The Controversial Relationship Between Benign Prostatic Hyperplasia and Prostate Cancer: The Role of Inflammation

Abstract

Context

Prostate cancer (PCa) is the most common cancer in the adult male, and benign prostatic hyperplasia (BPH) represents the most frequent urologic diagnosis in elderly males. Recent data suggest that prostatic inflammation is involved in the pathogenesis and progression of both conditions.

Objective

This review aims to evaluate the available evidence on the role of prostatic inflammation as a possible common denominator of BPH and PCa and to discuss its possible clinical implication for the management, prevention, and treatment of both diseases.

Evidence acquisition

The National Library of Medicine Database was searched for the following Patient population, Intervention, Comparison, Outcome (PICO) terms: male, inflammation, benign prostatic hyperplasia, prostate cancer, diagnosis, progression, prognosis, treatment, and prevention. Basic and clinical studies published in the past 10 yr were reviewed. Additional references were obtained from the reference list of full-text manuscripts.

Evidence synthesis

The histologic signature of chronic inflammation is a common finding in benign and malignant prostate tissue. The inflammatory infiltrates are mainly represented by CD3⁺ T lymphocytes (70–80%, mostly CD4), CD19 or CD20 B lymphocytes (10–15%), and macrophages (15%). Bacterial infections, urine reflux, dietary factors, hormones, and autoimmune response have been considered to cause inflammation in the prostate. From a pathophysiologic standpoint, tissue damage associated with inflammatory response and subsequent chronic tissue healing may result in the development of BPH nodules and proliferative inflammatory atrophy (PIA). The loss of glutathione S-transferase P1 (GSTP1) may be responsible in patients with genetic predisposition for the transition of PIA into high-grade intraepithelial neoplasia (HGPIN) and PCa. Although there is growing evidence of the association among inflammatory response, BPH, and PCa, we can only surmise on the immunologic mechanisms involved, and further research is required to better understand the role of prostatic inflammation in the initiation of BPH and PCa. There is not yet proof that targeting prostate inflammation with a pharmacologic agent results in a lower incidence and progression or regression of either BPH or PCa.

Conclusions

Evidence in the peer-reviewed literature suggested that chronic prostatic inflammation may be involved in the development and progression of chronic prostatic disease, such as BPH and PCa, although there is still no evidence of a causal relation. Inflammation should be considered a new domain in basic and clinical research in patients with BPH and PCa.

Introduction

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are significant health concerns that may become increasingly prevalent in the coming years in relation to the gradual aging of the population [1], [2], [3]. PCa is the leading cause of nonskin cancer among men worldwide and, after lung cancer, is the second most common cause of death from cancer in men in the United States [4]. BPH represents the most common urologic disease among elderly males, affecting about one-quarter of men in their 50 s, one-third in their 60 s, and about half of octogenarian men [5], [6].

BPH and PCa form in different areas of the prostate. The former is known to develop from the transitional zone (TZ) and central zone of the gland, while the latter develops from the peripheral zone (PZ). Only in about 20% of cases do the conditions coexist in the same zone [7]. BPH and PCa are considered chronic diseases, with early initiation and slow progression. BPH starts as a simple micronodular hyperplasia, evolving into a macroscopic nodular enlargement that gradually translates into a clinical entity. Similarly, PCa develops through early and late precancerous histologic modifications [3]. Furthermore, although there is no clear molecular and genetic relationship between BPH and PCa and they present two distinct pathogenetic pathways, epidemiologic studies suggest that because their incidence and prevalence rise with increased age, both conditions are hormone dependent and are associated with prostatic inflammation, which can represent a common denominator [1].

Neither BPH nor PCa is a single disease; rather, they express different features in terms of epithelial-to-stromal–ratio Gleason score or cancer volume. These aspects are often neglected in reference to prostate inflammation. We understand the difficulty in considering too many variables, but we are also concerned with the limitations of it.

Chronic inflammation secondary to infectious agents, to the exposure of other environmental factors, or to a combination of both is involved in the pathogenesis of about 20% of human cancers, including stomach, liver, and large intestine [8], [9]. Epidemiologic, histopathologic, and molecular pathologic studies provide the emerging evidence of the possible role of prostatic inflammation as a crucial part of PCa pathogenesis and progression [10].

The molecular and cellular mechanisms involving stromal and epithelial components of the prostate leading to BPH remain unclear, notwithstanding a causative role of prostatic inflammation in the pathogenesis of BPH, which was first suggested in 1937 [11]. Today, although it is not yet defined when and why chronic inflammation occurs, it has been hypothesised that BPH is an immune-mediated inflammatory disease [5], [12], [13], [14], [15], and recent clinical trials have also suggested a relationship between prostatic inflammations and lower urinary tract symptoms (LUTS) related to BPH [16], [17], [18]. Epidemiologic evidence of a link between the use of anti-inflammatory agents and the risk of cancer led to novel therapeutic approaches that were proposed as a new frontier in the prevention and treatment of PCa [1], [8]. In BPH patients, the relation between LUTS and inflammation is well known [2], as different prostatic conditions, including BPH, benefit from antibacterial and anti-inflammatory treatment.

We also acknowledge the lack of a standard definition of prostatic inflammation that probably exists only in the classification of chronic pelvic pain. The definition is clearly useful for clinical purposes but would be meaningless in research on prostate immunology. Inflammation is usually described in basic science papers in terms of cellular effectors and released mediators.

This is a nonsystematic review to evaluate the most recent evidence with respect to prostatic inflammation as a major pathway in the controversial relationship between BPH and PCa and discusses its potential clinical implications.