Prostate

Prostate is an exocrine gland, located below urinary bladder and in front of the rectum. In healthy males it weights 7-16 g, depending on the BMI. The gland is surrounded by (anterior) fibromuscular zone (stroma) that is continuous with the bladder and sheathed in the muscles of pelvic floor. Sperm from the testes flows via vasa deferentia to prostate. Prostate and seminal vesicles, located behind the prostate, excrete fluids that along with spermatozoa form the semen. The urethra runs from bladder through the prostate to the penis. The excretory ducts of each seminal gland unites with vas deference, forming two ejaculatory ducts, which pass through the prostate gland and drain into the urethra. Peripheral zone of prostate gland surrounds the distal urethra, and transition zone surrounds the proximal urethra. Transition zone grows throughout the life, causing benign prostatic enlargement (hyperplasia). The central zone surrounds the ejaculatory ducts; cancers in this region are not common, but aggressive and can invade the seminal vesicles.

Women have histologically similar organ, paraurethral gland, or Skene’s gland (Flamini et al., 2002).

Prostate cells contain ∼10-fold concentration of zinc in their mitochondria, compared to other cells. Zn2+ inhibits oxidation of citrate in TCA cycle, and citrate is produced and excreted into prostatic fluid in high concentration. In prostate cancer, cancer cells start to consume citrate, reducing citrate levels up to 40-fold (Iacobazzi & Infantino, 2014).

Prostate-specific antigen (PSA, KLK3) is a product of hK3 gene, which belongs to kallikrein family of 15 members with diverse functions. The first three family members encode for serine proteases, including PSA, which is secreted by prostatic epithelial cells into seminal fluid to liquefy semen. Expression of PSA is regulated by androgens. Normally only minimal amounts of PSA is leaked into plasma (<4 ng/mL), where it is mainly bound to protease inhibitors (Malm and Lilja, 1995). Prostate cancer cells do not overexpress PSA, but altered prostate-blood barrier can lead to very high PSA concentrations in the plasma. Plasma PSA has high sensitivity but low specificity for prostate cancer: cancer in found in only ∼25% of men with concentration higher than 4 ng/mL (Duijvesz and Jenster, 2013). Imaging has been recommended in patients with prostate cancer recurrence already when [PSA] > 0.2 ng/mL (Mapelli et al., 2015).

Prostate cancer

Prostate cancer is a common cancer in men, but remains to be difficult to treat and locate. Circulating PSA levels are used for screening of prostate cancer, but PSA levels can be increased for other reasons, such as prostate inflammation. High PSA expression in prostate tumours is associated with low angiogenic activity, and high PSMA expression with high angiogenic activity (Ben Jemaa et al., 2010). Biochemical recurrence (BCR) occurs in ∼20-40% of patients. The growth and survival of cancer cells is typically dependent on androgen receptors. Treatment includes androgen-deprivation therapy (ADT), but after 2-8 years of ADT, circulating PSA increases again, indicating metastatic castration-resistant (androgen-independent) prostate cancer (SchwarzenBoeck et al., 2017). Cancer cells may become hypersensitive to androgens, or develop other mechanisms to sustain growth. The main site of metastases is bone, representing >90% of patients with metastatic disease.

Multiparametric MRI (mpMRI) is important tool in detecting and local staging of prostate cancer, but its reported accuracy, sensitivity, and specificity are very variable (Fütterer et al., 2015).

[18F]FDG has poor sensitivity because of typically low glycolytic activity of prostate cancer and high radioactivity in the urinary bladder. Specificity is poor, too, because of high uptake in inflammation. [18F]FDG uptake is high in normal testis, but declines with age (Kosuda et al., 1997).

Lipid synthesis is increased in prostate cancer cells, causing increased uptake of choline and acetate tracers (Zadra et al., 2013). 11C- and 18F-labelled choline, and [11C]acetate offer somewhat better specificity and sensitivity than [18F]FDG, but not as good as mpMRI (von Eyben & Kairemo, 2016; Boustani et al., 2018; Malaspina et al., 2018). Combined choline PET and mpMRI can provide more reliable results than mpMRI alone (Gatidis et al., 2015).

Leucine analogue fluciclovine (anti-[18F]FACBC, Axumin®) has low renal clearance, and performs better than previous amino acid tracers (Nanni et al., 2016). In prospective studies, [18F]fluciclovine has shown equal or better performance as mpMRI (Jambor et al., 2018; Akin-Akintayo et al., 2018). Combined mpMRI or MRI and [18F]fluciclovine PET may offer additional benefits (Turkbey et al., 2014; Elschot et al., 2018).

Tissue perfusion is typically high in aggressive prostate cancer, which may help in risk assessment. [15O]H2O PET as a quantitative and reproducible method has been used to validate relative perfusion values obtained using MRI (Muramoto et al., 2002). Kurdziel et al. (2003) followed anti-angiogenic treatment response using [15O]H2O, [11C]CO, and FDG. Input function can be derived noninvasively either using population-based curve or LV cavity curve from another scan performed just before or after the scan of the pelvic region (Tolbod et al., 2018). 82Rb can also be used to quantify perfusion in prostate cancer noninvasively (Tolbod et al., 2015).

Androgen receptor (AR) ligands, such as [18F]fluorodihydrotestosterone ([18F]FDHT) have been used to follow metastases in advanced prostate cancer and in treatment evaluation (Larson et al., 2005; Fox et al., 2018; Vargas et al., 2018; Kramer et al., 2019).

Copper transporter 1 (CTR1) is upregulated in prostate cancer cells. Since Cu2+ is not excreted to urine, it is particularly suitable for detecting tumours in pelvic area. [64Cu]CuCl2 can be used for PET imaging of prostate cancer and its relapse (Capasso et al., 2015; Piccardo et al., 2018). [64Cu]CuCl2 has shown high uptake in prostate cancer and involved lymph nodes (Capasso et al., 2015).

The σ-receptor is being studied as a possible target for prostate cancer imaging (Yang et al., 2017).

GRP receptors are overexpressed in almost all prostate cancers, and several GRP/bombesin analogues have been developed and successfully used in imaging prostate cancer and other tumours (Sonni et al., 2017; Baratto et al., 2017; Wieser et al., 2017).

PSMA targeting radioligands have been found to have excellent sensitivity and accuracy, even better than mpMRI (Eiber et al., 2016; Maurer et al., 2016; Bailey & Piert, 2017; Mena et al., 2018; Hicks et al., 2018; Donato et al., 2019). [68Ga]PSMA-11 is superior to [18F] and [11C]choline in detection of lymph node and other metastases (Morigi et al., 2015; Pfister et al., 2016; Schwenck et al., 2017; Jilg et al., 2019), with lower effective radiation dose (Pfob et al., 2016). Perfusion parameters from DCE MRI correlate positively and oxygenation parameters from BOLD MRI negatively with PSMA PET (Reynolds et al., 2019). [18F]Fluoride PET may detect more bone metastases than [68Ga]PSMA-11 (Uprimny et al., 2018; Zacho et al., 2018), but [68Ga]PSMA-11 may be better than [18F]fluoride for evaluation of treatment response (Uprimny et al., 2015). Combination of PSMA PET-CT and mpMRI further improves the detection of lesions (Rhee et al., 2016; Freitag et al., 2017; Chen et al., 2019). Eiber et al (2018) have proposed a molecular imaging TNM system (miTNM) as a standardized reporting framework for PSMA-ligand PET/CT and PET/MRI. Werner et al (2018) have proposed a MI-RADS framework for targeted radiotracers with theranostic implications, including RADS classification for PSMA-targeted PET imaging (PSMA-RADS). Semi-automatic software can be used to calculate whole-body tumour volume and total lesions uptake (same as metabolic tumour volume and total lesion activity in case of metabolic PET tracers); total lesions PSMA uptake has been shown to correlate well with PSA, and could be used to assess individual tumour burden (Schmidkonz et al., 2017; Brito et al., 2019; Gafita et al., 2019). For assessment of osseous tumour burden in prostate cancer, PET-CT -based calculation of BPISUV has been proposed, and software for quantification of bone metastasis load has been developed (Hammes et al., 2018). Treatment response of bone metastases can also be evaluated using PSMA PET (Schmidkonz et al., 2019).

Development in PET scanners and reconstruction methods can further improve the results (Behr et al., 2018; Alberts et al., 2020).

ADT is used in treatment for high-risk, recurrent or metastatic prostate cancer. Androgens, by activating the androgen receptor (AR), are important regulators of prostate cancer cell growth and survival, and therefore androgen synthesis needs to be reduced by either surgical or chemical castration. In castration-resistant prostate cancer the number or activity of ARs can be increased, in which case AR inhibitors, such as darolutamide, can be used as treatment.

Many patients who are referred to PSMA PET are on ADT, which in short-term increases PSMA expression (Wright et al., 1996), but in long-term decreases PSMA radioligand uptake via reducing the tumour size; this temporal relationship between PSMA expression and initiation of ADT may explain some of the variability in the detection sensitivities seen in PSMA PET studies (Meller et al., 2015; Afshar-Oromieh et al., 2018; Emmett et al., 2019; Vaz et al., 2020). In treatment-naïve prostate cancer patients the increase in [68Ga]PSMA-11 uptake was best seen 3-4 weeks after ADT; the increase was heterogeneous, and most prominent in bone metastases (Ettala et al., 2020).

CYP17A1 enzyme inhibition (orteronel, abiraterone) reduces indirectly the production of androgens and estrogens. Mid-treatment response assessment with 99mTc-MDP SPECT and [18F]Fluoride PET often shows initially higher uptake in bone lesions and increased number of detected bone lesions (“bone flair”), which indicates bone repair process and successful therapy (Weisman et al., 2019).

Animal models

Canine species spontaneously develop prostate cancer with advancing age (Waters et al., 1998). In an orthotopic dog prostate cancer DPC-1 model, DPC-1 cells are implanted in the prostate of immune suppressed dog, leading to metastatic disease with high cancer burden (Anidjar et al., 2012). The model is suitable for molecular imaging (Chevalier et al., 2015).

In rats, xenograft models have been used. In vivo [68Ga]PSMA-11 uptake in mouse model has been shown to be reproducible and to correlate with PSMA expression (Lückerath et al., 2018).

Peripheral ganglia in healthy rats can be used as target structures for evaluating PSMA imaging ligands (Endepols et al., 2019). In human studies the normal PSMA expression in peripheral ganglia could be misinterpreted as lymph node metastases (Krohn et al., 2015; Kanthan et al., 2017; Werner et al., 2017; Rischpler et al., 2018; Bialek & Malkowski, 2019).

References:

Cook G (ed.): PET/CT in Prostate Cancer. Springer, 2017. ISBN 978-3-319-57624-4. doi: 10.1007/978-3-319-57624-4.

Culig Z (ed.): Prostate Cancer - Methods and Protocols. Springer, 2018. doi: 10.1007/978-1-4939-7845-8.

Hong H, Zhang Y, Sun J, Cai W. Positron emission tomography imaging of prostate cancer. Amino Acids 2010; 39: 11-27. doi: 10.1007/s00726-009-0394-9.

Kim SH, Cho JY (eds.): Oncologic Imaging - Urology. Springer, 2017. doi: 10.1007/978-3-662-45218-9.

Li R, Ravizzini GC, Gorin MA, Maurer T, Eiber M, Cooperberg MR, Alemozzaffar M, Tollefson MK, Delacroix SE, Chapin BF. The use of PET/CT in prostate cancer. Prost Cancer Prostatic Dis. 2018; 21: 4-21. doi: 10.1038/s41391-017-0007-8.

Polascik TJ (ed.): Imaging and Focal Therapy of Early Prostate Cancer, 2nd ed. Springer, 2017. doi: 10.1007/978-3-319-49911-6.

Tewari A (ed.): Prostate Cancer: A Comprehensive Perspective. Springer, 2013. doi: 10.1007/978-1-4471-2864-9.

Zimmerman ME, Meyer AR, Rowe SP, Gorin MA. Imaging of prostate cancer with positron emission tomography. Clin Adv Hematol Oncol. 2019; 17(8): 455-463. PMID: 31449514.

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Updated at: 2020-01-30
Created at: 2018-01-09
Written by: Vesa Oikonen