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The Link Between Benign Prostatic Hyperplasia and Inflammation
EUROPEAN UROLOGY SUPPLEMENTS 12 (2013) 103–109
available at www.sciencedirect.com journal homepage: www.europeanurology.com
The Link Between Benign Prostatic Hyperplasia and Inflammation Maria J. Ribal * Uro-Oncology Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain
Article info
Abstract
Keywords: Benign prostatic hyperplasia Inflammation Metabolic syndrome Pathogenesis Prostate
Context: Benign prostatic hyperplasia (BPH) is one of the most common diseases associated with the aging process in men, particularly men aged >50 yr, yet only a few predictive factors have been identified. In recent years, attention has focused on the role of prostatic inflammation in the pathogenesis and progression of BPH. Objective: This article reviews recent findings related to the potential link between local and systemic inflammation and BPH. Evidence acquisition: In March 2013, at the annual meeting of the European Association of Urology in Milan, Italy, a satellite symposium entitled ‘‘Benign Prostatic Hypertrophy (BPH) and Inflammation, from Lab to Clinic,’’ was held with the goal of reviewing the latest data relating to the link between inflammation and BPH. This paper is based on one of the presentations at this symposium. A structured PubMed literature search was performed, and emphasis was placed on results from the past 10 yr. Evidence synthesis: BPH is characterized by progressive hyperplasia of stromal and glandular cells, and clinically it is defined by lower urinary tract symptoms. In recent years, there has been accumulating evidence linking prostatic inflammation with BPH. The inflammatory infiltrates observed in patients with BPH are composed primarily of chronically activated T-lymphocytes. Cytokines and growth factors released from inflammatory cells create a proinflammatory environment that may support the fibromuscular growth seen in BPH and may also be responsible for inducing a state of relative hypoxia as a result of the increased oxygen demand of the proliferating cells. A number of clinical studies have confirmed the presence of inflammatory infiltrate in men with BPH, and this infiltrate has been shown to be involved in the pathogenesis, clinical appearance, and progression of this disorder. There is evidence emerging that systemic inflammation may also play a role in BPH, since in men with metabolic syndrome there was a significant correlation between prostate diameter/volume and the number of metabolic syndrome components. Conclusions: It is clear that a number of different mechanisms are involved in the development and progression of BPH. Prostatic inflammation is an important feature, since it appears to be involved in the pathogenesis, symptomatology, and progression of the disease. # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
* Corresponding author. Department of Urology, Hospital Clinic University of Barcelona, Villarroel 170, Escalera 12, planta 1a, 08036 Barcelona, Spain. E-mail address: [email protected].
1569-9056/$ – see front matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology. http://dx.doi.org/10.1016/j.eursup.2013.08.001
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Introduction
Benign prostatic hyperplasia (BPH) is a histologic condition defined by hyperplastic growth of both epithelial (glandular) and stromal tissues. This well-established and progressive disorder is characterized by prostate enlargement and is often accompanied by lower urinary tract symptoms (LUTS) [1,2]. BPH is a disease associated with aging in males. It has been estimated that approximately 40–50% of men aged 51–60 yr have histologic evidence of BPH, and the prevalence increases to approximately 70% in men aged 61– 70 yr and to 80–90% in men aged 81–90 yr (Fig. 1A) [1,3–5]. The presence of LUTS parallels that of histologic BPH, and increases in prevalence from the fifth decade of life secondary to an enlarged prostate gland (Fig. 1B) [3,4,6]. However, not all men develop clinical symptoms as a consequence of prostate enlargement. In a U.S. study, the odds of developing moderate to severe LUTS increased in men aged >50 yr and were 3.5 times greater in men with prostate volumes >50 ml and 2.4 times greater in men with a flow rate of <10 ml/s [4]. The possible link between inflammation and prostate hyperplasia was suggested almost 80 yr ago [7]. During the intervening years, this relationship has been the focus of many reports, and our knowledge of the pathophysiologic processes involved has improved. For example, in 1979, Kohnen and Drach examined 162 surgically resected prostate glands and found evidence of inflammation in
98.1% [8]. Six different morphologic patterns of inflammation were observed, with the most common being a segregated glandular inflammation characterized by intraluminal neutrophils and foamy macrophages, and by the presence of inflammatory cells in the surrounding stroma [8]. The aim of this review is to examine the link between inflammation and BPH based on a review of recent literature in this clinical setting. 2.
Evidence acquisition
In March 2013, at the annual meeting of the European Association of Urology in Milan, Italy, a satellite symposium entitled ‘‘Benign Prostatic Hypertrophy (BPH) and Inflammation, from Lab to Clinic,’’ was held with the goal of reviewing the latest data relating to the link between inflammation and BPH. This paper is based on one of the presentations at this symposium. Data were acquired by a search of PubMed using keywords such as benign prostatic hyperplasia, prostatic hyperplasia, and prostatic hypertrophy in combination with inflammation. Additional references were identified from the reference sections of identified publications. Although English language was not a specific search parameter, publications were limited to those in English. The main search was based on results from the past 10 yr, and older data were selected from major reviews in this therapeutic setting. 3.
Evidence synthesis
Aging remains the single most significant risk factor for prostate enlargement and the development of BPH, as well as for the onset of LUTS [1,3–5]. However, as noted, not all men develop symptoms; other mechanisms have been implicated in the onset and progression of BPH and LUTS, including inflammation, hormonal changes, tissue remodeling (changing the structure of the stroma in the prostate), and metabolic syndrome [1]. 3.1.
Fig. 1 – (A) Presence of benign prostatic hyperplasia by autopsy and (B) prevalence of moderate to severe lower urinary tract symptoms by age group. Adapted from Berry et al. [5] and Chute et al. [6].
The role of inflammation in benign prostatic hyperplasia
In recent years there has been increased focus on the role of chronic inflammation in the pathogenesis of BPH, and inflammatory infiltrates have been demonstrated in the majority of pathologic specimens (Table 1) [8–17]. Like the intestine, the prostate is considered an immunocompetent organ and is normally populated by small numbers of T cells, B cells, macrophages, and mast cells, which are scattered in the stromal and glandular tissue (Fig. 2A) [18,19]. The number of T cells generally increases with age but is most pronounced in BPH (approximately 30-fold); at the same time, the ratio between helper CD4 T cells and cytotoxic/ suppressor T cells is reversed [20,21]. Inflammatory infiltrates are mainly composed of chronically activated T cells (approximately 70%), B lymphocytes (approximately 15%), and macrophages (approximately 15%), and these infiltrating cells are responsible for the production and release of cytokines, which may support the fibromuscular growth
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Table 1 – Details from studies supporting the role of inflammation in the pathophysiology of benign prostatic hyperplasia Study Kohnen and Drach [8] Kramer et al. [9] Kramer and Marberger [10] Theyer et al. [11] Steiner et al. [12] Steiner et al. [13] Kakehi et al. [14] Handisurya et al. [15] Royuela et al. [16] Giri and Ittmann [17]
Key findings High inflammatory infiltrate prevalence in BPH specimens Chronic inflammation supporting the process of fibromuscular growth in BPH Inflammation associated with significantly larger prostates, higher PSA levels, and greater risk of acute urinary retention BPH tissue containing a disseminated infiltration of T lymphocytes, B lymphocytes, and macrophages Inflammation mediators chronically activated in BPH Upregulation of IL-17 in infiltrating T cells Downregulation of the gene for MIC-1 in BPH Upregulation of IL-15 in stromal cells Upregulation of IFN-g in basal and stromal cells Upregulation of IL-8 in epithelial cells
BPH = benign prostatic hyperplasia; IFN-g = interferon-g; IL = interleukin; MIC-1 = macrophage inhibitory cytokine-1; PSA = prostate-specific antigen. Adapted with permission from Elsevier [1].
associated with BPH (Fig. 2B) [3,9,13,18]. Focal proliferation of smooth muscle cells leads to the nodular arrangement that is characteristic of BPH. Briganti and colleagues suggested that the inflammation found in BPH may contribute to tissue injury, and the cytokines produced by inflammatory cells might increase growth factor production and angiogenesis in the prostate as a type of wound-healing response [1]. Although the presence of inflammatory infiltrate in human prostates is well documented, its origin remains unclear [18]. The prostatic inflammation observed in patients with BPH is associated with cytokine release that creates a proinflammatory environment and a state of relative hypoxia as a result of the increased oxygen demand of the proliferating cells [18]. Cytokines and growth factors released from inflammatory cells may interact not only with immune effectors but also with stromal and epithelial cells; in turn, the epithelial cells have been shown to
release inflammatory mediators [22]. Kramer and colleagues investigated the effect of lymphocyte-derived growth factors on prostatic stromal cell growth [9]. They demonstrated that BPH tissue contains infiltrates of T cells, B cells, and macrophages that are chronically activated and responsible for the release of cytokines (mostly interleukin [IL]-2, interferon-g [IFN-g], and transforming growth factorb) that may support fibromuscular growth in BPH. A number of different proinflammatory cytokines (particularly IL-17 in infiltrating T cells, IL-15 in stromal cells, IFN-g in basal and stromal cells, and IL-8 in epithelial cells) have been reported to be upregulated in BPH [1]. A number of cytokines and growth factors, released from various infiltrating cells, have a potential role in the chronic inflammation of BPH (Table 2) [9,11,13,20,23–39]. Accumulation of chronically activated T cells in the stroma and epithelium suggests a link between T-cell–derived cytokines and the fibromyomatous growth of BPH. The proinflammatory environment associated with BPH results in a hyperproliferative state (initially in the stroma, which becomes enlarged with an altered cellular composition), as well as other characteristic histologic changes including basal cell hyperplasia of the epithelium (for further details see Ficarra et al. [40], in this Supplement) [41]. BPH is a multifactorial disease involving endocrine, environmental, and genetic factors; while no specific gene mutations define BPH, DNA methylation is globally reduced [42]. To better understand the molecular differences underlying BPH, Prakash and coworkers performed gene expression profiling from prostate transition zone samples obtained from healthy individuals and from patients with symptomatic BPH, asymptomatic BPH, or prostate cancer (PCa) using microarrays [43]. These researchers identified a set of 511 differentially expressed genes that could distinguish between symptomatic and asymptomatic BPH. The authors noted a strong correlation between genes expressing several inflammatory mediators and genes found in symptomatic BPH tissue. 3.2.
Clinical findings involving prostate inflammation and
benign prostatic hyperplasia Fig. 2 – Role of inflammation in benign prostatic hyperplasia: (A) normal prostate and (B) benign prostatic hyperplasia. Adapted from De Marzo et al. [19], with permission of Dr. Ficarra. IL = interleukin; IFNg = interferon-g; TGF-b = transforming growth factor b.
The Reduction by Dutasteride of Prostate Cancer Events trial reported findings from 8224 men at increased risk of
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Table 2 – Immune cell types and their potential role in benign prostatic hyperplasia Inflammatory cell types
Role in BPH
T cells (no further details)
Stimulation of stromal growth Recognition of prostatic (auto)antigens Hypothetical role in morphogenesis of prostate gland Gland destruction in more advanced BPH Maintenance of peripheral tolerance Stimulation of stromal and epithelial cell proliferation Augmentation of IL-15 production by stromal cells Recruitment of more T cells into BPH areas Increased prostatic synthesis of active androgens via production of IL-4 and IL-13 Production of IL-17, stimulation of stromal and epithelial growth by promotion of stromal cell cytokine secretion (IL-6, IL-8) Stimulation of secretion of proinflammatory cytokines by epithelial, endothelial, and fibroblastic cells Autoimmune-mediated tissue destruction Immune response against epithelial-associated intracellular microorganisms Unknown, probable role in antigen presentation and humoral (auto)immune response Increased attraction into BPH tissue by downregulation of MIC-1, antigen presentation, or regulation of COX-2 expression in BPH epithelium Unknown Unknown Suppression of chronic nonbacterial prostatitis in Sprague-Dawley rats Unknown
CD8+ cytotoxic T cells CD8+ suppressor T cells CD4+ T-helper 1 cells
CD4+ T-helper 2 and T-helper 0 cells T-helper 17 cells
gd T cells B cells Macrophages Dendritic cells NK cells NK T cells Mast cells
Citation [9,23] [24–26] [11,27] [28] [29,30] [22,23] [9] [9,13] [31,32] [13] [33] [34] [35,36] [37] [38,39]
[30]
BPH = benign prostatic hyperplasia; IL = interleukin; MIC-1 = macrophage inhibitory cytokine 1; COX-2 = cyclooxygenase 2; NK = natural killer. Adapted with permission from Elsevier [20].
developing PCa who underwent prostate biopsy testing at baseline and who were randomly allocated to treatment with dutasteride or placebo [44]. In this cohort of older males (aged 50–75 yr), approximately 80% presented with chronic inflammation (89% mild and 11% moderate), and approximately 15% presented with acute inflammation (98% mild and 2% moderate). Comparing baseline biopsy data with the clinical characteristics of BPH demonstrated a significant relationship between inflammation on the one hand and prostate volume and total International Prostate Symptom Score (IPSS) on the other hand. Therefore, inflammation is involved in not only the pathogenesis of BPH but also its clinical symptomatology. It has been hypothesized that the presence of inflammation may be a predictor of BPH progression. Baseline prostate biopsies in a subgroup of 1197 patients in the Medical Therapy of Prostatic Symptoms study found that there was a chronic inflammatory infiltrate in 43% of the men. There was a highly clinically significant difference in the BPH progression rate based on the presence or absence of inflammation [45]. Patients in all groups with inflammation were more likely to progress clinically in terms of BPH symptoms, acute urinary retention, or BPH-related surgery (Fig. 3). Using data from the Prostate Cancer Prevention Trial, Schenk and colleagues investigated the link between serum inflammatory biomarkers and the risk of symptomatic BPH [46]. They found that high levels of C-reactive protein and IL-6, and low levels of soluble tissue necrosis factor receptor II, were associated with increased risk of BPH. Similarly, an immunohistochemical study involving clinical outcome tissue microarrays from 282 patients treated surgically for BPH noted the presence of inflammatory infiltrates in prostate samples [47]. CD8 T lymphocytes and macrophages were present in >80% of patients, and the role of inflammation in BPH progression was highlighted by
the strong correlation between histologic inflammation and IPSS scores and prostate volume [46]. In another study involving 374 patients undergoing surgery (transurethral resection of the prostate), 70% of the men had acute or chronic inflammation, compared with only 45% of men with LUTS [48]. Again, these data highlight the importance of prostatic inflammation in the pathogenesis and progression of BPH. BPH progression has been linked not only to local (prostatic) inflammation but also to systemic inflammation. Perhaps the most convincing evidence comes from patients with metabolic syndrome. The precise nature of the association between BPH and metabolic syndrome is poorly understood [49], but it has been shown that males with metabolic syndrome are more likely to undergo surgery for BPH [50] and to have faster-progressing disease [51].
Paents (%) 25 21.0 20 15
No inflammaon inflammaon Inflammaon 13.2
10
7.3 5.6 3.9
5 0
0.0 Progression
Surgery
AUR
Fig. 3 – Impact of inflammation at baseline on benign prostatic hyperplasia (BPH) progression, BPH-related surgery, and acute urinary retention in placebo-treated patients in the Medical Therapy of Prostatic Symptoms trial. Adapted from Roehrmann [44]. AUR = acute urinary retention.
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(B)
95
95% CI A-P prostate diameter, mm
95% CI prostate volume, ml
(A)
85 75 65 55 45 35
65
55
45
35
25 0
1
2
3
4
5
0
1
No. of posive parameters of METs
2
3
4
5
No. of posive parameters of METs
Fig. 4 – Correlation between (A) prostate volume and (B) prostate anteroposterior diameter and the number of individual components of metabolic syndrome in 271 patients with benign prostatic hyperplasia. Adapted with permission from the Nature Publishing Group [51]. A-P = anteroposterior; CI = confidence interval; METs = metabolic syndrome.
Recently, Gacci and colleagues investigated the link between BPH severity/LUTS, prostatic inflammatory infiltrates, and metabolic syndrome preoperatively in 271 men undergoing prostatectomy [52]. Almost one-third of the cohort had metabolic syndrome, and there was a significant positive correlation between prostatic volume (r = 0.151; p < 0.03) and the anteroposterior diameter of the prostate (r = 0.267; p < 0.0001) with the number of metabolic syndrome components (Fig. 4). In these patients, there was also a strong correlation between intraprostatic inflammation and glandular disruption on the one hand and BPH symptoms as assessed by IPSS scores on the other hand. The authors concluded that metabolic syndrome can be regarded as a new determinant of prostatic inflammation and BPH progression. However, the situation is not always so clear, as was recently shown by Willder et al. in Scotland [53]. This group used Glasgow scores as a measure of systemic inflammation and Klintrup-Makinen criteria and tissue necrosis as a Basic science
Mechanisms Inflammatory cascades Neurogenic mechanisms Endocrine influences Genetic predictors
measure of local inflammation in 392 patients with histologically confirmed BPH. There was a trend for increased local inflammation and tissue necrosis to be associated with shorter time to failure of preoperative medical treatment of BPH ( p = 0.096 and 0.088, respectively), but there was no correlation of systemic inflammation with treatment failure. This group concluded that it was unclear whether targeting inflammation in BPH has therapeutic potential. 4.
Conclusions
Based on a review of current best evidence in the literature, it seems clear that a number of different mechanisms are involved in the development and progression of BPH. Immune inflammatory changes in the prostate gland appear to be important features involved in the pathogenesis and progression of the disease, although the processes involved are not fully understood. A translational approach to
Translational science
Clinical sciences
Pathology and epidemiological observation
Clinical observation in patients
Potential biomarkers
Epidemiology of selected biomarkers in targeted populations
Potential therapeutic target
Evaluation of epidemiological evidence
Prospective evaluation of biomarkers and their clinical utility
Pilot studies (proof of concept)
Large prospective randomized clinical trials
Improved management of target population Fig. 5 – A proposed translational approach (bench to bedside) to future research of benign prostatic hyperplasia (BPH) to further our understanding of the association between inflammation and lower urinary tract symptoms due to BPH and to help identify patients at risk and in need of more focused treatment. Reproduced with permission from Elsevier [3].
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research (bench to bedside) has been advocated to help focus future research efforts and to help clarify the full nature of the inflammation–BPH association (Fig. 5) [3]. A better understanding of the role of inflammation in BPH and clinical detection of this inflammation will expand our understanding of the mechanisms involved in BPH pathogenesis and progression. Such information should also enable us to identify patients at risk and ultimately may assist us in developing improved treatment strategies. Early data have identified a positive correlation between the number of metabolic syndrome components and prostate volume, and chronic systemic inflammation has been proposed as a possible mechanism linking metabolic syndrome and BPH. However, further epidemiological research and prospective clinical trials are still required to help us elucidate the nature of this association and how we may use such knowledge in everyday practice.
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Conflicts of interest
[17] Giri D, Ittmann M. Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign
Maria J. Ribal has received fees for serving as a speaker and/ or consultant for Ipsen, Janssen, Olympus, and Pierre Fabre within the last 3 yr.
prostatic hyperplasia. Am J Pathol 2001;159:139–47. [18] De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol 2011;60:106–17.
Funding support The author’s participation in the satellite symposium at the European Urology Association meeting on March 17, 2013, in Milan, Italy, was supported by a grant from Pierre Fabre Medicament, France.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
The Link Between Benign Prostatic Hyperplasia and Inflammation Maria J. Ribal * Uro-Oncology Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain
Article info
Abstract
Keywords: Benign prostatic hyperplasia Inflammation Metabolic syndrome Pathogenesis Prostate
Context: Benign prostatic hyperplasia (BPH) is one of the most common diseases associated with the aging process in men, particularly men aged >50 yr, yet only a few predictive factors have been identified. In recent years, attention has focused on the role of prostatic inflammation in the pathogenesis and progression of BPH. Objective: This article reviews recent findings related to the potential link between local and systemic inflammation and BPH. Evidence acquisition: In March 2013, at the annual meeting of the European Association of Urology in Milan, Italy, a satellite symposium entitled ‘‘Benign Prostatic Hypertrophy (BPH) and Inflammation, from Lab to Clinic,’’ was held with the goal of reviewing the latest data relating to the link between inflammation and BPH. This paper is based on one of the presentations at this symposium. A structured PubMed literature search was performed, and emphasis was placed on results from the past 10 yr. Evidence synthesis: BPH is characterized by progressive hyperplasia of stromal and glandular cells, and clinically it is defined by lower urinary tract symptoms. In recent years, there has been accumulating evidence linking prostatic inflammation with BPH. The inflammatory infiltrates observed in patients with BPH are composed primarily of chronically activated T-lymphocytes. Cytokines and growth factors released from inflammatory cells create a proinflammatory environment that may support the fibromuscular growth seen in BPH and may also be responsible for inducing a state of relative hypoxia as a result of the increased oxygen demand of the proliferating cells. A number of clinical studies have confirmed the presence of inflammatory infiltrate in men with BPH, and this infiltrate has been shown to be involved in the pathogenesis, clinical appearance, and progression of this disorder. There is evidence emerging that systemic inflammation may also play a role in BPH, since in men with metabolic syndrome there was a significant correlation between prostate diameter/volume and the number of metabolic syndrome components. Conclusions: It is clear that a number of different mechanisms are involved in the development and progression of BPH. Prostatic inflammation is an important feature, since it appears to be involved in the pathogenesis, symptomatology, and progression of the disease. # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
* Corresponding author. Department of Urology, Hospital Clinic University of Barcelona, Villarroel 170, Escalera 12, planta 1a, 08036 Barcelona, Spain. E-mail address: [email protected].
1569-9056/$ – see front matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology. http://dx.doi.org/10.1016/j.eursup.2013.08.001
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Introduction
Benign prostatic hyperplasia (BPH) is a histologic condition defined by hyperplastic growth of both epithelial (glandular) and stromal tissues. This well-established and progressive disorder is characterized by prostate enlargement and is often accompanied by lower urinary tract symptoms (LUTS) [1,2]. BPH is a disease associated with aging in males. It has been estimated that approximately 40–50% of men aged 51–60 yr have histologic evidence of BPH, and the prevalence increases to approximately 70% in men aged 61– 70 yr and to 80–90% in men aged 81–90 yr (Fig. 1A) [1,3–5]. The presence of LUTS parallels that of histologic BPH, and increases in prevalence from the fifth decade of life secondary to an enlarged prostate gland (Fig. 1B) [3,4,6]. However, not all men develop clinical symptoms as a consequence of prostate enlargement. In a U.S. study, the odds of developing moderate to severe LUTS increased in men aged >50 yr and were 3.5 times greater in men with prostate volumes >50 ml and 2.4 times greater in men with a flow rate of <10 ml/s [4]. The possible link between inflammation and prostate hyperplasia was suggested almost 80 yr ago [7]. During the intervening years, this relationship has been the focus of many reports, and our knowledge of the pathophysiologic processes involved has improved. For example, in 1979, Kohnen and Drach examined 162 surgically resected prostate glands and found evidence of inflammation in
98.1% [8]. Six different morphologic patterns of inflammation were observed, with the most common being a segregated glandular inflammation characterized by intraluminal neutrophils and foamy macrophages, and by the presence of inflammatory cells in the surrounding stroma [8]. The aim of this review is to examine the link between inflammation and BPH based on a review of recent literature in this clinical setting. 2.
Evidence acquisition
In March 2013, at the annual meeting of the European Association of Urology in Milan, Italy, a satellite symposium entitled ‘‘Benign Prostatic Hypertrophy (BPH) and Inflammation, from Lab to Clinic,’’ was held with the goal of reviewing the latest data relating to the link between inflammation and BPH. This paper is based on one of the presentations at this symposium. Data were acquired by a search of PubMed using keywords such as benign prostatic hyperplasia, prostatic hyperplasia, and prostatic hypertrophy in combination with inflammation. Additional references were identified from the reference sections of identified publications. Although English language was not a specific search parameter, publications were limited to those in English. The main search was based on results from the past 10 yr, and older data were selected from major reviews in this therapeutic setting. 3.
Evidence synthesis
Aging remains the single most significant risk factor for prostate enlargement and the development of BPH, as well as for the onset of LUTS [1,3–5]. However, as noted, not all men develop symptoms; other mechanisms have been implicated in the onset and progression of BPH and LUTS, including inflammation, hormonal changes, tissue remodeling (changing the structure of the stroma in the prostate), and metabolic syndrome [1]. 3.1.
Fig. 1 – (A) Presence of benign prostatic hyperplasia by autopsy and (B) prevalence of moderate to severe lower urinary tract symptoms by age group. Adapted from Berry et al. [5] and Chute et al. [6].
The role of inflammation in benign prostatic hyperplasia
In recent years there has been increased focus on the role of chronic inflammation in the pathogenesis of BPH, and inflammatory infiltrates have been demonstrated in the majority of pathologic specimens (Table 1) [8–17]. Like the intestine, the prostate is considered an immunocompetent organ and is normally populated by small numbers of T cells, B cells, macrophages, and mast cells, which are scattered in the stromal and glandular tissue (Fig. 2A) [18,19]. The number of T cells generally increases with age but is most pronounced in BPH (approximately 30-fold); at the same time, the ratio between helper CD4 T cells and cytotoxic/ suppressor T cells is reversed [20,21]. Inflammatory infiltrates are mainly composed of chronically activated T cells (approximately 70%), B lymphocytes (approximately 15%), and macrophages (approximately 15%), and these infiltrating cells are responsible for the production and release of cytokines, which may support the fibromuscular growth
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Table 1 – Details from studies supporting the role of inflammation in the pathophysiology of benign prostatic hyperplasia Study Kohnen and Drach [8] Kramer et al. [9] Kramer and Marberger [10] Theyer et al. [11] Steiner et al. [12] Steiner et al. [13] Kakehi et al. [14] Handisurya et al. [15] Royuela et al. [16] Giri and Ittmann [17]
Key findings High inflammatory infiltrate prevalence in BPH specimens Chronic inflammation supporting the process of fibromuscular growth in BPH Inflammation associated with significantly larger prostates, higher PSA levels, and greater risk of acute urinary retention BPH tissue containing a disseminated infiltration of T lymphocytes, B lymphocytes, and macrophages Inflammation mediators chronically activated in BPH Upregulation of IL-17 in infiltrating T cells Downregulation of the gene for MIC-1 in BPH Upregulation of IL-15 in stromal cells Upregulation of IFN-g in basal and stromal cells Upregulation of IL-8 in epithelial cells
BPH = benign prostatic hyperplasia; IFN-g = interferon-g; IL = interleukin; MIC-1 = macrophage inhibitory cytokine-1; PSA = prostate-specific antigen. Adapted with permission from Elsevier [1].
associated with BPH (Fig. 2B) [3,9,13,18]. Focal proliferation of smooth muscle cells leads to the nodular arrangement that is characteristic of BPH. Briganti and colleagues suggested that the inflammation found in BPH may contribute to tissue injury, and the cytokines produced by inflammatory cells might increase growth factor production and angiogenesis in the prostate as a type of wound-healing response [1]. Although the presence of inflammatory infiltrate in human prostates is well documented, its origin remains unclear [18]. The prostatic inflammation observed in patients with BPH is associated with cytokine release that creates a proinflammatory environment and a state of relative hypoxia as a result of the increased oxygen demand of the proliferating cells [18]. Cytokines and growth factors released from inflammatory cells may interact not only with immune effectors but also with stromal and epithelial cells; in turn, the epithelial cells have been shown to
release inflammatory mediators [22]. Kramer and colleagues investigated the effect of lymphocyte-derived growth factors on prostatic stromal cell growth [9]. They demonstrated that BPH tissue contains infiltrates of T cells, B cells, and macrophages that are chronically activated and responsible for the release of cytokines (mostly interleukin [IL]-2, interferon-g [IFN-g], and transforming growth factorb) that may support fibromuscular growth in BPH. A number of different proinflammatory cytokines (particularly IL-17 in infiltrating T cells, IL-15 in stromal cells, IFN-g in basal and stromal cells, and IL-8 in epithelial cells) have been reported to be upregulated in BPH [1]. A number of cytokines and growth factors, released from various infiltrating cells, have a potential role in the chronic inflammation of BPH (Table 2) [9,11,13,20,23–39]. Accumulation of chronically activated T cells in the stroma and epithelium suggests a link between T-cell–derived cytokines and the fibromyomatous growth of BPH. The proinflammatory environment associated with BPH results in a hyperproliferative state (initially in the stroma, which becomes enlarged with an altered cellular composition), as well as other characteristic histologic changes including basal cell hyperplasia of the epithelium (for further details see Ficarra et al. [40], in this Supplement) [41]. BPH is a multifactorial disease involving endocrine, environmental, and genetic factors; while no specific gene mutations define BPH, DNA methylation is globally reduced [42]. To better understand the molecular differences underlying BPH, Prakash and coworkers performed gene expression profiling from prostate transition zone samples obtained from healthy individuals and from patients with symptomatic BPH, asymptomatic BPH, or prostate cancer (PCa) using microarrays [43]. These researchers identified a set of 511 differentially expressed genes that could distinguish between symptomatic and asymptomatic BPH. The authors noted a strong correlation between genes expressing several inflammatory mediators and genes found in symptomatic BPH tissue. 3.2.
Clinical findings involving prostate inflammation and
benign prostatic hyperplasia Fig. 2 – Role of inflammation in benign prostatic hyperplasia: (A) normal prostate and (B) benign prostatic hyperplasia. Adapted from De Marzo et al. [19], with permission of Dr. Ficarra. IL = interleukin; IFNg = interferon-g; TGF-b = transforming growth factor b.
The Reduction by Dutasteride of Prostate Cancer Events trial reported findings from 8224 men at increased risk of
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Table 2 – Immune cell types and their potential role in benign prostatic hyperplasia Inflammatory cell types
Role in BPH
T cells (no further details)
Stimulation of stromal growth Recognition of prostatic (auto)antigens Hypothetical role in morphogenesis of prostate gland Gland destruction in more advanced BPH Maintenance of peripheral tolerance Stimulation of stromal and epithelial cell proliferation Augmentation of IL-15 production by stromal cells Recruitment of more T cells into BPH areas Increased prostatic synthesis of active androgens via production of IL-4 and IL-13 Production of IL-17, stimulation of stromal and epithelial growth by promotion of stromal cell cytokine secretion (IL-6, IL-8) Stimulation of secretion of proinflammatory cytokines by epithelial, endothelial, and fibroblastic cells Autoimmune-mediated tissue destruction Immune response against epithelial-associated intracellular microorganisms Unknown, probable role in antigen presentation and humoral (auto)immune response Increased attraction into BPH tissue by downregulation of MIC-1, antigen presentation, or regulation of COX-2 expression in BPH epithelium Unknown Unknown Suppression of chronic nonbacterial prostatitis in Sprague-Dawley rats Unknown
CD8+ cytotoxic T cells CD8+ suppressor T cells CD4+ T-helper 1 cells
CD4+ T-helper 2 and T-helper 0 cells T-helper 17 cells
gd T cells B cells Macrophages Dendritic cells NK cells NK T cells Mast cells
Citation [9,23] [24–26] [11,27] [28] [29,30] [22,23] [9] [9,13] [31,32] [13] [33] [34] [35,36] [37] [38,39]
[30]
BPH = benign prostatic hyperplasia; IL = interleukin; MIC-1 = macrophage inhibitory cytokine 1; COX-2 = cyclooxygenase 2; NK = natural killer. Adapted with permission from Elsevier [20].
developing PCa who underwent prostate biopsy testing at baseline and who were randomly allocated to treatment with dutasteride or placebo [44]. In this cohort of older males (aged 50–75 yr), approximately 80% presented with chronic inflammation (89% mild and 11% moderate), and approximately 15% presented with acute inflammation (98% mild and 2% moderate). Comparing baseline biopsy data with the clinical characteristics of BPH demonstrated a significant relationship between inflammation on the one hand and prostate volume and total International Prostate Symptom Score (IPSS) on the other hand. Therefore, inflammation is involved in not only the pathogenesis of BPH but also its clinical symptomatology. It has been hypothesized that the presence of inflammation may be a predictor of BPH progression. Baseline prostate biopsies in a subgroup of 1197 patients in the Medical Therapy of Prostatic Symptoms study found that there was a chronic inflammatory infiltrate in 43% of the men. There was a highly clinically significant difference in the BPH progression rate based on the presence or absence of inflammation [45]. Patients in all groups with inflammation were more likely to progress clinically in terms of BPH symptoms, acute urinary retention, or BPH-related surgery (Fig. 3). Using data from the Prostate Cancer Prevention Trial, Schenk and colleagues investigated the link between serum inflammatory biomarkers and the risk of symptomatic BPH [46]. They found that high levels of C-reactive protein and IL-6, and low levels of soluble tissue necrosis factor receptor II, were associated with increased risk of BPH. Similarly, an immunohistochemical study involving clinical outcome tissue microarrays from 282 patients treated surgically for BPH noted the presence of inflammatory infiltrates in prostate samples [47]. CD8 T lymphocytes and macrophages were present in >80% of patients, and the role of inflammation in BPH progression was highlighted by
the strong correlation between histologic inflammation and IPSS scores and prostate volume [46]. In another study involving 374 patients undergoing surgery (transurethral resection of the prostate), 70% of the men had acute or chronic inflammation, compared with only 45% of men with LUTS [48]. Again, these data highlight the importance of prostatic inflammation in the pathogenesis and progression of BPH. BPH progression has been linked not only to local (prostatic) inflammation but also to systemic inflammation. Perhaps the most convincing evidence comes from patients with metabolic syndrome. The precise nature of the association between BPH and metabolic syndrome is poorly understood [49], but it has been shown that males with metabolic syndrome are more likely to undergo surgery for BPH [50] and to have faster-progressing disease [51].
Paents (%) 25 21.0 20 15
No inflammaon inflammaon Inflammaon 13.2
10
7.3 5.6 3.9
5 0
0.0 Progression
Surgery
AUR
Fig. 3 – Impact of inflammation at baseline on benign prostatic hyperplasia (BPH) progression, BPH-related surgery, and acute urinary retention in placebo-treated patients in the Medical Therapy of Prostatic Symptoms trial. Adapted from Roehrmann [44]. AUR = acute urinary retention.
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(B)
95
95% CI A-P prostate diameter, mm
95% CI prostate volume, ml
(A)
85 75 65 55 45 35
65
55
45
35
25 0
1
2
3
4
5
0
1
No. of posive parameters of METs
2
3
4
5
No. of posive parameters of METs
Fig. 4 – Correlation between (A) prostate volume and (B) prostate anteroposterior diameter and the number of individual components of metabolic syndrome in 271 patients with benign prostatic hyperplasia. Adapted with permission from the Nature Publishing Group [51]. A-P = anteroposterior; CI = confidence interval; METs = metabolic syndrome.
Recently, Gacci and colleagues investigated the link between BPH severity/LUTS, prostatic inflammatory infiltrates, and metabolic syndrome preoperatively in 271 men undergoing prostatectomy [52]. Almost one-third of the cohort had metabolic syndrome, and there was a significant positive correlation between prostatic volume (r = 0.151; p < 0.03) and the anteroposterior diameter of the prostate (r = 0.267; p < 0.0001) with the number of metabolic syndrome components (Fig. 4). In these patients, there was also a strong correlation between intraprostatic inflammation and glandular disruption on the one hand and BPH symptoms as assessed by IPSS scores on the other hand. The authors concluded that metabolic syndrome can be regarded as a new determinant of prostatic inflammation and BPH progression. However, the situation is not always so clear, as was recently shown by Willder et al. in Scotland [53]. This group used Glasgow scores as a measure of systemic inflammation and Klintrup-Makinen criteria and tissue necrosis as a Basic science
Mechanisms Inflammatory cascades Neurogenic mechanisms Endocrine influences Genetic predictors
measure of local inflammation in 392 patients with histologically confirmed BPH. There was a trend for increased local inflammation and tissue necrosis to be associated with shorter time to failure of preoperative medical treatment of BPH ( p = 0.096 and 0.088, respectively), but there was no correlation of systemic inflammation with treatment failure. This group concluded that it was unclear whether targeting inflammation in BPH has therapeutic potential. 4.
Conclusions
Based on a review of current best evidence in the literature, it seems clear that a number of different mechanisms are involved in the development and progression of BPH. Immune inflammatory changes in the prostate gland appear to be important features involved in the pathogenesis and progression of the disease, although the processes involved are not fully understood. A translational approach to
Translational science
Clinical sciences
Pathology and epidemiological observation
Clinical observation in patients
Potential biomarkers
Epidemiology of selected biomarkers in targeted populations
Potential therapeutic target
Evaluation of epidemiological evidence
Prospective evaluation of biomarkers and their clinical utility
Pilot studies (proof of concept)
Large prospective randomized clinical trials
Improved management of target population Fig. 5 – A proposed translational approach (bench to bedside) to future research of benign prostatic hyperplasia (BPH) to further our understanding of the association between inflammation and lower urinary tract symptoms due to BPH and to help identify patients at risk and in need of more focused treatment. Reproduced with permission from Elsevier [3].
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research (bench to bedside) has been advocated to help focus future research efforts and to help clarify the full nature of the inflammation–BPH association (Fig. 5) [3]. A better understanding of the role of inflammation in BPH and clinical detection of this inflammation will expand our understanding of the mechanisms involved in BPH pathogenesis and progression. Such information should also enable us to identify patients at risk and ultimately may assist us in developing improved treatment strategies. Early data have identified a positive correlation between the number of metabolic syndrome components and prostate volume, and chronic systemic inflammation has been proposed as a possible mechanism linking metabolic syndrome and BPH. However, further epidemiological research and prospective clinical trials are still required to help us elucidate the nature of this association and how we may use such knowledge in everyday practice.
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Conflicts of interest
[17] Giri D, Ittmann M. Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign
Maria J. Ribal has received fees for serving as a speaker and/ or consultant for Ipsen, Janssen, Olympus, and Pierre Fabre within the last 3 yr.
prostatic hyperplasia. Am J Pathol 2001;159:139–47. [18] De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol 2011;60:106–17.
Funding support The author’s participation in the satellite symposium at the European Urology Association meeting on March 17, 2013, in Milan, Italy, was supported by a grant from Pierre Fabre Medicament, France.
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