Detection of prostate cancer using magnetic resonance spectroscopy

Janesya Sutedjo, CHEN Hui-you, WANG Li-wei, YIN Xin-dao

Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China

南京医科大学附属南京医院(南京市第一医院)医学影像科，南京 210006

1 Introduction

Based on the GLOBOCAN 2008 estimates,prostate cancer is the second most commonly diagnosed cancer and also the sixth leading cause of mortality in cancer in males worldwide[1].An early detection of the prostate cancer is an important part to have an effective treatment of prostate cancer[2-3].For this reason, detection of the prostate cancer is a major topic of diagnostic imaging, while screening for prostate cancer is still problematic and remains controversial[3-4].

Presently, the common methods used for detecting the prostate cancer are digital rectal examination (DRE), serum prostate-specific antigen(PSA) level, transrectal ultrasound (TRUS), and sextant biopsy[2-3,5-8].The gold standard of prostate cancer diagnosis includes a histological examination of biopsy specimens obtained via a blinded sextant TRUS directed biopsy for patients with elevated PSA levels or abnormal DRE[3,9].However, this method is still insufficient and limited in the detection and local staging of prostate cancer because of the low sensitivity and specificity to indicate the malignancy,as the result from the location of the sextant biopsy that chosen randomly and the heterogeneous distribution of the tumor within the prostate[2-4,8-10].

Magnetic resonance imaging (MRI) of the prostate is better in giving a clear and detailed image of soft-tissue structure than other imaging methods, it provides a high-resolution anatomical images based on numerous basic tissue characteristics that could show the best description of prostate contour and anatomy of the internal zone.The degree of details and high resolution of images given by MRI, makes it an excellent tool for early diagnosis and staging of prostate cancer[2,6,11-13].The role of MRI has advanced in the past decade with development of newer techniques to localize, stage, and obtain functional information about the tumor.Such as diffusionweighted imaging (DWI), dynamic contrast-enhanced MRI (DCE-MRI), and MR spectroscopy (MRS),which are highly sensitive and specific for detection,staging, and localization of prostate cancer, also could describe the extracapsular spread due to high soft tissue resolution[2,5,14-15].MRS is the most commonly used functional MRI technique for prostate cancer detection[3].

In this article we will talk about how the MRS work and the different strength of magnetic fi eld, and coils that commonly used nowadays.

2 Prostate Metabolism

2.1 Normal Prostate

Normal prostate gland epithelial cells contain a high concentration of zinc.These high concentrations of zinc are primarily due to increased expression of ZIP-type plasma membrane Zn uptake transporters(primarily Human ZIP-1).Zinc suppresses aconitase activity that caused suppression of the first step of Krebs’ cycle that converts citrate to isocitrate.Thus, preventing the consumptions of citric acid and causing the prostate to synthesize and secrete large amounts of citrate into the glandular cavity, which resulting in high levels of citrate.Normal prostate epithelial cells also contain very high concentrations of polyamines, particularly spermine[6,10-11,16].So MRS of a healthy prostate will have a high peak of citrate and polyamine, and a low peak of choline[11,16].

2.2 Prostate Cancer

Prostate cancers frequently occur in the peripheral zone of the prostate gland.Human ZIP-1 is reduced and zinc levels are dramatically reduced in prostate cancer and the malignant epithelial cells, and there exists evidence that the loss of the capability to retain high levels of zinc is an important factor in the development and progression of prostate cancer[17-18].It is also believed that the transformation of prostate epithelial cells to citrateoxidizing cells, which increases energy production capability, is essential to the process of malignancy and metastasis[19].

In addition, in cancer cells, there is an elevation of choline-containing metabolites [phosphocholine(PC), glycerophosphocholine (GPC), free choline(Cho)]and the over and under-expression of key enzymes in phospholiopid membrane sysnthesis and degradation, specifically choline kinase and a number of the phospholipases, have been associated with the presence, progression and therapeutic response of a variety of human cancers including prostate[16,20].

Similar to citrate, polyamines are dramatically reduced in prostate cancer and this reduction is associated with significant changes of the degree of polyamine metabolism regulatory genes expression.The first step of spermine synthesis, ornithine decarboxylase catalyzes has been found to be overexpressed in prostate cancer.The polyamines also exert diverse effects on protein synthesis and act as inhibitors of numerous enzymes including several kinases.However, similar to citrate high levels of spermine found in the prostatic ducts and the observed changes in spermine may also be due to the loss of ductal morphology or a reduction in the secretion of polyamines in cancer[11].

So MRS of a prostate cancer mostly in its peripheral zone will have an increased level of choline and a decreased level of citrate and polyamine compared to the healthy prostate tissue.These metabolic changes in prostate tissue might occur before morphological changes in tissues and theoretically might be valuable to detect hidden,unsuspected prostate cancer where routine histological sections have failed to detect malignancy[6].

3 Magnetic Resonance Spectroscopy

3.1 How it works

MRS is one of functional methods of MRI that indirectly measures the relative metabolite concentration of specific biochemical compound of tissue in a single or multiple voxels by detecting the chemical shift differences of metabolites.Thus, MRS can assess the normal and abnormal prostate tissue metabolism[4,8,21].On prostate MRS, the resonances for the prostate metabolic fingerprint which are choline, creatine, polyamines, and citrate, that occur at distinct frequencies (≈ 3.2, 3.0, 3.1, and 2.6 ppm,respectively) or positions in the spectrum[5,9,22].

Areas of prostate cancer were metabolically recognized based on the ratio of choline plus creatine to citrate (CC/C) and choline to creatine (C/C) peak area ratios[13,22-23].The first ratio is used because the creatine peak is very close to the choline peak in the spectral trace, the two may be inseparable; so, the CC/C is used for the spectral analysis in the clinical setting[3,24].MR spectra from areas of prostate cancer specifically shows a significant decrease or absence of citrate and polyamines, while the choline level is increased relative to the creatine level, thus resulting in significant changes in the CC/C in areas of cancer[23,25].Since the polyamine peak is not always resolvable from creatine and choline in healthy tissues, it was incorporated in the choline plus creatine peak area.For the same reason, the choline to creatine peak area ratio was only reliable in regions containing cancer, partially or completely, where polyamines are markedly decreased or absent subsequently[23,26].

3.2 Diagnosis Method

There are varieties methods to diagnose prostate cancer based on the CC/C or C/C ratio value.Some of them vary in the cut-off value that they use to diagnose the prostate cancer.Some are also different in the classification of the malignancy of the lesion based on the value given by the ratio.Some of the methods use the CC/C ratios for different tissue in the prostate on a 5-point scale to diagnose the lesion as definitely benign tissue; probably benign tissue;possible malignant tissue; probably benign tissue; or definitely malignant tissue[27-28].

Some other method is using a qualitative approach to diagnosed prostate cancer.All spectroscopic data were scored through a 4-point scale 1 = normal (citrate peak at least two times higher than choline/creatine peak); 2 = probably benign (citrate peak smaller than two times or equal to choline/creatine peak); 3 = probably malignant(choline/creatine peak smaller than two times but higher than citrate peak); 4 = definitely malignant(choline/creatine peak at least two times higher than citrate peak)[29-31].

The benefit of MRS for detecting, localizing, and characterizing prostate cancer is highly dependent on the quality of the spectral examinations obtained[9].The quality of the spectral depends on the magnetic field strength and the coil chosen during the MRS examination.

3.3 Equipments Choice

There are several methods of choice that we could use for the MRS scanning based on the combination of the magnetic field strength and the coils.But the minimum standard is the MRI with magnetic field strength of 1.5 T[5,21,24-32].Below are the methods of choice that are commonly used in the clinical.

3.3.1 1.5 T with body-surface coils

The use of body-surface coils, especially in 1.5 T MRI, has been considered technically difficult because of the small size and deep location of the prostate gland with low signal-to-noise ratio[33].But Kumar et.al[34].study demonstrates good spectral acquisition and has obtained clear spectra in all subjects with high signal-to-noise ratio, they got(0.31±0.25) of the CC/C ratio.

3.3.2 1.5 T with endorectal coils

Nowadays the most popular clinical studies of prostate MRS that published are studies using 1.5 T magnet MRI with endorectal coil.The body coil was used for homogenous excitation, and an endorectal coil for signal reception, granting maximum signal-to noise ratio (SNR)[7].Casciani et al[35]study has a CC/C cut-off value of 0.75 that obtained 89% sensitivity and 79% specificity.Wetter et al[7]got a sensitivity of 100% and a specificity of 69% with a CC/C cut-off value of 0.6.Amsellem-Ouazana et al[36]with CC/C cut-off value of 0.86 got a 76% sensitivity and 68%specificity.

3.3.3 3.0 T with body-surface coils

Theoretically, doubling in SNR is expected when moving from 1.5 to 3.0 T.Although a full doubling of SNR is not reached in clinical applications due to Specific Absorption Rate (SAR) (measure of the rate of absorption of RF energy in the body) related sequence modifications, the SNR gain at 3.0 T maybe utilized to reduce the voxel size for high resolution imaging or to reduce the acquisition time in MRI of the pelvis[37].Alternatively, the improvement in SNR may be invested in turn into less patient’s discomfort and the use of more comfortable receiver coils setups by the use of “non-invasive” external bodysurface coils at 3.0 T instead of “invasive” internal endorectal coils at 1.5 T[12,37].In Caivano et al[38]study they use a CC/C cut-off value of 1 got a 93%sensitivity and a 78% specificity.

3.3.4 3.0 T with endorectal coils

The use of an endorectal coils in MRS for localizing prostate cancer at 3T slightly but significantly increased the localization performance compared with the use of body-surface coils[28].A 3.0 T MRI of the prostate with an endorectal coil may be considered as state-of-the-art as it yields very good results in terms of high diagnostic accuracy[37].Yakar et al[28]study showed that diagnosis using MRS for the more experienced readers with an endorectal coils had a high specificity (82%—92%), but a low sensitivity(20%—57%) and for the novice reader, MRSI with the use of an endorectal coils had a high sensitivity(80%) and a low specificity (34%).

4 Conclusion

Nowadays there are a lot of methods to diagnose prostate cancer and it still becomes the controversy which one is the best method for early detection of the prostate cancer.MRS is one of the methods that is promising.But there are a lot of varieties of choice in MRS like the magnetic field strength and the choice of coils.In clinical usage the most used method is scanning with 1.5 T MRI with endorectal coils, but the best way to get a good SNR and images for a rateable MRS voxel is 3.0 T MRI with endorectal coils.Although for the sake of the comfort of the patients we could use the 3.0 T MRI with body-surface coils which still could give us the result that is comparable to 1.5 T MRI with endorectal coils.

Outside the clinical usage there are some studies using MRI magnetic field strength more than 3.0 T.Further improvement of SNR could be expected from the use of even higher field strengths, such as 4.0 T and 7.0 T, so we could get higher sensitivity and specificity in the future[39-41].

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