Abstract
Purpose
Currently, there is a dearth of data concerning the impact of hypogonadism on prostate cancer detection by imaging. In this study, we evaluated the performance of multiparametric MRI (mpMRI) and mpMRI-TRUS fusion biopsy in hypogonadal patients.
Materials and methods
Clinical and pathologic data from a prospectively maintained, single-institution database of patients who underwent 3T mpMRI and fusion biopsy between 2007 and 2016 were analyzed. Hypogonadism was defined by an institutional cutoff of serum testosterone ≤ 180 ng/dL; T2, DWI, and DCE scores were calculated from mpMRI. Cancer detection rates were compared by Chi-square tests. Multivariate logistic regression was undertaken to evaluate the impact of hypogonadism on clinically significant cancer detection by systematic and fusion biopsy.
Results
We included 522 patients in our study who had total testosterone levels measured within 90 days of mpMRI. Of these, 49 (9.4%) were hypogonadal. Median total testosterone was 148 ng/dL (IQR 41) in the hypogonadal group, and 304 ng/dL (IQR 132) in the normogonadal group (p < 0.001). Imaging results were comparable between the hypo and normogonadal groups. In the hypogonadal group, systematic biopsy detected clinically significant cancer in 28.6% of patients compared to 40.8% with fusion biopsy. In the normogonadal cohort, systematic and fusion biopsy detected 37.3% and 43.2% CS cancer, respectively. In the hypogonadal cohort, fusion biopsy detected 12.2% more CS cancers compared to systematic biopsy, while it detected only 5.9% more in the normogonadal cohort. On multivariate analysis, hypogonadism was found to be an independent predictor of decreased CS cancer detection on systematic (p = 0.048), but not on fusion biopsy (p = 0.170).
Conclusions
Hypogonadism is an independent predictor of lower CS cancer detection on systematic biopsy. However, it fails to significantly impact CS detection on fusion biopsy with comparable cancer detection rates in both groups. Patients with hypogonadism may benefit more from fusion biopsy than normogonadal patients.
Keywords: Hypogonadism, Prostatic neoplasms, Magnetic resonance imaging, Image-guided biopsy
Introduction
The relationship between serum testosterone levels and prostate cancer (PCa) has traditionally been an area of much debate. While several studies have demonstrated an association between higher levels of testosterone and increased risk of PCa [1, 2], there is also a large body of evidence supporting the inverse that low levels of testosterone lead to increased risk [3, 4]. When looking specifically at the effect of hypogonadism on PCa detection, although some studies have indicated little association between serum testosterone and detection of PCa [5], others have found that patients with low serum testosterone have an increased rate of upgrading at surgery when the initial biopsy result is performed in a systematic fashion [6]. This suggests that systematic biopsy may perform more poorly in these patients and that they may benefit even more from image-guided biopsy [6, 7].
Over the last several years, multiparametric MRI (mpMRI)-guided prostate biopsies have played an increasing role in the detection of PCa. Such biopsies overcome one of the limitations of systematic biopsy, namely that a specific abnormality can be sampled, rather than randomly sampling the prostate. It is possible that hypogonadal patients harbor tumors that are more difficult to detect with random sampling and, therefore, mpMRI-guided biopsies may be particularly useful.
In this study, we aim to compare the rates of PCa detection on systematic biopsies and those obtained with MRI-TRUS fusion biopsy in both hypogonadal and normogonadal populations.
Methods
Patient selection
Between 2007 and 2016, 1528 patients were enrolled in an institutional review board-approved protocol and underwent mpMRI followed by mpMRI-TRUS fusion prostate biopsy. Five hundred and twenty-two patients, without any history of prior radiation or androgen deprivation therapy, and whose total serum testosterone levels (obtained within 90 days of mpMRI) were available were included in the study.
Imaging protocol
All patients underwent a diagnostic mpMRI of the prostate, consisting of triplanar T2-weighted, axial dynamic contrast-enhanced, axial diffusion-weighted imaging with apparent diffusion coefficient (ADC) mapping and high b-value imaging. mpMRIs were performed using a 3.0 Tesla (Achieva, Philips Healthcare) scanner with an endorectal coil (BPX-30, Medrad) and a 16-channel cardiac surface coil (SENSE, Philips Healthcare), as previously described [8]. mpMRI images underwent centralized radiologic evaluation by two highly experienced genitourinary radiologists and were assigned internal NIH MRI suspicion scores of low, low–moderate, moderate, moderate–high, or high as well as T2, DWI, and DCE scores. PI-RADS scores were not analyzed, as they were not in use consistently throughout the study period.
Biopsy protocol
Lesions suspicious for PCa were identified on mpMRI and their locations recorded electronically (DynaCAD, Invivo). These lesions were then biopsied using the UroNav MR/ultrasound fusion device (Invivo), or pre-commercialization versions of the same device as previously described [9]. Fusion biopsy was followed by systematic biopsy using a standard 12 core biopsy sampling from the lateral and medial aspects of the left and right sides of the base, mid and apical regions of the prostate.
Data collection
All demographic, clinical, and pathologic data were collected from a prospectively collected database of patients undergoing mpMRI-US fusion prostate biopsy at our institution. Patients were considered hypogonadal if their total serum testosterone was below an institutional cut off of 180 ng/dL regardless of clinical symptoms. T2W, DWI, and DCE scores were considered positive if they were reported as “positive” by the radiologist. Clinically significant cancer was defined as Gleason 3 + 4 or higher on biopsy.
Statistical analysis
Statistical analysis was performed with SPSS version 21 (Chicago, IL). Pearson Chi-square and Mann–Whitney methods were used to compare the differences between categorical and continuous variables. T2W, DWI, and DCE scores were analyzed as binary variables and considered “positive” if the imaging findings indicated suspicion for prostate cancer on that parameter and “negative” if they did not. Statistical significance was considered at p < 0.05.
Results
Patient demographics
Five hundred and twenty-two patients had total serum testosterone measured within 90 days of the mpMRI. Median total testosterone level was 292 ng/dL (IQR 145). Median age and PSA was 64 years (IQR 10) and 6.9 ng/ml (IQR 5.5). Forty-nine patients (9.4%) were deemed hypogonadal. Compared to normogonadal patients (total testosterone ≥ 180 ng/dL), hypogonadal patients (total testosterone < 180 ng/dL) had comparable age (63 vs 65 years, p = 0.698), PSA (7.0 vs 6.9 ng/ml, p = 0.192), and PSAD (0.14 vs 0.13, p = 0.653). Median total testosterone was 148 ng/dL (IQR 41) in the hypogonadal cohort, and 304 ng/dL (IQR 132) in the normogonadal cohort (p < 0.001) (Table 1).
Table 1.
Characteristics of patients with testosterone measured at time of mpMRI
| Normogonadal | Hypogonadal | Total | p value | |
|---|---|---|---|---|
| Patients, n (%) | 473 (90.6) | 49 (9.4) | 522 | |
| Testosterone (ng/dL), median (IQR) | 304 (132) | 148 (41) | 292 (145) | < 0.001 |
| Age (years), median (IQR) | 65 (10) | 63 (7) | 64 (10) | 0.698 |
| Race, n (%) | ||||
| White | 372 (79.3) | 31 (63.3) | 403 (77.8) | 0.028 |
| Black | 76 (16.2) | 13 (26.5) | 89 (17.2) | |
| Other | 21 (4.5) | 5 (10.2) | 26 (5.0) | |
| PSA (ng/ml), median (IQR) | 6.9 (5.3) | 7.0 (8.3) | 6.9 (5.5) | 0.192 |
| PSAD (ng/ml/cc), median (IQR) | 0.13 (0.12) | 0.14 (0.11) | 0.13 (0.12) | 0.653 |
| Clinical stage > ctlc, n (%) | 24 (5.5) | 1 (2.3) | 25 (5.2) | 0.354 |
| Imaging characteristics | ||||
| Prostate volume on MRI, median (IQR) | 49 (31) | 54 (35) | 50 (31) | 0.456 |
| NIH MRI score, n (%) | ||||
| Low to moderate | 307 (67.3) | 30 (62.5) | 337 (66.9) | 0.499 |
| Moderate-high to high | 149 (32.7) | 18 (37.5) | 167 (33.1) | |
| Cancer detection on individual imaging modalities, n (%) | ||||
| T2W | 449 (95.1) | 48 (98.0) | 497 (95.4) | 0.368 |
| DWI | 438 (93.2) | 47 (95.9) | 485 (93.4) | 0.463 |
| DCE | 432 (91.7) | 47 (95.9) | 479 (92.1) | 0.299 |
| Biopsy results | ||||
| Max Gleason score, n (%) | ||||
| 6 | 94 (19.9) | 11 (22.4) | 105 (20.1) | 0.855 |
| 7 | 138 (29.2) | 15 (30.6) | 153 (29.3) | |
| ≥ 8 | 102 (21.6) | 8 (16.3) | 110 (21.1) | |
| Clinically significant PCa detection, n (%) | ||||
| Systematic biopsy | 176 (37.3) | 14 (28.6) | 190 (36.5) | 0.228 |
| mpMRI-TRUS fusion biopsy | 204 (43.2) | 20 (40.8) | 224 (43.0) | 0.746 |
| Combined biopsy* | 240 (50.7) | 23 (46.9) | 263 (50.4) | 0.612 |
mpMRI multiparametric MRI, PSA prostate-specific antigen, PSAD PSA density, T2W T2 weighted, DWI diffusion-weighted imaging, DCE dynamic contrast-enhanced, TRUS transrectal ultrasound, PCa prostate cancer
Combined systematic and fusion biopsy
Imaging parameters
Prostate volume on MRI was 54 cc (IQR 35 cc) vs 49 cc (IQR 31 cc) for hypo and normogonadal patients, respectively (p = 0.456). The distribution of high MRI suspicion scores was also comparable between the two groups (37.5% vs 32.7% Moderate–High to High, p = 0.499). When the scores of each individual imaging parameter were analyzed separately, one or more suspicious lesion was identified on T2-weighted imaging 98.0% of the time in hypogonadal patients and 95.1% of the time in normogonadal patients (p = 0.368); DWI was positive in 95.9% and 93.2% (p = 0.463), and DCE was positive in 95.9% and 91.7% (p = 0.299), respectively.
Biopsy results
In the biopsy detection of CS cancer, fusion biopsy outperformed systematic biopsy, in both hypogonadal (40.8% vs 28.6%, targeted vs systematic) and normogonadal (43.2% vs 37.3%, targeted vs systematic) patients. However, there was no statistically significant difference in CS cancer detection between the two groups by fusion (p = 0.746) or systematic (p = 0.228) biopsy. In the hypogonadal cohort, fusion biopsy detected 12.2% (95% CI − 6.3, 30.7) more CS cancers compared to systematic biopsy, while it detected only 5.9% (95% CI − 0.5, 6.4) more in the normogonadal cohort. The increase in PCa detection of fusion biopsy in the hypogonadal cohort, while twice that of the normogonadal cohort, was not statistically different (difference 6.3%, 95% CI − 3.4, 15.2%, p = 0.213). On multivariate analysis, however, hypogonadism was found to be an independent predictor (OR 0.445, 95% CI 0.199–0.994, p = 0.048) of decreased CS cancer detection on systematic biopsy, indicating that hypogonadal patients are less than half as likely to have CS cancer detected on systematic biopsy, when adjusted for various clinical and demographic factors. On the other hand, CS cancer detection on fusion biopsy was not significantly impacted by hypogonadism (OR 0.545, 95% CI 0.229–1.298, p = 0.170) (Table 2).
Table 2.
Association of hypogonadism with detection of clinically significant prostate cancer on mpMRI and mpMRI-TRUS fusion biopsy
| Unadjusted |
Adjusted* |
|||||||
|---|---|---|---|---|---|---|---|---|
| mpMRI-TRUS fusion |
Systematic |
mpMRI-TRUS fusion |
Systematic |
|||||
| OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | |
| Testosterone < 180 ng/dL | 1.141 (0.739–1.759) | 0.552 | 1.057 (0.679–1.645) | 0.806 | 0.545 (0.229–1.298) | 0.170 | 0.445 (0.199–0.994) | 0.048 |
Adjusted for patient age, race, PSA density, highest NIH MRI suspicion score, and clinical stage
Post-prostatectomy pathology
We had post-prostatectomy pathology results on 76 patients in our cohort. Of these, hypogonadal patients had higher rates of positive margins (22.2% vs 16.4%), positive lymph nodes (11.1% vs 7.5%), seminal vesicle invasion (11.1% vs 3.0%), and Gleason score upgrade from biopsy to whole mount pathology (22.2% vs 14.1%).
Discussion
The relationship between serum testosterone and risk and outcomes of prostate cancer has been explored in numerous studies over the last several decades [1–4,10]. However, due to widely differing results, the relationship between serum testosterone and prostate cancer outcomes remains uncertain. An analysis of patients from the Baltimore Longitudinal Study of Aging found that increases in the free testosterone index were associated with higher risk PCa [1]. Similarly, an analysis of the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events Trial found that the lowest testosterone values were correlated with the lowest risk of PCa; however, no association was found between higher testosterone and PCa risk [11]. In contrast to these studies, the placebo arm of the Prostate Cancer Prevention Trial found no significant association between testosterone and the risk of PCa [5], results that were substantiated in a meta-analysis by Roddam et al. [12]. Several theories have been proposed to explain these apparent inconsistencies. Salonia et al. suggested the existence of a non-linear relationship between testosterone and PCa outcomes, proposing a “u-shaped” association, indicating a higher likelihood of high-risk PCa at both low and high extremes of testosterone [2]. Another theory by Xu et al. proposed a “dynamic model”, stating that it was the degree of decrease in testosterone values, and not their absolute value, that would predict PCa risk [13]. This theory has yet to be tested but may provide additional insight into the complicated relationship between sex hormones and PCa. While several studies have evaluated the impact of serum testosterone levels and hypogonadism on PCa risk and outcomes, the relationship between hypogonadism and PCa detection on prostate mpMRI and mpMRI-TRUS fusion biopsy has not been previously explored [14, 15].
In the current study, we compared mpMRI imaging in patients with hypogonadism and normogonadism. In many ways, the two cohorts were very similar. For instance, we did not find a significant difference in the distribution of highest MRI suspicion scores, nor in individual MRI parameters (T2W, DWI, DCE) between hypo and normogonadal patients. Similarly, no difference in MRI prostate volume was found. This finding concurs with Llukani et al. and Leon et al. who also found that neither total nor free serum testosterone affected prostate volume or weight on post-prostatectomy pathology [17, 18]. However, the prostate is an androgen-dependent organ and, as such, relies on testosterone for its growth and development [19]. When examining the effect of androgen deficiency on prostate volume, Jin et al. determined that total prostate volume was significantly lower in hypogonadal men [20]. The lack of effect on prostate volume and imaging parameters seen in our analysis may be partially explained by the saturation theory, which suggests that only a low level of testosterone is necessary to adequately stimulate androgen receptors in the prostate [16]. It is possible that the testosterone levels at the cut off value used in this analysis are sufficiently high to maintain a prostate architecture and size similar to that of normogonadal patients.
In terms of detection of clinically significant cancer, hypogonadism was found to be an independent predictor of decreased CS cancer detection on systematic biopsy, but not on mpMRI-TRUS fusion biopsy. This discrepancy raises the possibility that systematic biopsy is less accurate in detecting PCa in hypogonadal patients. Pichon et al. in 2015 found that low testosterone was an independent predictor for PCa upgrading on post-prostatectomy pathology [6], and noted that “Gleason Score is more often under-evaluated by the prostate biopsies in hypogonadal patients.” In addition, an analysis of active surveillance patients, selected on the basis of systematic biopsy, found that low testosterone was predictive of a fourfold increase in the risk of disease reclassification [21]. One explanation for the relatively poor performance of systematic biopsy is that tumors might be smaller in hypogonadal patients [17], which may affect their ability to be sampled without the use of targeted biopsy techniques. The use of fusion biopsy may compensate for the limitations of systematic biopsy, particularly in these populations.
Of the relatively few patients who underwent prostatectomy, hypogonadal patients had higher proportions of adverse histopathologic outcomes (positive margins, positive lymph nodes, seminal vesicle invasion, Gleason score upgrade). Although these differences failed to achieve significance, they do reflect trends seen in the literature. Lower testosterone levels have been correlated with worse pathologic stage, increased risk of positive margins, and increased risk of extraprostatic disease [22–24]. It is theorized that testosterone-deficient environments induce dedifferentiation of PCa cells, leading to more aggressive cancers [3]. Although these results are suggestive, more definitive analyses are necessary to further elucidate the relationship between hypogonadism and adverse pathologic outcomes.
The study has several limitations inherent in its retrospective design. The relatively small number of hypogonadal patients limited the power of our comparative analysis leading to a lack of statistically significant differences in spite of clear trends. A larger study could address this issue. Also, our analysis focused on total testosterone, instead of free testosterone or sex hormone-binding globulin, as it was the most common metric used in our cohort. It is unclear if the results would have been different if another assessment of testosterone level was utilized. An additional limitation is the nature of our patient population—as our cohort is comprised of individuals who underwent mpMRI-TRUS fusion biopsy, all patients had MRI-visible lesions. Additional studies, including patients without MRI-visible lesions, may further highlight differences between hypo and normogonadal patients on MRI.
Conclusions
Hypogonadism is an independent predictor of lower CS cancer detection on systematic biopsy. However, it fails to significantly impact CS detection on fusion biopsy with comparable cancer detection rates in both groups. Patients with hypogonadism might benefit from mpMRI fusion biopsy to a greater extent than normogonadal patients as systematic biopsy underperforms in this patient population. Larger multi-institutional studies may be needed to further explore and delineate the relationship between hypogonadism and prostate cancer detection on prostate mpMRI and fusion biopsy.
Acknowledgements
Supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research, Center for Interventional Oncology, and the National Institutes of Health Medical Research Scholars Program, a public–private partnership supported jointly by National Institutes of Health and contributions to the Foundation for National Institutes of Health from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities Inc., Mr. and Mrs. Joel S. Marcus, the Howard Hughes Medical Institute and other private donors (http://fnih.org/work/education-training-0/medical-research-scholars-program).
Footnotes
Compliance with ethical standards
Conflict of interest The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field.
Ethical standards All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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