MR Imaging of Prostatic Calcifications

The traditional prostate cancer (PCa) screening, diagnosis, and treatment options comprising of prostate-specific antigen (PSA) testing, random transrectal ultrasound (TRUS) biopsy, and prostatectomy/radiation have significant limitations. PSA is a nonspecific test, which is elevated in many benign situations. The American Cancer Society's estimate of 161,360 new cases of PCa in the United States in 2017 is a significantly lower number than that of 2016 (180,890) and 2015 (220,800), mostly due to the United States Preventative Services Taskforce (USPTF) recommendations against routine PSA testing. Random TRUS biopsy is notorious for the conundrum of overdiagnosis of low-risk PCa and under detection of high-risk PCa. Random biopsy of the prostate to diagnose or exclude cancer is performed nearly 1,000,000 times annually in the United States, most frequently as a result of elevated PSA. Less than one-third of these are positive. Both prostatectomy and radiation are associated with high risks of incontinence and impotence. Many patients with low- and intermediate-risk disease unnecessarily undergo these aggressive treatment options.

There is considerable ongoing effort to improve the deficiencies in the diagnostic and treatment approaches. For example, better screening methodologies are being developed, including strategies on how to incorporate prostate magnetic resonance imaging (MRI) into the screening algorithm. The improvement in prostate MRI techniques and advent of targeted biopsy techniques has enabled physicians to actually see and target the risk driving "index" lesion. In the treatment realm, a wide range of minimally invasive modalities has been tested for whole-gland, partial-gland, and focal treatments. Therapeutic ultrasound is a popular FDA-approved, nonsurgical, "no-needle" ablative therapy that does not use ionizing radiation. Theoretically, therapeutic ultrasound has the potential to markedly reduce treatment-related complications that affect urinary and sexual function. While prostate therapeutic ultrasound is FDA-approved, it is not reimbursed by major insurance carriers and its efficacy is still under investigation.

As with diagnostic ultrasound, therapeutic ultrasound can be blocked by calcifications leading to sub-optimal delivery of the thermal dose to the tumor foci. Also, if MR guidance is being used, the most commonly used method of MR thermometry (proton resonance frequency shift) doesn't work well in areas with calcifications. Currently, most major manufacturers of prostate therapeutic ultrasound equipment have limitations related to calcifications:

1. Sonablate (transrectal ultrasound guided high-intensity focused ultrasound (HIFU) device, FDA approved) user manual states that "As with any ultrasound technology, significant changes in tissue density such as calcifications and/or cysts (depending on size) may have an effect on ultrasound attenuation and overall energy and may impact the patient's suitability for treatment".
2. Ablatherm (FDA approved, similar to Sonablate): While calcifications in ablation volume are not a contra-indication for prostate ablation with this device, it can treat only small prostates with larger prostates (> 24 mm AP) requiring cytoreduction via transurethral resection (TURP) presumably removing most calcifications which are usually found along the pseudocapsule.
3. TULSA-PRO: This is a transurethral MR guided device which is currently undergoing clinical trials. Calcifications greater than 1 cm are a contra-indication for whole gland ablation. However, even smaller calcifications can prevent heating of the index lesion if focal therapy is being attempted. This uses high energy directional ultrasound (HIDU).
4. ExAblate Prostate: This is a transrectal MR guided device which is currently undergoing clinical trials. Calcifications 2 mm or greater in the ultrasound beam path and less than 5 mm from the rectal wall are a contra-indication.

Prostate calcifications are commonly found in elderly men, up to 50% by some estimates with higher incidence in men who have lower urinary tract symptoms. These are mostly made up of calcium apatite. They are mostly seen at the junction of transitional zone and peripheral zone with other locations being rare. Prostate calcifications can be seen as echogenic foci on ultrasound which may or may not shadow depending on their size. However, cross sectional information about the calcification is more beneficial especially while therapy planning. Computed tomography imaging is the current gold-standard for prostate calcification imaging. Current widely used MR techniques do not adequately image prostate calcifications. Calcifications are usually T1 and T2 dark but can be bright on both. T1 bright microcalcifications are noted frequently in the brain. Calcifications have also been shown to be bright on T2 weighted images (Fahr disease and chondrocalcinosis). The change in signal is thought to be related to closely associated water molecules in the microcalcification lattice. Gradient echo images cannot differentiate between calcifications and hemorrhage. There is definite need to develop and validate MR imaging techniques to visualize focal calcifications, especially for focal therapy planning and monitoring. It will obviate need for CT correlation, help in focal ablation modality selection and give true relative location of the calcification vis-à-vis visualized tumor without need for fusion. Imaging calcifications and evaluation of their effect on high energy ultrasound will help us define clinically significant calcifications. It is also the first step in development of techniques to mitigate effect of calcifications on therapeutic ultrasound.

3 promising MR techniques are available:

• A study by Zhu WZ et al., showed that both calcification and hemorrhage manifested low signal on susceptibility weighted images, but they presented opposite signal features on the corrected phase images. Significant difference was found in average phase shift between calcification and hemorrhage (t=74.69, p<0.05). These have been applied in the prostate before but size correlation has not been reported. An example of SWI imaging for calcification is provided.
• Zero-time echo (ZTE) and Ultra-short time echo (UTE) images have also been shown to image tissues with short T2 times like cortical bone. These can be used to study some stages of calcifications. To our knowledge, these have not been applied in the prostate before.
• Temperature uncertainty images can also be used to visualize calcifications in the prostate. This was observed in the currently undergoing clinical pivotal clinical trial of transurethral prostate ablation.

Comparison between these three MRI sequences, and the gold standard CT imaging of the pelvis will be performed to determine whether MRI can reliably identify and accurately measure the size of the prostate calcifications.