Prostate carcinoma is the most commonly diagnosed malignancy and the second most common cause of male cancer death in the USA Citation[1]. Autopsy and early observational studies have shown that approximately one out of three men above the age of 50 years has histologic evidence of prostate carcinoma. While a portion of these tumors may be very aggressive and lethal, others are possibly clinically insignificant Citation[2]. Identifying the lethal form of this tumor remains a challenge in this heterogeneous malignancy. The clinical presentation of prostate cancer may range from an asymptomatic condition to a rapidly progressive systemic illness. Prostate specific antigen (PSA) screening has resulted in earlier detection and a downstaging of prostate cancer at diagnosis. At the same time, the commonly used PSA cutoff of 2.5 ng/ml, used by urologists for biopsy, also leads to a significant number of unnecessary biopsies, leading to overdiagnosis and overtreatment of indolent disease Citation[3]. Thus far, imaging has only played a relatively small role in the management of localized prostate cancer. The current standard imaging techniques, such as transrectal ultrasound (TRUS), MRI, computed tomography (CT) and nuclear medicine studies, are not able to detect early disease, and only provide limited information for tumor, node, metastasis staging Citation[4].
However, the role of imaging in patients with prostate cancer is evolving. New techniques are under investigation, either alone or combined with standard imaging techniques. TRUS is usually used to guide biopsies and to place brachytherapy seeds, but it does not reliably differentiate healthy from malignant prostate gland tissue. Contrast-enhanced color Doppler imaging, intermittent harmonic imaging and contrast-enhanced flash-replenishment imaging are now combined with standard TRUS. Contrast-enhanced ultrasound takes advantage of an increased density of microvasculature in cancerous tissue compared with benign prostate tissue. Using microbubble contrast agents, which diffuse into microvessels, this technique selectively enhances areas with increased vascularity. However, because of the relatively large size of microbubbles (∼5–10 µm), leakage into the tumor cannot be well visualized and enhancement can also be due to benign conditions, such as prostatitis Citation[5]. In a recent study of 114 patients with elevated PSA levels and previous negative biopsy contrast-enhanced advanced dynamic flow, Doppler reliably detected prostate cancer with a sensitivity of 100%, but limited specificity of 48% Citation[6].
Functional MRI techniques such as diffusion-weighted MR imaging (DWI), dynamic contrast-enhanced MRI (DCE–MRI) and MR spectroscopy (MRS) have been investigated for their potential to complement morphologic T2-weighted MRI in improving prostate cancer localization. DWI assesses the Brownian motion of free water in tissue and has been used successfully in the diagnosis of acute strokes, where motion of water is believed to be restricted by cytotoxic edema. Owing to their high cellular density, cancer tissue also demonstrates restricted diffusion. Healthy prostate tissue is rich in glandular tissue and shows higher water diffusion rates. These differences can be depicted on apparent diffusion coefficient maps obtained with multiple b-field gradient values. DWI alone shows a sensitivity and specificity for tumor detection of 57–93.3% and 57–100%, respectively, depending on the applied technical parameters and characteristics of the studied patient population Citation[5]. While DWI has improved the detection accuracy of prostate cancer in conjunction with MRI or MRS, further trials are required for validation Citation[7,8]. The injection of a gadolinium chelate contrast agent on DCE-MRI leads to rapid enhancement and early washout of signal intensity in areas of hypervascularization with highly permeable vessels, such as prostate cancer. Tumors with minimal vascularization are not detectable with this technique, and several benign conditions and postbiopsy hemorrhage can mimic tumors on DCE–MRI. DCE–MRI alone ranges between 52 and 96% in sensitivity and between 65 and 95% in specificity for tumor detection Citation[5]. Again, these numbers vary highly depending on the selection of patients, imaging parameters and method of analysis, as well as choice of diagnostic criteria. Combined DCE–MRI and T2-weighted MRI has improved accuracy for both detection and staging of prostate cancer, but a standardized technique and finer analytic tools need to be developed Citation[9,10]. This lack of standardization for MRI of the prostate gland clearly hinders its clinical application. Metabolic activity and pathologic biochemical changes can be measured noninvasively using MRS based on relative concentrations of metabolites in tissues, such as citrate, choline and creatine. A decreased concentration of citrate and an elevated concentration of choline in the peripheral zone are found in prostate cancer tissue relative to healthy prostate. Currently, increased choline levels or an elevated choline-to-citrate ratio on MRS are considered an indicator for malignancy, and higher choline-to-citrate ratios are associated with more aggressive tumors Citation[11,12]. A recent multi-institutional study found no incremental benefit for MRI–MRS compared with MRI alone Citation[13], while several studies demonstrated a benefit from adding functional information from MRS to morphologic information of MRI to localize cancerous tissue and predict tumor grade Citation[12,14]. MRS has been shown to predict volume and extracapsular extension of the tumor, as well as radiotherapy response and cancer recurrence after radiotherapy Citation[15–17]. MRS is one of the longer MRI sequences (set-up time and acquisition time ∼20 min) and also technically challenging. Higher field strengths and signal-to-noise ratios have already led to decreases in acquisition time, while rendering accurate separation of metabolic peaks. Robust fat-and water-suppression techniques are required to further improve MR spectra Citation[5].
PET/CT is emerging as another molecular imaging technique to depict metabolic processes in cancer cells. 18F-FDG PET is generally ineffective in the diagnosis of prostate cancer because of the low metabolic glucose activity of prostate cancer cells compared with other malignancies, and its uptake in benign prostatic hyperplasia nodules. Also, 18F-FDG is excreted via the kidneys leading to high bladder activity, which can mask prostate tumors. 11C-acetate (11C AC) is a promising tracer for PET, which is believed to be involved in lipid synthesis and incorporated into cell membrane lipids in cancer cells. One major advantage is its excretion via the pancreas and intestines, which leaves the bladder region unobscured of activity. 11C AC has a short half-life of approximately 20 min, which allows for multitracer evaluation in a single imaging session, but also requires that scanning be performed near a cyclotron. Several clinical trials have been performed to investigate the sensitivity of 11C AC-PET for staging and restaging in prostate cancer, and found values ranging from 70 to 100% Citation[5]. Another important compound in phospholipid synthesis in cell membranes and transmembrane signaling, lipid and cholesterol transport and metabolism, is choline. 11C-labeled choline can be used for targeted imaging of prostate cancer, as upregulated choline kinase activity and elevated choline levels have been detected in this malignancy. It is taken up rapidly within prostate tissue and cleared from the blood within 7 min, which allows 11C-choline PET imaging shortly after its injection. Its short half-life is its major limitation for routine clinical use but a choline analogue, 18F-fluorocholine (18F-FCH), has a half-life of approximately 110 min and although mainly excreted in the urine, has shown very promising results in localized and metastatic prostate cancer when imaged prior to urinary excretion Citation[5,18,19]. Novel PET tracers such as 11C-methionine, an amino acid analog that reflects tumor cell proliferation and cell turnover, or anti-1-amino-3–18F-fluorocyclobutane-1-carboxylic acid (anti-18F-FACBC), a synthetic L-leucine analog, are underway and have shown promising results in clinical trials.
The expression of prostate-specific membrane antigen (PSMA) is usually low but increases in prostate cancer cells, in particular in androgen-independent prostate cancer, and shows a positive correlation with tumor grade Citation[5]. In 1996, the FDA approved a radiolabeled murine monoclonal antibody, 111In capromab pendetide (ProstaScint®, Cytogen), which targets an intracellular domain of PSMA. 111In capromab pendetide imaging can allow detection of recurrent cancer after prostatectomy, and of lymph node and occult metastasis. Owing to its intracellular target, cell membranes need to be disrupted (apoptosis, ischemia) for antigen–antibody binding which leads to a high background signal in addition to a poor spatial resolution. Imaging is performed with planar projection γ-cameras and cross-sectional SPECT. Although fusion with anatomic images and combined SPECT-CT improves specificity, overall accuracy is still low Citation[5]. PSMA antibodies targeted at the external domain of the antigen may provide more satisfactory results and are under development.
Imaging can provide dynamic real-time data of morphology and bodily functions, and allows for repeated measurements while it is non- or only minimally invasive. The potential role of accurate prostate imaging modalities lies in risk stratification, initial staging, active surveillance and, ideally, in stimulating the development of focal therapies for prostate cancer. It is of critical importance to standardize imaging measurements within and across the different techniques in order to assess the meaning of these measurements in relation to a specific clinical outcome. Recent improvements in prostate cancer imaging need to translate into more adequate treatment selection and more accurate imaging-guided therapies. Hopefully, this will contribute to long-term improvements in quality of life and decreases in prostate cancer morbidity, as well as diminish mortality rates from this common disease. New molecular biomarkers may help to avoid overdiagnosis and overtreatment, whilst also preventing underestimating cancers with lethal biological potential. The imaging tools we currently have available in daily clinical routine only provide less than precise predictions. Adding functional and anatomic imaging information to clinical nomograms will enhance their accuracy for predicting outcomes and directing therapies.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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