We read with great interest the recent review by Zarakowska et al [1] on the relationship between prostate cancer (PCa) and benign prostatic hyperplasia (BPH), which thoughtfully explores the roles of inflammation, oxidative stress, and epigenetics as common pathogenic links. The authors correctly highlight that chronic inflammation is a key factor in both conditions and cite epidemiological evidence suggesting that a diagnosis of BPH is associated with an increased risk of PCa incidence and mortality.
However, we wish to present a complementary and contrasting body of evidence suggesting that the physical manifestation of BPH—a large prostate gland—is inversely associated with the aggressiveness of PCa. This viewpoint is strongly supported by numerous studies analyzing radical prostatectomy specimens. The landmark study by Freedland et al [2] demonstrated that men with smaller prostates had more high-grade disease, more advanced pathological stage, and a greater risk of biochemical progression.
This finding has been consistently corroborated. A recent propensity score-matched analysis by Gamal et al [3] found that patients with very large prostates (>150 g) had significantly more favorable pathological outcomes, including a higher proportion of organ-confined (pT2) disease and lower rates of positive surgical margins. Similarly, Hong et al [4] used preoperative magnetic resonance imaging (MRI) and confirmed that smaller prostate volume was significantly associated with adverse pathologic features.
This robust inverse relationship can be explained by a dual “mechanical-inflammatory” protective mechanism. First, the mechanical compression hypothesis posits that the expanding transition zone, the primary site of BPH, exerts physical pressure on the peripheral zone (PZ), where 80%–85% of PCa originates. Wolpert et al [5], using a novel combination of MRI and histopathology, provided direct evidence for this by demonstrating significant PZ glandular atrophy in larger prostates.
This atrophy may physically inhibit tumorigenesis. Furthermore, a mechanobiological computer model, cited by Nandalur et al [6], supports that hydrostatic stress from BPH growth can mechanically impede tumor progression.
Second, as our group has previously proposed [78], this mechanical compression likely has a crucial secondary anti-inflammatory effect. The etiology of chronic prostatic inflammation has long been linked to the intra-prostatic reflux of urine and seminal fluid, as first demonstrated by Kirby et al [9] and further theorized by Wadhera [10]. An enlarged central gland from BPH may compress and flatten the PZ ducts and their outlets, increasing resistance to reflux and thereby reducing the exposure of the PZ to inflammatory stimuli.
This mitigates a key driver of carcinogenesis.
In conclusion, while Zarakowska et al [1] correctly identify inflammation as a common pathway, the relationship between BPH and PCa is more complex than a simple positive correlation of incidence. Evidence from pathological, imaging, and biomechanical studies strongly suggests that large prostate volume, a direct consequence of BPH, may confer a protective effect against the development of high-grade, aggressive PCa. Distinguishing between epidemiological risk of diagnosis and the biological risk of aggressive disease is critical for accurate risk stratification and patient counseling.