Lipid and Foam Cell Accumulation as Novel Pathological Features of Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH) encompasses a heterogeneous set of pathological processes that instigate lower urinary tract symptoms (LUTS). Using a mouse model of steroid hormone imbalance-induced lower urinary tract dysfunction, we identified luminal lipid-laden foamy macrophages, although their presence and contribution to human pathology have not yet been established. The objective of this study was to determine whether luminal macrophages are associated with human BPH and to assess how lipid accumulation relates to underlying pathological features and clinical parameters.

Whole-mount tissue sections from simple prostatectomy specimens and prostates from healthy donors were used to evaluate the association of luminal macrophages by immunohistochemistry and lipid content by Oil Red O staining. For a systematic assessment of inflammatory cells (CD45⁺ and CD68⁺), collagen content (Picrosirius Red), glandular proportion (H&E), and lipid accumulation, prostate tissues were obtained from patients undergoing holmium laser enucleation of the prostate (HoLEP). Clinical data, including IPSS and LURN symptom scores, were collected, and relevant clinical variables were extracted by chart review. Pathological subtypes were subsequently identified using unsupervised hierarchical clustering.

Lumens containing CD68⁺ macrophages were increased 6.2-fold and 6.6-fold in glandular nodules and internodular regions, respectively, compared with the transition zone of donors. Overall lipid content was also elevated by 2.8-fold in glandular nodules relative to healthy transition zone tissue. In HoLEP specimens, lipid content showed positive correlations with glandular proportion, CD45⁺ and CD68⁺ cell abundance, prostate volume, and serum PSA, and negative correlations with collagen content and body mass index. Unsupervised hierarchical clustering of pathological features identified four distinct subtypes: a small, stromal-fibrotic phenotype; a glandular-enriched, low-immune phenotype; a large-prostate subtype characterized by high lipid content and inflammation; and a macrophage-enriched phenotype. Notably, the small stromal-fibrotic subtype was enriched for patients receiving 5α-reductase inhibitor therapy.

In summary, our findings identify luminal macrophages and lipid accumulation as previously underrecognized pathological features of BPH. Lipid accumulation is associated with prostatic inflammation and may represent a therapeutic target. Luminal macrophages may further contribute to disease progression, and comprehensive transcriptomic and proteomic characterization of these cells in human tissue will be essential to elucidate their pathological functions. Importantly, effective implementation of subtype-informed BPH management will require improved biomarkers and imaging strategies to enable accurate disease stratification and personalized treatment selection.