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Association of Prostate Volume and the Incidence of Prostate Cancer Determined on MRI-Fusion Biopsy: A systemic Review - Beyond the Abstract

The prostate is a unique organ, as a matter of fact, 95-98% of elderly men with a prostate condition as their “primary organ disease” consulting a urologist, have either the clinical diagnosis of benign prostate hyperplasia (BPH), prostate cancer (PCa) or both. Other diagnoses of the prostate such as organ-confined bacterial infection, sarcoma, lymphoma, or metastasis from other primaries are extremely rare entities. Furthermore, PCa is the most common non-skin cancer in men worldwide and more than 80% of patients with PCa also have histo-anatomical findings of benign prostate hyperplasia (BPH).1 Although BPH and PCa are very common and are both characterized by tissue growth, the interaction is currently not well understood. Numerus clinical studies over the recent years have reported an inverse/negative relationship between prostate/ BPH size and incidence as well as aggressiveness of PCa, thus supporting the hypothesis that prostate-size may be protective against cancer.2 Even patients with large prostates and diagnosed with PCa have shown to have a better prognosis.3,4

A systemic review and meta-analysis on 41 TRUS (transrectal ultrasound)-biopsy studies in 2021 found in 39 (95%) a statistically significant inverse/negative correlation between prostate size and incidence of biopsy-proven PCa.5 No study was found showing the contrary (a higher PCa incidence in larger prostates). However, the shortcoming of these studies has been the issue of ‘sampling error’ experienced with systemic TRUS prostatic biopsy that tends to be more prevalent in larger prostates as the biopsy-sites are arbitrarily assigned by the operator. In other words: A small and same sized cancer lesion has a greater chance to be hit randomly by a biopsy needle in a smaller prostate compared to a larger prostate. This is less of an issue with MRI technology as specific and suspicious lesions can be well identified and targeted for biopsy. This advantage of MRI over TRUS imaging of the prostate initiated the idea of a systemic review of reported MRI-Fusion study results regarding any correlation between prostate/ BPH volume and the incidence of biopsy-proven PCa. To our knowledge, our recently published study is the first systemic review of reported MRI-Fusion biopsy data on this important clinical question.6

This dedicated literature search was conducted on the PubMed database from January 2000 through February 2022 applying the Preferred Reporting Items for Systemic Reviews (PRISMA) guidelines, and it resulted in twelve articles that met the inclusion criteria. Table 1 demonstrates the specific details of these identified reports.

Table 1: List of Studies and Relationship between Prostate Size and Incidence of Prostate Cancer on MRI-Fusion biopsies.
First author Journal Year published number of patients p-value* of Inverse Correlation between prostate size and biopsy-proven PCa
Wei European Journal of Radiology 2020 364 <0.001
Zheng PLOS ONE 2019 422 <0.001
Sellers Therapeutic Advances in Urology 2021 204 <0.0004
Hussein Urologic Oncology 2020 247 <0.001
Lophatananon Journal of Clinical
Urology		 2021 2767 <0.0001
Salami Journal ofMagnetic Resonance Imaging 2017 312 <0.001
Sankineni Journal of Clinical Oncology 2015 33 0.0497
Westhoff World Journal of Urology 2019 202 0.003
Chen International Journal of Medical Sciences 2020 316 0.048
Costa American Journal of Roentgenology 2021 1238 <0.001
Xu Journal of Cancer Research and Clinical Oncology 2018 528 0.01
Qi Journal of Magnetic Resonance Imaging 2020 199 0.003
Notes: a p-values calculated and presented by each study

The total number of patients included in this systemic review was 6832, and they had been recruited in single and multi-institutional cohorts. For instance, Lophatananon et al. correlated prostate volume and cancer detection rates in 2767 patients by using multi-parametric MRI-guided prostate biopsies.7 They found “mean gland volume was higher in men with a benign diagnosis (68.1 mL, SD = 35.5) compared to any cancer or significant cancer diagnosis (52.5 mL, SD = 29.0 and 51.9 mL, SD = 30.0, respectively; p < 0.0001 for both)”. Furthermore, Hussein et al. reported in 247 patients that men with significant PCa had smaller prostate volumes (39.20 mL) compared to those without having significant prostate cancer (55.10mL) with a p-value of <0.001.8 All twelve articles in this review showed a statistically significant inverse (negative) relationship between prostate size and the incidence of PCa with a p-value of at least <0.05 (see Table 1).  Cohorts with lower numbers of participants showed lower level of significance (but still p< 0.05) when compared to cohorts with larger numbers. Interesting is the observation that the cohort with the largest number of patients revealed the highest level of significance (p < 0.0001).7 Using Fisher’s method9 the total p-value for all studies was highly significant (0.0001). In this PRISMA-guided search, none of these studies showed a positive correlation between prostate volume and the incidence of PCa.

The unique anatomy of the prostate may provide guidance for the interpretation of the above findings. The prostatic gland is divided into four regions: central zone (CZ), transition zone (TZ), peripheral zone (PZ), and the anterior fibromuscular stroma. It is well documented that these regions arise from different embryologic origins and are differentiated by their anatomic boundaries, biological function, and vulnerability to specific disease entities.10 From clinical standpoint the TZ and PZ are the main relevant zones within the growing BPH prostate. With ultrasound, even though significantly better with MRI, the PZ can be well differentiated from the “rest” of the prostate, which is referred by radiologists as the “central gland”. This term must be distinguished from the term “central zone”. Compared to TRUS, MRI is very useful in determining specific measurements of the different prostatic zones. TRUS has the limitation in outlining the exact boundary between the TZ and PZ, whereas by multiparametric MRI this boundary is well identified.11 Micro US is a technologically advanced form of standard ultrasound that provides higher frequency and almost 300% better resolution than traditional TRUS scanners.12 However, this comes at a cost of reducing wave penetration beyond a depth of 6 cm. Due to this reduction in wave penetration Micro US performs poorly in detecting anterior lesions within larger prostates.12

Numerous imaging and anatomical studies have shown that BPH originates in the TZ while 80-85% of PCa originates in the PZ.13 A recent paper has well summarized the histo-anatomical changes seen within the PZ secondary to BPH growth leading to significant tissue transformation - or fibrosis - within the PZ.13 This fibrotic transformation of the PZ with thickening of the prostatic capsule in larger BPH prostates becomes a unique plane, also called the surgical capsule by experienced urologists. These histo-anatomical changes are much less pronounced in smaller prostates. It is well documented that these histo-anatomical changes cause epithelial cell atrophy within the PZ likely due to immediate pressure-related tissue injury and decreased blood flow caused by the enlarging TZ in expanding BPH. Guzman et al. thoroughly illustrated this disease process and zonal histo-anatomical changes.14

Furthermore, Sellers et al. reported on MRI readings that once a total prostate volume (TPV) above 80 cc is reached, a noticeable drop in PZ thickness is seen.15 As 80-85% of PCa originate from glandular epithelium within the PZ, this MRI observation supports the theory that the above-mentioned unique interaction between the enlarging TZ and compressed PZ may explain one of the main factors causing the decreased incidence of PCa in large BPH prostates.

This inverse relationship between prostate size and the incidence of PCa could also explain the results of the Prostate Cancer Prevention Trial, where almost 19,000 patients received continuous Finasteride, 5-alpha reductase inhibitors (5ARI). In contradiction to the initial hypothesis, the patients in the treatment group showed a more than twofold increase in high grade aggressive PCa. Finasteride has proven to reverse the growth of the TZ, thus causing shrinkage of this zone (in particular in large prostates), and therefore, giving the glandular epithelium of the PZ more space to proliferate and grow. Though this interpretation of the Finasteride study may be controversial, Lorenzo et al. confirmed in mathematical simulation studies that the shrinkage of the prostate induced by 5ARIs reduces the hydrostatic and mechanical stress by the TZ on the PZ, which leads to a mechanical state favoring the development of PCa.16,17

We are aware of some limitations: this systemic MRI review includes a relatively small number of articles that met the search criteria. Though all studies of this review showed statistically significant results indicating lower incidence for PCa in larger prostates (and no study reported the contrary), these individual studies varied in their biopsy protocols. In some studies MRI-suspicious lesions were biopsied only, whereas in others additional extended (random) needle biopsies were done. Some clinical investigators suggested that increasing the number of biopsies for larger prostates may also increase the PCa detection rates (issue of ‘sampling error’). However, studies have proven that the detection rate for PCa does not increase with the number of biopsies taken past a certain gland size or prostatic volume.18,19 Furthermore, most studies listed in our review were cross-sectional and observational, causing them to be prone to different bias categories which are difficult to further investigate and calculate. Additionally, some degree of bias is involved as this review was limited to the PubMed database and the expertise of the authors involved. Even when considering these limitations, this systematic review of MRI-Fusion studies within the last 20 years strongly supports the hypothesis that large BPH prostates may be protective against development and progression of clinically significant PCa. If the above delineated hypothesis of the dynamic interactions between the transition zone and the peripheral zone within a growing prostate is correct, it will have important clinical implications on future diagnostics and management of BPH and PCa.

Written by: Mia Ivos, MD, Pranav Sharma, MD, & Werner T.W. de Riese, MD, PhD, Department of Urology, Texas Tech University HSC, School of Medicine, Lubbock, Texas

References:

  1. F. C. Liu, K. C. Hua, J. R. Lin, et al: Prostate resected weight and postoperative prostate cancer incidence after transurethral resection of the prostate: A population-based study. Medicine, 2019: vol. 98, no. 3, p. e13897, doi: 10.1097/MD.0000000000013897.
  2. J. Sellers, W.T. de Riese: Evolving Hypothesis that Prostate/BPH Size Matters in Protection against Prostate Cancer. Explor Res Hypothesis Med, 2022: published online, doi: 10.14218/EHRM.2022.00028.
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  6. A. S. Knight, P. Sharma et al: MRI determined prostate volume and the incidence of prostate cancer on MRI-fusion biopsy: A systemic review of reported data for the last 20 years.  International Urology and Nephrology, 2022: doi: 10.1007/s11255-022-03351-w.
  7. A. Lophatananon et al: Re-evaluating the diagnostic efficacy of PSA as a referral test to detect clinically significant prostate cancer in contemporary MRI-based image-guided biopsy pathways. Journal of Clinical Urology, 2021: p. 205141582110590, doi:10.1177/20514158211059057.
  8. B. al Hussein Al Awamlh et al: Multicenter analysis of clinical and MRI characteristics associated with detecting clinically significant prostate cancer in PI-RADS (v2.0) category 3 lesions. Urologic Oncology: Seminars and Original Investigations, 2020: vol. 38, no. 7, pp. 637.e9-637.e15, doi: 10.1016/j.urolonc.2020.03.019.
  9. G. Alves and Y. K. Yu: Combining independent, weighted p-values: Achieving computational stability by a systematic expansion with controllable accuracy.  PLoS ONE, 2011: vol. 6, no. 8, doi: 10.1371/journal.pone.0022647.
  10. A. Bhavsar, S. Verma: Anatomic imaging of the prostate. Biomed Res Int, 2014: 728539, doi: 10.1155/2014/728539.
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  13. K. Holder, B. Galvan, J. Sakya, and W. de Riese: Anatomical changes of the peripheral zone depending on benign prostatic hyperplasia size and their potential clinical implications: a review for clinicians. Urology Practice, 2021: vol. 8, no. 2, pp. 259–263, doi: 10.4111/icu.20200605.
  14. J. A. Guzman, P. Sharma, L. A. Smith et al: Histological changes of the peripheral zone in small and large prostates and possible clinical implications. Research and Reports in Urology, 2019: vol. 11, pp. 77–81, doi: 10.2147/RRU.S182781.
  15. J. Sellers, R. G. Wagstaff, N. Helo et al: Quantitative measurements of prostatic zones by MRI and their dependence on prostate size: Possible clinical implications in prostate cancer. Therapeutic Advances in Urology, 2021: vol. 13, doi: 10.1177/17562872211000852.
  16. G. Lorenzo, T. J. R. Hughes, A. Reali et al: 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: vol. 362, doi: 10.1016/j.cma.2020.112843.
  17. G. Lorenzo, T. J. R. Hughes, P. Dominguez-Frojan, A. Reali, and H. Gomez: Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer growth. Proc Natl Acad Sci U S A, 2019: vol. 116, no. 4, pp. 1152–1161, doi: 10.1073/pnas.1815735116.
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