Possible Clinical Implications of Prostate Capsule Thickness and Glandular Epithelial Cell Density in Benign Prostate Hyperplasia (2024)

The prostate is an interesting organ where only two diagnoses (Benign Prostatic Hyperplasia (BPH) and prostate cancer (PCa)) cover more than 95% of the cases where a prostate patient is seeing a urologist. Other specific diagnoses of the prostate such as metastatic disease from other organs or lymphoma of the prostate are extremely rare and suitable as case reports. BPH and prostate cancer are both cell growth-related disease entities, but their interaction is not well understood. In theory, there are three possible models of interaction: 1. BPH is precancerous (the more cell growth due to BPH, the higher the incidence of PCa); 2. There is no interaction between them (like migraine is not associated with the incidence of bone fractures); 3. BPH is protective of PCa (the larger the prostate due to BPH, the lower the incidence of PCa). No other options of interaction are possible. Although this is a clinically important question even lay people do understand, the official textbooks in Urology do not provide any definitive answers.

Benign Prostatic Hyperplasia (BPH) and Prostate Cancer (PCa) have been heavily investigated over the last decades. Both pathologies are characterized by proliferation of prostatic tissue and cell growth, but how do these two entities relate?

In a meta-analysis review of the literature pertaining to the relationship between PCa and BPH, 90% of all clinical studies published from 1997 to the present, report a negative correlation between BPH and PCa (the bigger the prostate in size, the lower the incidence of PCa). No study could be found showing a positive correlation between prostate size and incidence of PCa.1 While many studies have focused on this correlation, the exact mechanism is not well-understood and poorly investigated.

It is well documented in the literature that 100% of all BPH originates in the transition zone (TZ) of the prostate, whereas 80-85% of PCa originates in the peripheral zone (PZ).2 We think this well-documented observation is important in the understanding of interactions between both disease entities. As the TZ grows, it can compress tissue, glands, and cells within other zones of the prostate, particularly in the PZ, causing changes in tissue organization.3 One of these noted changes of the PZ is the development of a fibrotic layer adjacent to the anatomical capsule. The anatomical capsule is a false capsule of the prostate in younger males that forms posteriorly and laterally around the prostate, derived from periprostatic pelvic fascia.4 Prostates with BPH have been shown to possess a fibrotic layer that extends inwardly from the anatomical capsule. This thickened fibrotic layer has been deemed the surgical capsule in the literature. The presence of this surgical capsule is a well-known phenomenon seen in the surgical treatment of BPH-prostates with a volume >80-90cc, wherein the surgical capsule serves as a tactile marker for the boundary of the expanding TZ, allowing surgical enucleation of the BPH component alone.5,6

In Investigative and Clinical Urology, we reported the results of quantitative prostatic PZ glandular epithelial cell density and prostatic capsule thickness and how they relate to prostate size in radical prostatectomy specimens. In this study, we found that as the volume of the prostate increases, PZ glandular epithelial cell density decreases, and prostate capsule thickness increases.7 Our data suggest that growth of the TZ in BPH causes widespread atrophy and apoptosis of PZ glands and fibrosis of the surrounding stroma. The widespread fibrosis and collagen deposition within the PZ tissues explain the thicker surgical capsule seen in larger prostate specimens as demonstrated in Investigative and Clinical Urology.7 A significant limitation of this study is that the boundary between TZ and PZ cannot be identified on histo-anatomical specimens/slides. Due to this limitation, we were unable to measure the exact thickness of the PZ itself and whether it undergoes expansion or shrinkage in growing BPH-prostates. While we cannot see the exact border of the TZ and PZ on histo-anatomical specimens, multiparametric MRI imaging is capable of visualizing the exact border between the TZ and the PZ within the prostate. Using MRI pelvic scans from a large male cohort, Sellers et al recently showed that in large BPH-prostates (above a total glandular volume of 90 ml) a significant decrease in PZ thickness occurs.8 These results suggest that as the TZ expands in BPH, it exerts pressure on the PZ that, above a certain threshold, results in thinning of the PZ.

In the landmark Prostate Cancer Prevention Trial, finasteride was supposed to reduce the incidence of PCa in men treated with this 5-alpha-reductase inhibitor (5ARI). However, due to the higher incidence of aggressive PCa in the men belonging to the finasteride treatment arm, finasteride use failed to prevent PCa.9 In a recent numerical simulation study, Guillermo et al. developed a mechanically-coupled computer model of PCa growth, demonstrating that expansion of the TZ within the central gland (CG) of BPH-prostates exerts mechanical stress on co-existing PCa, and thus limiting its growth.10 In this context it should be mentioned that “central gland” (CG) is a MRI-related term of the prostate, defining the prostate gland (volume) subtracted by the PZ (which is well defined on MRI); within the central gland the other prostate zones such as the TZ cannot be well visualized on MRI, however, the CG is a good surrogate for the volume measurement of the PZ as the other zones within the CG are small. The Guillermo study mentioned above showed that 5ARI treatment caused volumetric reduction of the central gland of the prostate, resulting in reduced hydrostatic stress exerted on co-existing PCa located in the PZ, and thus creating an environment that favors more aggressive PCa.11

Summarizing clinical and scientific studies (1. Review of the literature, 2. Histo-anatomical and 3. MRI studies of the prostate, as well as 4. numerical simulation studies), all have shown overwhelming evidence of the inverse/ negative correlation between BPH-prostate size and incidence/ development of PCa: Expansion of the TZ by BPH growth causes compression of the PZ, resulting in atrophy and fibrosis of glands within the PZ and an overall reduction in the volume of the PZ. As 80-85% of PCa arises in the PZ, and 95% of PCa is adenocarcinoma derived from the acinar epithelium [2], the atrophy, apoptosis as well as the total volume reduction of the PZ due to increased TZ volume in growing BPH apparently reduce the incidence of PCa, and thus, would explain the protective mechanism of BPH against the development of PCa. If this described phenomenon between BPH and PCa is confirmed in future studies, it will have relevant clinical implications on the diagnosis and treatment of benign prostate hyperplasia (BPH) and prostate cancer.

Written by:Preston E. Weaver & Werner T.W de Riese,Department of Urology, Texas Tech University HSC, Lubbock, Texas

References:

  1. Moolupuri A, Camacho J, de Riese WT. Association between prostate size and the incidence of prostate cancer: a meta-analysis and review for urologists and clinicians. International Urology and Nephrology. 2021. doi:10.1007/s11255-021-02892-w
  2. Al-Khalil S, Ibilibor C, Cammack JT, de Riese W (2016) Association of prostate volume with incidence and aggressiveness of prostate cancer. Res Rep Urol 8:201–205 (22)
  3. Frost, J.M., Smith, L.A., Sharma, P. et al. Int Urol Nephrol (2019) 51: 1721. https://doi.org/10.1007/s11255-019-02221-2
  4. Ayala AG, Ro JY, Babaian R, Troncoso P, Grignon DJ (1989) The prostatic capsule: does it exist? Its importance in the staging and treatment of prostatic carcinoma. Am J Surg Pathol 13(1):21–27
  5. Semple J (1963) Surgical capsule of the benign enlargement of the prostate its development and action. BMJ 1:1640–1643 (16)
  6. Rosenkrantz A, Taneja S (2014) Radiatolgist, be aware: tend pitfalls that confound the interpretation of multi-parametric prostate mri. AJR 202:109–120
  7. Holder KG, Galvan B, Knight AS, et al. Possible clinical implications of prostate capsule thickness and glandular epithelial cell density in benign prostate hyperplasia. Investigative and Clinical Urology. 2021;62. doi:10.4111/icu.20200605
  8. Sellers J, Wagstaff RG, Helo N, de Riese WT. Quantitative measurements of prostatic zones by MRI and their dependence on prostate size: possible clinical implications in prostate cancer. Therapeutic Advances in Urology. 2021;13:175628722110008. doi:10.1177/17562872211000852
  9. Thompson, I. M. et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 369, 603–610 (2013).
  10. Guillermo L, Hughes T, Dominguez-Frojan O, Reali A, Gomez H (2019) Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer growth. Natl Acad Sci 116(4):1152–1161 (20)
  11. Lorenzo G, Hughes TJR, Reali A, Gomez H. A numerical simulation study of the dual role of 5α-reductase inhibitors on tumor growth in prostates enlarged by benign prostatic hyperplasia via stress relaxation and apoptosis upregulation. Computer Methods in Applied Mechanics and Engineering. 2020;362:112843. doi:10.1016/j.cma.2020.112843

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Possible Clinical Implications of Prostate Capsule Thickness and Glandular Epithelial Cell Density in Benign Prostate Hyperplasia (2024)

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