The Challenges with Prostate Cancer Diagnosis
Prostate cancer is the most commonly diagnosed male cancer, yet the standards for diagnosis remain blurry. Based on elevated PSA level or abnormal digital rectal exam, men will typically undergo a standard 10-12 core transrectal ultrasound-guided (TRUS) biopsy. Although the idea is to systematically sample the whole prostate, the majority of cores are taken from the peripheral zone. Due to its distance from the rectum, the anterior is rarely sampled, while areas in the midline are undersampled to avoid the urethra. The transrectal route also makes it more difficult to target the apex.1 The TRUS biopsy is considered “blind” or “random” because the appearance of cancer is pretty ambiguous on the conventional, low-frequency ultrasound. This often leads to the underdetection of clinically significant cancer and the overdetection of low-grade (clinically insignificant) cancers.2 The high false negative rate and potential for infectious complications make matters even worse for men with suspected low grade cancer. Unfortunately, the current standard of care to monitor low grade prostate cancer relies on repeat TRUS biopsy every 6-24 months. Due to the random nature of systematic biopsies, pathology results can differ significantly, with up to 37%-48% of men with low grade cancer receiving a benign diagnosis on confirmatory biopsy.3 This form of active surveillance repeatedly subjects patients to the potential undergrading of disease, overuse of antibiotics, invasive surgery and risk of sepsis.
High Frequency Micro-Ultrasound
Novel advances in diagnostic imaging have led to vast improvements in both ultrasonic and multiparametric MRI (mpMRI) technologies. High-frequency micro-ultrasound is a relatively recent development that offers high resolution imaging by operating at 29MHz, rather than 9-12MHz.3 As a new technology, the supporting evidence for micro-ultrasound is limited. It is touted to be as effective as mpMRI in detecting cancer, with a sensitivity of up to 90% and negative predictive value of up to 82%. Despite its ability to exclude clinically significant cancer, many abnormalities found were not actually high-grade cancer.4
Compared to mpMRI, which is graded in advance by a trained radiologist using the universal PI-RADS system, micro-ultrasound uses a specialized scoring system that must be assessed by the urologist during the procedure. With the micro-ultrasound workflow, the urologist must first scan the entire prostate, since they can’t refer to an MRI, in hopes of identifying images that match the unique patterns associated with the scoring system. This adds extensive time to the procedure and puts the responsibility on the urologist to learn and recall the various patterns that are indicative of cancer. Whereas with an MRI-targeted fusion biopsy workflow, the work of identifying cancer is performed by the radiologist and the fusion platform guides the urologist to the targets, minimizing the potential for missing cancers.
Unlike its low frequency precursor, micro-ultrasound struggles with the phenomena of signal loss deep in the anterior, especially with larger prostates. As such, the specialized protocol is designed to grade the 70%-80% of cancer that is located in the peripheral zone.3 This neglects the anterior region which accounts for 20%-30% of all prostate cancers.5,6 Anterior tumors often require multiple standard biopsies for diagnosis and yield smaller areas of cancer on core biopsies, which can lead to an undergrading of disease and delayed treatment.6 Unfortunately, supporting “targeted” micro-ultrasound with the standard TRUS biopsy is unlikely to address the issue.
Multiparametric MRI (mpMRI)
The advantages of mpMRI for cancer detection and as a triage test are well researched and have been proven to prevent up to 40% of unnecessary biopsies, detect more clinically significant cancer and reduce the detection of clinically insignificant cancer when used in combination with MRI-targeted fusion biopsies.7 Thus far, little to no evidence suggests the potential use of micro-ultrasound as a triage test. Studies like the PROMIS trial showed that the sensitivity and negative predictive value (NPV) of mpMRI is 93% and 89%, whereas the standard TRUS biopsy is 48% and 74%, respectively.7 Due to the existing issue of anterior signal loss, anterior prostate cancer is becoming increasingly recognized as clinically important, especially for those undergoing active surveillance and men with previous negative TRUS biopsy. The excellent resolution and ability to selectively identify harmful cancers makes mpMRI the ideal candidate for diagnosing, monitoring and targeting tumors. It has proven accurate in not only detecting anterior prostate cancer, but also differentiating the tumors from other anterior prostatic structures such as benign prostatic hyperplasia (BPH) and the anterior fibromuscular stroma (AFMS).8
Due to its anatomical position, the prostate is the only organ where the blind sampling technique is standard practice. It is clear that the conventional ultrasound is subpar for detecting prostate cancer. High-frequency micro-ultrasound proposes a 300% improvement from the current standard, but suffers from anterior signal loss. Although it boasts sensitivity and specificity scores comparable to mpMRI, the majority of the supporting evidence is limited to a handful of studies with relatively small sample sizes ranging from 9 to 100 patients. In contrast, the benefits of mpMRI are well researched and proven, which is why it is included in the guidelines of both the American Urological Association (AUA) and the European Association of Urology (EAU) for the management of prostate cancer. Unlike micro-ultrasound, mpMRI can be used as a triage test, saves the urologist time during the procedure and is accurate for both posterior and anterior zones.
1 Bosaily, A. E., Parker, C., Brown, L., Gabe, R., Hindley, R., Kaplan, R., . . . Ahmed, H. (2015). PROMIS — Prostate MR imaging study: A paired validating cohort study evaluating the role of multi-parametric MRI in men with clinical suspicion of prostate cancer. Contemporary Clinical Trials, 4226-40. doi:10.1016/j.cct.2015.02.008
2 Kasivisvanathan, V., Rannikko, A. S., Borghi, M., Panebianco, V., Mynderse, L. A., Vaarala, M. H., . . . Moore, C. M. (2018). MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. New England Journal of Medicine, 378(19), 1767-1777. doi:10.1056/nejmoa1801993
3 Eure, G., Fanney, D., Lin, J., Wodlinger, B., & Ghai, S. (2018). Comparison of conventional transrectal ultrasound, magnetic resonance imaging, and micro-ultrasound for visualizing prostate cancer in an active surveillance population: A feasibility study. Canadian Urological Association Journal, 13(3). doi:10.5489/cuaj.5361
4 Wallis, C. J. (2019, May). AUA 2019: Diagnostic Accuracy of Targeted Prostate Biopsies: Comparing Micro-Ultrasound with Multiparametric MRI for the Detection of Prostate Cancer. UroToday.
5 Kim, M., Choi, S., Park, M., Shim, M., Song, C., Jeong, I. G., . . . Ahn, H. (2016). Characteristics of Anteriorly Located Prostate Cancer and the Usefulness of Multiparametric Magnetic Resonance Imaging for Diagnosis. Journal of Urology, 196(2), 367-373. doi:10.1016/j.juro.2016.03.075
6 Bott, S., Young, M., Kellett, M., & Parkinson, M. (2002). Anterior prostate cancer: Is it more difficult to diagnose?. BJU International, 89(9), 886-889. doi:10.1046/j.1464-410x.2002.02796.x
7 Goldberg, H., MD. (2020, June). AUA 2020: Reviewing the Current Indispensable Role of Prostate MRI. UroToday.
8 Moosavi, B., Flood, T., Al-Dandan, O., Breau, R., Cagiannos, I., Morash, C., . . . Schieda, N. (2016). Multiparametric MRI of the anterior prostate gland: Clinical–radiological–histopathological correlation. Clinical Radiology, 71(5), 405-417. doi:10.1016/j.crad.2016.01.002