Identification and understanding of molecular and genetic alterations that lead to neuroendocrine differentiation in prostate cancers is crucial for the development of novel targeted therapies [19]. The most important molecular alterations in applied clinical practice currently are N-myc proto-oncogene (MYCN) and aurora kinase A (AURKA), androgen receptor gene amplification, and ETS gene family fusions. It may also include RE1-silencing transcription factor (REST) gene downregulation or loss, TP54 loss, RB1 loss, PTEN loss, MYCL amplification or upregulation of proliferative genes (e.g., cyclin D1) ^{[20][21][22][23]}[20,21,22,23].

Imaging of the prostate includes various modalities, including multiparametric ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), and positron emission technique (PET), including evolving molecular imaging techniques.

Multiparametric US imaging includes various US techniques used for anatomic assessment, such as grayscale US, color doppler US (CDUS), transrectal US (TRUS) biopsy, US elastography (real time and strain), contrast-enhanced US (CEUS), and computer-aided US imaging analysis ^[24][25][24,25]. US imaging for prostate cancer has quite a few drawbacks. For example, benign lesions of the prostate, such as benign prostatic hyperplasia (BPH) and prostatitis, can both have the same hypoechoic appearance of prostate cancer and early-stage cancers can appear isoechoic. Initial TRUS can miss up to 47% of cancer cases and around 60% of suspicious prostatic lesions on grayscale US, are benign ^[24][26][27][24,26,27]. CEUS has the ability to visualize the asymmetrical tumor microvasculature pattern and makes it superior to CDUS, which is limited to larger macrovessels [28]. As prostate cancers are usually more stiff than normal prostatic tissue due to increased collagen deposition around the tumor, increased cellularity and vascularity, US elastography is emerging as an important diagnostic tool for primary prostatic evaluation [29].

Most of the literature states that MDCT typically plays no role in the detection of PNEC and is not recommended for diagnosis. The only role of CT is for nodal staging, but it is also limited for this purpose, due to its inability to detect neoplastic architectural changes within less than 10 mm normal-sized lymph nodes (LNs) ^[30][31][30,31]. MDCT plays an important role in M staging for detection and restaging for bone and lung metastases in these cases.

Multiparametric MRI (mpMRI) is now considered to be the standard imaging evaluation of choice when suspecting prostate cancer. Members of PI-RADS (version 2.1) steering committee recommend using 3T MRI scanners over 1.5T machines for prostatic evaluation, as it increases the signal-to-noise ratio (SNR), leading to an increase in both temporal and spatial resolution. If only 1.5T scanners are available or in the case of inherently low SNR sequences, such as DWI, they recommend the use of endorectal coil (ERC) which has the ability to increase SNR at any magnetic field strength [32]. Most tumors appear isointense to normal prostate tissue on T1-weighted sequences which serve as a baseline for the contrast-enhanced MRI, delineate the prostate outline, and can also demonstrate post-biopsy hemorrhage and periprostatic fat invasion. T2-weighted (T2W) sequences are used to evaluate prostatic zonal anatomy, primarily evaluate the transitional zone or central gland tumors, asses for seminal vesicle or nodal involvement, and detect extra-prostatic extension (EPE). Peripheral zone cancers usually demonstrate ill-defined T2 hypointense focal lesions with restricted diffusion and are primarily evaluated on ADC/DWI images. Transitional zone tumors appear hypointense with spiculated, ill-defined margins and smudgy appearance on T2W images. These lesions may also invade the urethral sphincter and anterior fibromuscular stroma ^[33][34][33,34]. While mpMRI is now considered the technique of choice for initial and local (T) tumor staging, PET/CT and PET/MRI have shown a great value in distant extraprostatic (N and M) staging, restaging after biomedical relapse, and response assessment after androgen deprivation therapy (ADR) ^{[35][36][37][38]}[35,36,37,38]. The sensitivity, specificity, positive predictive value, and negative predictive value of multiparametric MRI for detection of EPE, were 48.7%, 73.9%, 35.9%, and 82.8%, respectively ^[39][40][39,40].

mpMRI can also differentiate prostatic carcinoid from usual prostatic adenocarcinoma based on the considerably larger size and mild hyperintensity of the tumor on T2W images [41]. Recently, biopsy guided by the fusion of MRI and transrectal US images (called MRI-TRUS fusion biopsy) is increasingly used where MRI findings are used as reference for US-guided biopsy, allowing for increased accuracy and precision [42].

Molecular imaging in prostate cancer offers the advantage of improved sensitivity over conventional imaging. Multiple PET tracers are available for the evaluation of prostate carcinoma, particularly in the restaging setting. The FDA-approved radiotracers include 18F-FDG, 18F-NaF, 11C/18F-Choline, and 18F-Fluciclovine. 68Ga-DOTATATE PET has been found to be promising and is now being established for the evaluation of neuroendocrine neoplasms of the lungs, thyroid gland, and gastrointestinal tract. However, it is still not used for routine clinical use in patients with NEPC ^[43][44][43,44]. PSMA has received attention as a useful biomarker in the imaging of prostate cancer, particularly detecting disease at lower PSA levels. However, the expression may be reduced that can potentially lead to false negatives in highly evolved tumors with neuroendocrine features [45]. Another emerging PET tracer is an analog of bombesin or antagonist of the gastrin releasing peptide receptor. Bombesin-like peptides are also overexpressed in NEPC and are an area of active research [46].