothesis that prostate inflammation could contribute to the development and worsening of LUTS.