Evolving Technologies In Imaging Of The Prostate Gland

The emergence of disease-targeted ablative therapies, such as cryosurgery, bra-chytherapy, high-intensity focused ultrasound, and intensity-modulated radiation therapy, has necessitated accurate pretreatment tumor localization and staging. These techniques also require a means by which to assess posttreatment tumor response. Although standard endorectal coil MRI provides excellent anatomic detail of the prostate, it is limited by decreased specificity with regards to tumor detection and localization. As has been seen, a large number of false-positive diagnoses can occur due to hemorrhage, prostatitis, and therapeutic effects, causing low signal intensity on T2-weighted imaging (116,120). A number of emerging approaches have shown promise in improving upon these limitations in MRI specificity.

Magnetic Resonance Spectroscopy

General Principles of MRS

Magnetic resonance spectroscopy (MRS) provides metabolic information from multiple contiguous voxels within the prostate and has been shown to improve tumor localization (121), prediction of extracapsular spread of tumor (122), and response to therapy (123-126).

MR spectroscopy of the prostate is based on the relative concentrations of metabolites that exist in prostate cells and extracellular ducts. Healthy prostate gland cells produce and secrete large amounts of citrate, due to high levels of zinc in the prostate, which inhibit the enzyme aconitase and thereby prevent oxidation of citrate in the Krebs cycle (Fig. 15A and B). In comparison, in prostate cancer cells, zinc levels decrease significantly, citrate metabolism increases, and prostate epithelial cells lose their ability to produce large amounts of citrate. The transformation of prostate gland cells into citrate-oxidizing cells increases energy production, which promotes accelerated proliferation of malignant tissue (127,128). Decreased citrate in prostate cancer cells is also attributed to changes in the organization of the tissue because there is loss of normal ductal morphology (123). There is also an elevation of choline-containing compounds in carcinoma cells relative to normal peripheral gland tissue. This is a less understood mechanism but is attributed to altered metabolism of phospholipids in growing malignant cells (123,129,130).

The three metabolites—citrate, choline, creatine (the last remaining relatively constant in both normal and abnormal prostatic tissue)—produce distinct frequencies in the resonance spectrum and can be detected when spectroscopy is added to a routine clinical endorectal MR examination. Both studies use the same scanner and coil. The ability of MRS to detect elevated choline and decreased citrate levels in tumor cells depends on adequate suppression of adjacent water and lipid signal that exist in the prostate and periprostatic tissue (Fig. 16A and B) (120).

Three-dimensional MRS imaging is a methodology that can assess citrate and other metabolites in the entire prostate with a voxel size of 0.24 cc (129). The data may be subsequently overlaid on a corresponding T2-weighted MR image. The

Dimensions Endorectal Coil

Figure 15 Sixty-four-year-old with a normal metabolic profile of the prostate gland. (A) Axial T2-weighted image demonstrates a normal region of peripheral zone of the left prostate gland demarcated by the cursor. (B) The NMR spectra of this same tissue reveal a normal pattern of a high citrate peak (thick black arrow) and a low choline peak (thin black arrow). Abbreviation: NMR, nuclear magnetic resonance.

Figure 15 Sixty-four-year-old with a normal metabolic profile of the prostate gland. (A) Axial T2-weighted image demonstrates a normal region of peripheral zone of the left prostate gland demarcated by the cursor. (B) The NMR spectra of this same tissue reveal a normal pattern of a high citrate peak (thick black arrow) and a low choline peak (thin black arrow). Abbreviation: NMR, nuclear magnetic resonance.

Figure 16 Sixty-two-year-old man with prostate cancer and abnormal MR spectroscopy. (A) Axial T2-weighted image reveals a box (numbered 1-6) that demarcates normal tissue (boxes 1 and 2), indeterminate tissue (boxes 3 and 4), and low signal intensity cancerous tissue (boxes 5 and 6). (B) The corresponding MR spectra reveal a normal pattern of high citrate and relatively low choline levels in boxes 1 to 4 and an abnormal pattern of a suppressed citrate peak and relatively elevated choline peak reflecting cancer in boxes 5 and 6 (Ci = citrate and Ch = choline). Abbreviation: MR, magnetic resonance.

Figure 16 Sixty-two-year-old man with prostate cancer and abnormal MR spectroscopy. (A) Axial T2-weighted image reveals a box (numbered 1-6) that demarcates normal tissue (boxes 1 and 2), indeterminate tissue (boxes 3 and 4), and low signal intensity cancerous tissue (boxes 5 and 6). (B) The corresponding MR spectra reveal a normal pattern of high citrate and relatively low choline levels in boxes 1 to 4 and an abnormal pattern of a suppressed citrate peak and relatively elevated choline peak reflecting cancer in boxes 5 and 6 (Ci = citrate and Ch = choline). Abbreviation: MR, magnetic resonance.

3D acquisition allows the dataset to be viewed in any plane and the spectroscopic voxel position to be changed to better match an abnormality on T2-weighted imaging (128,129). The concordance of MRI and MRS leads to a more confident diagnosis of cancer and extracapsular tumor spread, which helps minimize the interreader variability that can result in the reported wide range of accuracies (56% to 93%) (120,122).

Localization of Tumor and Assessment of Extracapsular Spread of Tumor

Accurate tumor localization can help target TRUS-guided biopsies in patients with elevated PSA levels but negative previous biopsies, guide targeted therapies, and monitor the progress of patients who have chosen watchful waiting as a treatment option (83). Combined MRI-MRS has an accuracy rate similar to biopsy for localization of tumor in a specific sextant of the prostate and at the apex of the gland, is better than biopsy. The addition of MRS to standard MRI provides better detection of cancer than MRI alone and increases the specificity of tumor diagnosis from 46% to 61% up to 94% (121). Postbiopsy hemorrhage may hinder the interpretation of standard T2-weighted images because blood products can persist as long as four months and mimic low T2-signal intensity tumor (52). Kaji et al. showed that adding MRS to conventional endorectal MRI significantly improves the accuracy (from 52% to 75%) and specificity (from 26% to 66%) of tumor detection in the background of postprocedural hemorrhage (54).

Attempts have been made to use MRS to evaluate the central gland for tumors. As many as 30% of cancers occur in the transitional zone. These are often missed on routine endorectal MRI because they cannot be distinguished from the heterogeneous appearance of coexisting, surrounding, or adjacent BPH. Unfortunately, decreased citrate and elevated choline levels have been found in stromal BPH. Therefore, the broad range of metabolite ratios precludes the use of a single ratio to distinguish cancers from benign tissue (131).

The presence and extent of extracapsular spread of tumor greatly affects the choice of tumor therapy and has been the focus of recent MRS investigations. Although endorectal coil imaging with T2-weighted sequences has improved the detection of tumor spread, men are being diagnosed at earlier stages with microscopic spread that is not visible on MR images (8). Prostate cancer volume has been shown to be a good predictor of extracapsular spread on histopathologic studies (132). Tumor volume, as estimated by MRS, is higher in patients with extracapsular spread than in patients without spread and has improved the diagnostic accuracy of staging (9,120).

Assessment of Cancer Therapy

Local recurrence of cancer after treatment is often suspected due to rising or detectable PSA levels. However, PSA is not specific for tumor, can take one to two years to reach a nadir after treatment, and can be difficult to interpret in the setting of hormonal deprivation. The only way to definitively diagnose recurrent disease is by biopsy, but this method is subject to sampling errors. Because treatments with radiation, cryosurgery, and hormonal therapy result in necrosis of both normal glandular tissue and cancer cells, they can produce diffuse low T2-signal intensity and loss of zonal anatomy (35,96,97,124,133,134), making tumor detection difficult. Standard MRI may have difficulty in distinguishing benign prostatic tissue, inflammatory cells, and necrotic tissue from cancer cells. MRS can be extremely helpful in this setting. MRS shows histologically necrotic tissue to have no discernible citrate or choline. Although citrate is uniformly suppressed in areas of both necrosis and tumor and cannot be used for assessment, elevation of choline in a particular voxel raises the suspicion that recurrent or residual cancer is present (134).

Following radiotherapy, accurate early measurement of tumor response is important in assessing dose escalation and treatment failures that may require salvage therapy (124). When cryosurgery has been performed, MRS increases the sensitivity in detecting local recurrence in patients who still have elevated PSA after the procedure. MRI-MRS can also help identify lesions for repeat biopsy or cryosurgery (125,126).

Recently, hormonal ablation (or deprivation) therapy has been used as a primary or adjuvant therapy for patients with localized disease (123,135,136). Hormonal therapy deprives both healthy and malignant cells of androgen, which results in tissue atrophy and a decrease in overall gland and tumor volume. The marked glandular shrinkage and increased periglandular fibrous tissue results in a small prostate with poor zonal differentiation and diffuse low T2-signal intensity throughout the peripheral gland, which makes it difficult to identify tumor (97,137,138). The low T2-signal intensity results in an overestimation of tumor presence and extracapsular spread. A time-dependent loss of all metabolites (metabolic atrophy) occurs in a certain percentage of patients on long-term therapy and is greater in regions of cancer when compared to healthy peripheral glandular tissue. Citrate levels decrease faster than that of other metabolites because of hormonal control of citrate production and secretion (137). Recent studies have shown that residual choline may be used as a substitute marker for cancer after prolonged hormonal ablation therapy and that the combination of MRI and MRS can provide better localization of tumor (139).

Diffusion-Weighted Imaging

Diffusion-weighted MR imaging (DWI) is a technique that relates image intensities to the relative mobility of endogenous tissue water molecules. The microenvironment of the water molecules influences the freedom of diffusion and is reflected in the measurement of the apparent diffusion coefficient (ADC). Preliminary work on DWI in the prostate gland has shown that the mean ADC is lower in malignant peripheral zone tissue than in benign or normal peripheral zone tissue (140,141). This significant reduction of the mobility of water molecules observed in tumors may be secondary to replacement of water-rich acinar cells by numerous, closely packed cancerous cells and to an increased nuclear-to-cytoplasmic ratio. ADC values are higher in normal peripheral zone relative to the central gland, which again reflect the higher mobile water content in the luminal spaces of the peripheral gland relative to the compact central gland (140,141). DWI of the prostate gland is in its infancy, even as a research tool, but may establish a role in the future as a noninvasive marker for treatment response of prostate cancer.

Role of MRI in Radiotherapy Treatment

Radiation therapy of prostate cancer has more recently focused on conformal radiotherapy (CRT), which delivers high radiation doses to the target volume while sparing normal tissue and intensity-modulated radiotherapy, which customizes the dose

Penile Gland Lesion

Figure 17 Sixty-three-year-old man with prostate carcinoma undergoing radiation therapy. (A) Axial T2-weighted image demonstrates the peripheral gland of the prostatic apex (black arrow). (B) A coronal T2-weighted image also clearly delineates the peripheral gland of the prostate (long black arrow) and the penile bulb (short black arrow) which will aid in customizing the delivered dose to the tumor.

Figure 17 Sixty-three-year-old man with prostate carcinoma undergoing radiation therapy. (A) Axial T2-weighted image demonstrates the peripheral gland of the prostatic apex (black arrow). (B) A coronal T2-weighted image also clearly delineates the peripheral gland of the prostate (long black arrow) and the penile bulb (short black arrow) which will aid in customizing the delivered dose to the tumor.

distribution and delivers a nonuniform dose to the target (142,143). A higher level of accuracy is needed for localization of tumor and for delineating the prostate and other structures in the pelvis, such as the penile bulb, rectum, and bladder. CT overestimates prostate volume and cannot clearly separate the prostate from the bladder base, seminal vesicles, rectal wall, and neurovascular bundle (142,144,145). Using axial and coronal MRI images to delineate the prostatic apex and other structures has allowed for a reduction in dose to the rectum and penile bulb, thereby minimizing rectal and urologic complications of treatment (Fig. 17A and B) (142,145,146). Fusion of the CT and MRI data currently provides valuable anatomic information for radiation treatment planning (147) and in the future will also integrate functional imaging, such as MRS, to more accurately define the spatial extent of the cancer (148).

MR-Guided Intervention in Prostate Cancer

Patients are now able to undergo MR-guided procedures of the prostate gland due to the development of real-time intraoperative MR systems (149). A transperineal prostate biopsy has been successfully performed on an open configuration, 0.5-T MRI scanner in patients who are unable to undergo transrectal ultrasound-guided biopsies because of prior rectal surgery (150-152).

Brachytherapy, which is a form of radiation therapy in which the radiation is delivered to the target site by the temporary or permanent insertion of radioactive seeds, can also be performed under MR guidance via the transperineal approach (153). A growing number of patients are choosing brachytherapy as their primary treatment modality, with the seeds traditionally placed into the prostate under ultrasound guidance (153-155). This technique can sometimes result in suboptimal placement of radioactive material leading to rectal bleeding, urinary incontinence, and fistula formation (156). Until recently, the primary role of MRI in brachytherapy had been to evaluate the distribution of seeds in the prostate, as well as to detect any extraprostatic seeds and treatment-related changes in the prostate (157-161).

Research on real-time 3D MR-guided seed implantation using an open configuration double-magnet scanner is on going. This scanner configuration allows the perineum to be accessed for seed placement, while the patient's head is accessible for anesthesia (150,153,162). The seed number, strength, and catheter trajectory can be checked for accuracy and modified within seconds (153).

Recently, a more sophisticated method of real-time dosimetric feedback has allowed for more effective delivery of radiation dose to the target volume. These techniques can provide high dose coverage within the prostate without exceeding the maximal dose allowed for surrounding normal tissue, which ultimately may improve treatment options for localized cancer because of reduced morbidity (163).

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