Molecular imaging of cancer: MR spectroscopy and beyond

European Journal of Radiology 81 (2012) 566–577

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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad

Review

Molecular imaging of cancer: MR spectroscopy and beyond K. Pinker a , A. Stadlbauer c , W. Bogner b , S. Gruber b , T.H. Helbich a,b,∗ a

Department of Radiology, Division of Molecular and Gender Imaging, Medical University Vienna, Austria MR Centre of Excellence, Department of Radiology, Medical University Vienna, Austria c Department of Neurosurgery, Neurocenter, University of Erlangen-Nuremberg, Erlangen, Germany b

a r t i c l e

i n f o

Article history: Received 12 March 2010 Received in revised form 25 April 2010 Accepted 27 April 2010 Keywords: Molecular imaging MR spectroscopy Cancer Sodium imaging Diffusion-weighted imaging Breast Prostate Brain

a b s t r a c t Proton magnetic resonance spectroscopic imaging is a non-invasive diagnostic tool for the investigation of cancer metabolism. As an adjunct to morphologic and dynamic magnetic resonance imaging, it is routinely used for the staging, assessment of treatment response, and therapy monitoring in brain, breast, and prostate cancer. Recently, its application was extended to other cancerous diseases, such as malignant soft-tissue tumours, gastrointestinal and gynecological cancers, as well as nodal metastasis. In this review, we discuss the current and evolving clinical applications of proton magnetic resonance spectroscopic imaging. In addition, we will briefly discuss other evolving techniques, such as phosphorus magnetic resonance spectroscopic imaging, sodium imaging and diffusion-weighted imaging in cancer assessment.

1. Introduction Since the 1980s, two complementary techniques – magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopic imaging (1 H-MRSI) – have emerged. MRI investigates anatomic changes associated with neoplastic disease, while 1 HMRSI is able to examine the biochemistry of tissue and to detect spatial deviations from normal biochemistry in neoplastic tissues. Although the evolution of 1 H-MRSI over the past 25 years in the clinical setting has been rather slow, MRI has matured more rapidly and now plays a key role in the assessment and therapeutic monitoring of neoplastic disease. However, with advances in technology within recent years, 1 H-MRSI has entered the clinical routine [1,2] and is now routinely used as an adjunct method to MRI for the pre-therapeutic diagnosis, assessment of therapy response, and therapeutic monitoring of brain [3–9], breast [10–14], and prostate [15–20] cancer. In addition, within the past few years, the application of 1 H-MRSI is now expanding to the investigation of other malignant processes, such as the assessment of soft-tissue tumours [21,22], cervical [23–25] and ovarian cancer [26], and lymph node involvement [27].

∗ Corresponding author at: Department of Radiology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail address: [email protected] (T.H. Helbich). 0720-048X/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2010.04.028

© 2010 Elsevier Ireland Ltd. All rights reserved.

This article will discuss the role of molecular imaging with 1 HMRSI in brain, breast, and prostate cancer, as well as new emerging applications of 1 H-MRSI. In addition, we will briefly discuss other evolving techniques which allows insight in molecular imaging, such as phosphorus magnetic resonance spectroscopic imaging, sodium imaging, and diffusion-weighted imaging in cancer assessment. 2. Primary brain tumours The accurate grading of brain tumours has important prognostic and therapeutic implications, as high-grade lesions are treated differently from low-grade lesions. Patients with high-grade lesions, both resectable and unresectable, receive either radiotherapy or combined radio–chemotherapy [28,29]. Low-grade gliomas (WHO grade I and II) are amenable to (radio) surgical resection with curative intent, and adjuvant radio/chemotherapy is only recommended for patients with incompletely resected grade II tumours or for patients older than 40 years of age, regardless of the extent of resection [30,31]. In an effort to preoperatively differentiate between high-grade and low-grade lesions and to determine the optimal patient treatment, a stereotactic biopsy is often performed preoperatively [31]. Burger et al. found that among histopathological features, such as cell frequency, nuclear atypia and mitotic activity, and necrosis and vascular proliferation, only vascular proliferation differentially predicted both the short- and long-term survival in patients with anaplastic astrocytomas [32].

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Fig. 1. Transverse, contrast-enhanced, T1-weighted MR images in a 34-year-old patient with an oligoastrocytoma WHO grade II of the right hemisphere, with the volume of interest of the MR spectroscopic examination (point-resolved spectroscopy box, pink). a) 1 H-MRS spectrum of healthy brain parenchyma of the contralateral side. b) Typical 1 H-MRS pattern of a primary brain tumour: increased levels of choline-containing compounds (Cho) and a reduction in the signal intensity of the Nacetylaspartate (NAA) and creatine (Cr).(For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Contrast-enhanced MRI is the current gold standard for the guidance of brain biopsies for diagnosis and grading of primary malignant brain tumours. However, this method can be ambiguous, as the absence or presence of contrast-enhancement does not necessarily coincide with high-grade. Therefore, a more accurate technique for the guidance of brain biopsy to the most metabolically active part of the lesion, and thus, a more accurate grading, is warranted. 2.1. Improved and accurate pre-therapeutic diagnosis 1 H-MRSI

is a non-invasive tool for investigating the spatial distribution of metabolic changes in malignant primary brain tumours. Although there is no tumour-specific metabolite per se, there are specific patterns in the changes of metabolite concentrations in tumourous tissue compared to normal brain, which can be assessed by 1 H-MRSI (Fig. 1). Numerous studies have reported increased levels of choline-containing compounds (Cho at 3.2 ppm) and a reduction in the signal intensity of N-acetylaspartate (NAA at 2.0 ppm) and creatine (Cr 3.0 ppm) in brain tumours [33–40]. The total choline signal observed in 1 H-MRS is composed of choline, phosphocholine, and glycerophosphocholine, and is thought to be a marker for increased membrane turnover or higher cellular density [41,42]. NAA is regarded as a neuronal marker primarily contained within neurons [43]. The total Cr peak is the summed signal from both Cr and phosphocreatine and plays a role in tissue energy metabolism [44]. The range of Cho increase and NAA decrease is compatible with the range of tumour infiltration [44,45]. For pathologic conditions that mimic brain tumours at MRI, variations in the changes of these three metabolites and others (myo-inositol, lactate, lipids, glutamine, and/or glutamate, and alanine) can be used for differential diagnosis [8,39,40,46–48]. Numerous studies have

demonstrated that the differentiation of the degree of malignancy of brain tumours is feasible [49,50]. In a recent study, Stadlbauer et al. [51] investigated high-spatial resolution 1 H-MRSI for the preoperative grading of suspected WHO grades II and III gliomas. In this study, 26 patients with suspected gliomas and 26 age- and sex-matched healthy control subjects underwent 1 H-MRSI before stereotactic 1 H-MRSI guided brain biopsy. The absolute metabolic concentrations for Cho, Cr, NAA, as well as metabolic maps of Cho/NAA ratios, were calculated. The metabolic maps were used for the stereotactic 1 H-MRSI-guided brain biopsy (Fig. 2). They concluded that 1 H-MRSI, with a high-spatial resolution, segmentation, and absolute quantification of metabolic changes, provides valuable information and allows a preoperative grading of gliomas. Surgical biopsies are the gold standard for diagnosis of tumour type and grade, but targeting the most appropriate tumour region can be difficult [39,40,52,53]. Several studies have confirmed that aiming the biopsy at the area of the maximum Cho/NAA ratio in 1 H-MRSI improves diagnosis [52–56]. 2.2. Assessment and monitoring of response to treatment A decrease in Cho, and an increase in Lactate (Lac) and/or lipids are indicative of response to therapy and reflect tumour necrosis. Moreover, a total absence of metabolites in the former tumour region is indicative of necrotic tissue. As gliomas are highly likely to recur after treatment, a diagnostic method for the early detection of recurrence is necessary. Currently, MRI is the method of choice for follow-up; however, as in primary diagnosis, the MRI findings at follow-up can be ambiguous. In equivocal cases, 1 HMRSI can provide predictive information, as changes in Cho/Cr prior to a subsequent increase in contrast-enhancement hint at tumour progression or recurrence. In serial studies, Wald et al. [57] and

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Fig. 2. 1 H-MRS and stereotactic brain biopsy in a 39-year-old female patient with a glioblastoma multiforme WHO grade IV. (A) Anatomic T2-weighted MR image overlaid with the biopsy sampling points (orange crosses), and the manually defined tumour border, based on conventional anatomic MRI (orange line) and based on MRSI (yellow line), respectively. (B) Corresponding metabolic map that was calculated from the MRSI data overlaid with the same information as in (A). Spectra fitted with LCModel (red line) corresponding to voxel positions at the biopsy sampling points. Biopsy #1 was sampled in the tumour border. The spectrum shows a slightly decreased NAA, but normal Cho- and Cr-signal. Biopsy #2 was sampled in the transition zone between the tumour border and the tumour centre. The spectrum shows a more decreased NAA- and an increased Cho-signal. Biopsy #3 was sampled in the tumour centre. The spectrum shows no NAA and a more increased Cho-signal. Note: the elliptical blue area depicts the result of a fiber-tracking procedure for determination of the pyramidal tract.(For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Tedeschi et al. [58] assessed response to treatment by 1 H-MRSI and demonstrated that an increase in Cho was associated with tumour progression. In patients (WHO II–IV), a more than 45% increase in Cho was suggestive of progression, whereas an increase of less than 35%, or even a decrease, was suggestive of stable disease. Today, the combination of both MRI and 1 H-MRSI are wellestablished in diagnosis [9,52], tissue sampling [53,55], treatment [9], and post-therapeutic follow-up [1], as the addition of 1 H-MRSI to the assessment of primary brain tumours offers a substantial advantage over contrast-enhanced MRI alone.

tions, and early diagnoses and monitoring of early response to therapy are the key information in the prevention and treatment of breast cancer. Contrast-enhanced magnetic resonance imaging (CE-MRI) of the breast has evolved as a non-invasive imaging modality with a reportedly excellent sensitivity (88–100%) and rather variable specificity, ranging from 37 to 97% [59–71]. It has been demonstrated that the additional application of 1 H-MRSI to CE-MRI aids in the differentiation of benign and malignant lesions [10,11,13,14,72–75]. 3.1. Improved and accurate pre-therapeutic diagnosis

3. Breast cancer Breast cancer is one of the most prevalent cancers of the female population in the Western world. The screening of risk popula-

The additional diagnostic value of 1 H-MRSI of the breast is typically based on the detection of elevated Cho levels, since Cho is a biomarker for active tumours. There is no Cho-peak in normal

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Fig. 3. Sixty-three-year-old healthy volunteer: contrast-enhanced (A), sagittal, high-field (3 T), high-spatial resolution, T1-weighted MR image. (B) 1 H-MRS pattern of healthy breast parenchyma of the left breast with no Cho-peak detectable.

breast tissue at a field strength of 1.5 T or 3 T [72,73,76] (Fig. 3). 1 HMRSI of the breast is usually performed on clinical magnets with a field strength of 1.5 T using dedicated breast coils and single-voxel localization. The limitations of this technique are the restriction to evaluating only one lesion at a time, and that fine tumour heterogeneity cannot be assessed due to the relatively poor spatial resolution. Several studies performed on 1.5 T MR scanners reported sensitivities of 70–100% and specificities of 67–100% for 1 H-MRSI of the breast [77–82]. In a recent study, Bartella and Huang [72] reported that single-voxel 1 H-MRSI of the breast can be incorporated into the clinical 1.5 T breast MR imaging protocol with an additional imaging time of only 10 min. They stated that the use of 1 H-MRSI of the breast, in conjunction with CE-MRI of the breast, significantly increases the positive predictive value of MR imaging and decreases the number of benign biopsy results. They concluded that 1 H-MRSI will enable the examination of the whole breast in the future, and, with the use of higher field strengths, the evaluation of smaller lesions will also be feasible [83]. In a pilot study, Gruber et al. developed a high-spatial resolution 3D-MR-spectroscopic imaging (3D-MRSI) protocol at 3 T, designed to cover a large fraction of the breast in a clinically acceptable measurement time of 12–15 min. The authors concluded that 3D-MRSI at 3 T in patients with breast lesions is possible with excellent data quality, and thus, has the potential to become a valuable adjunct to CE-MRI of the breast for differentiation of benign and malignant breast lesions [13,14] (Figs. 4 and 5). 3.2. Assessment and monitoring of response to treatment Neoadjuvant chemotherapy followed by surgery, and often, radiotherapy, is primarily used to treat patients with large (>3 cm) and/or locally advanced (T3, T4 or N2) breast cancers. Due to neoadjuvant chemotherapy, a down-staging of the cancer is often achieved, allowing surgical excision of a previously inoperable tumour. Neoadjuvant chemotherapy may also allow breast-conserving surgery in patients who otherwise would require mastectomy. Although neoadjuvant chemotherapy per se does not substantially increase survival over a postoperative regimen, the way in which a tumour responds to a chemotherapeutic drug can be used to predict treatment outcome [84,85]. Currently, CE-MRI of the breast is the method of choice for assessment of response to neoadjuvant chemotherapy. However, contrast-enhancement patterns may yield misleading findings and false-negative results due to chemotherapeutic agents. In contrast, 1 H-MRSI of the breast is a promising tool for the assessment of the direct effect of the agents.

A pilot study by Jagannathan et al. demonstrated that, after completion of neoadjuvant chemotherapy, a change in the total Cho concentration was observed and confirmed by histopathology. In a more recent study, Meisamy et al. [74] demonstrated that 1 H-MRSI of the breast was able to detect a change in Cho concentration from baseline (before receiving chemo) within 24 h of administration of the first dose of the regimen. This change had a statistically significant positive correlation with change in final size (p = 0.001). Therefore, it can be expected that the addition of 1 H-MRSI of the breast will offer a substantial advantage over contrast-enhanced MRI of the breast alone in the prediction of response to neoadjuvant chemotherapy. 4. Prostate cancer Prostate cancer is one of the leading causes of cancer-related mortality in men of the Western world. Although within recent years the 5-year survival rate has improved, prostate cancer still poses a compelling medical health problem. In clinical practice, a reliable detection and localization of often very small foci of prostate cancer is crucial for therapeutic decision-making, such as “active surveillance,” focal ablative therapy, or prostatectomy [86]. 4.1. Improved and accurate pre-therapeutic diagnosis Conventional morphologic MRI of the prostate plays an important role in localization of the cancer, in local staging, in guiding treatment selection and planning, and is complemented by the use of dynamic CE-MRI and 1 H-MRSI of the prostate. Prostate morphology, conventional MRI, and dynamic CE-MRI of the prostate are described elsewhere [20,87,88]. 1 H-MRSI provides a metabolic profile of the prostate gland. The metabolites that can be detected by in vivo 1 H-MRSI of the prostate are Cho (3.2 ppm), polyamines (3.1 ppm), Cr (3.0 ppm), and citrate (Cit, a doublet of doublets at 2.5–2.8 ppm). The elevation of the choline peak in prostate cancer is mainly attributed to cell membrane synthesis and degradation pathways [19]. The polyamine peak is substantially lower in prostate cancer than in benign prostatic tissue; however, with an MR scanner operating at a field strength of 1.5 T, the polyamine peak cannot be entirely resolved from Cho and Cr peaks. The Cr peak is reportedly hardly different in cancer than in normal peripheral zone (PZ) tissue [19,87]. Cit is synthesized, stored, and secreted by glandular tissue of the prostate. Cit concentration is high in the normal PZ and in glan-

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Fig. 4. Fifty-four-year-old patient with invasive ductal carcinoma G2 of the left breast. (A) 1 H-MRS spectrum of breast cancer with a Cho-peak at 3.2 ppm and (B) adjacent healthy breast parenchyma with no Cho-peak detectable. Spectra obtained at 3 T by using a 1 H-MRSI sequence with PRESS preselection (TR/TE = 750/145 ms). The sequence included spectral water and fat suppression and spatial outer volume suppression. Voxel size was 1 cm × 1 cm × 1 cm in all measurements. Corresponding contrast-enhanced (C) coronal and (D) colour-coded axial high-field (3 T), high-spatial resolution T1-weighted MR image.(For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

dular benign prostatic hyperplasia [19,87]. In prostate cancer, a decrease in Cit occurs, which is presumably a result of changes in cellular function and in the structural organization of its characteristic ductal morphology [19,87] (Fig. 6). Spectral interpretation differs for the PZ and transition zones (TZ) of the prostate gland. For the PZ, the (Cho + Cr)/Cit ratio described by Kurhanewicz et al. [18–20,89] is used to discriminate prostate cancer from normal prostate PZ tissue. Jung et al. [90] reported a standardized evaluation system, which uses a scale of 1 (benign) to 5 (malignant) for data interpretation. In this study, specificities of 84.6% and 89.3% were achieved when voxel scores of 4 or 5 were used to identify cancer. The standardized evaluation system incorporated the (Cho + Cr)/Cit ratio, as well as the presence or absence of polyamine peaks. The criteria for evaluation of MRSI data in

the TZ are still not fully understood due to the heterogeneity of the TZ tissue. The single retrospective study published by Zakian et al. [91] demonstrated a trend toward an increase of Cho and a decrease or lack of Cit in TZ tumours compared with benign TZ tissue. However, a prospective study is needed to validate those results. MRI/1 H-MRSI is not a first-line approach in the diagnosis of prostate cancer. Nevertheless, in patients with increased PSA levels suggestive of prostate cancer and negative previous biopsies, MRI/1 H-MRSI for targeted biopsies may be very useful. 1 H-MRSI has the potential for the non-invasive assessment of tumour aggressiveness, as the (Cho + Cr)/Cit ratio and the tumour volume measured by 1 H-MRSI correlate with the pathologic Gleason score [87,91].

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Fig. 5. Forty-eight-year-old patient with multifocal invasive ductal carcinoma G3 of the left breast: (A) 1 H-MRS pattern (LCModel fit) of the index lesion in the outer lower quadrant with a Cho-peak at 3.2 ppm. Colour-coded (B) axial and (C) sagittal, high-field (3 T), high-spatial resolution T1-weighted MR image of the index lesion in the outer lower quadrant with invasion of a complicated adjacent cyst and a second lesion behind the nipple.(For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Although several studies have demonstrated that the addition of 1 H-MRSI to MRI increases specificity in prostate cancer detection and improves tumour localization in the peripheral zone [87,89,92], recent results of the ACRIN prospective, multi-institutional clinicopathologic trial [89], which was conducted to determine the incremental benefit of combined endorectal MRI and 1 H-MRSI, as compared with endorectal MRI alone, were insightful. For sextant localization of PZ prostate cancer, the ACRIN trial demonstrated that the accuracy of combined endorectal MRI and 1 H-MRSI is equal to that of MR imaging alone. The addition of 1 H-MRSI to MRI at 1.5 T does not improve the ability to localize cancer within a sextant of the prostate [89]. In order to resolve this controversy, more studies, or more possible solutions to increase the sensitivity of 1 H-MRSI of prostate cancer, such as the utilization of higher field strengths (3 T or higher), will be needed.

4.2. Assessment and monitoring of response to treatment To date, the role of MRI in post-therapeutic assessment and follow-up is not well-established. After radiation therapy or hormonal treatment, the prostate is shrunken with indistinct zonal anatomy, and demonstrates diffusely low signal intensity on T2-weighted MRI, thereby limiting the ability of MRI to detect recurrence. However, 1 H-MRSI can be of value in the detection or exclusion of local recurrence after radiation therapy. In a preliminary study that included 21 patients with biochemical failure after external beam radiation therapy and subsequent biopsy verification of local recurrence, Coakley et al. demonstrated that the presence of three or more 1 H-MRSI voxels with elevated Cho (Cho/Cr > 1.5) had a sensitivity of 87% and 72%, respectively. The presence of complete metabolic atrophy had a negative predictive value of 100% for the exclusion of local recurrence [93].

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Fig. 6. Sixty-seven-year-old patient with increasing PSA levels for 12 months and a negative prostate biopsy. Endorectal MRI and 1 H-MRSI were suggestive of prostate cancer (PZ). Prostate cancer stage (T2a) was confirmed by histopathology after radical prostatectomy. (A) T2-weighted transversal image and (B) metabolic map of (Cho + Cr)/Cit ratio calculated for each spectrum and (C) colour-coded metabolic map. The mean (Cho + Cr)/Cit ratio (±SD) of histopathologically healthy 1 H-MRSI voxels was 0.61 ± 0.14. All voxels with a (Cho + Cr)/Cit ratio lower than mean ± SD were defined as healthy (marked by green) and all voxels with a (Cho + Cr)/Cit ratio greater than mean + 2 × SD were rated cancerous (marked by red). All voxels between those cut-off values were deemed suspicious and marked in yellow on the map.

5. Additional applications for MRSI Within recent years, the application of 1 H-MRSI has been expanded to the assessment of cancers other than brain, breast, or prostate. 5.1. Head and neck 1 H-MRSI

has been recently used to localize head and neck cancer and monitor therapy by depicting typical spectral patterns that are associated with active cancer, such as an increase in the total Cho signal intensity (SI) relative to Cr. In both in vitro and in vivo 1 H-MRSI studies, Mukherj et al. [94,95] demonstrated that Cho/Cr ratios are increased in untreated squamous cell carcinomas of the extra cranial head and neck compared to normal tissues. King et al. [96] demonstrated the feasibility of 1 H-MRSI for the evaluation of both primary and nodal nasopharyngeal cancers that are >1 cm3 in size, and confirmed that Cho/Cr ratios for the lesions were high compared with those for normal neck muscle. In addition, King et al. [97] investigated the application of 1 H-MRSI in thyroid cancer and showed that 1 H-MRSI is a feasible technique for the evaluation of malignant thyroid tumours larger than 1 cm3 , and that proton

spectra of malignant tumours differ from that of normal thyroid tissue. A case study by Van Zijl et al. [98] demonstrated that effective radiation therapy caused complete disappearance of metabolites in head and neck node metastasis. In a more recent study, Star-Lack et al. measured 1 H spectral intensities of total Cho, Cr, and lactate (Lac) in lymph node metastasis of head and neck cancer for comparison with normal muscular tissue, and examined the relationships between metabolite signal intensities and tissue oxygenation status. They found that Cho/Cr ratios are increased in pre-treated lymph node metastasis of head and neck cancer, compared to normal tissue, and that Lac and, to a lesser extent, Cho signal intensities are reflective of the oxygenation status. They conclude that 1 HMRSI is thus useful for the staging of metastatic nodal head and neck cancer and for monitoring of therapy. 5.2. Gynecological cancers Other applications for 1 H-MRSI include the assessment of cervical cancer. Delikatny et al. [99] have shown that the MR spectra of biopsy samples of cervical cancer are characterized by mobile triglycerides. Lee et al. [100] investigated invasive cervical can-

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cer by in vivo 1 H-MRSI, using a custom-made endovaginal surface coil and they concluded that this non-invasive method could successfully differentiate invasive cervical carcinoma from normal cervix by detecting a triglyceride peak at 1.3 ppm for squamous cell carcinoma and a unique peak at 2.0 ppm for adenocarcinoma. More recently, Mahon et al. [23,24] investigated the in vivo 1 HMRSI appearance in cervical cancer using an endovaginal coil, and corroborated the findings with magic-angle spinning (MAS) MR spectroscopy of the tissue samples obtained at surgery. They concluded that on in vivo 1 H-MRSI, the presence of mobile triglycerides could be used to detect and confirm the presence of cervical cancer. However, they found that technical improvements are necessary before routine clinical use is possible. In a recent study, Stanwell et al. [26] investigated the feasibility of acquiring in vivo proton magnetic resonance spectroscopy of ovarian lesions at 3 T to provide diagnostic biochemical information for lesion characterization. They found that 1 H-MRSI of ovarian masses can be recorded at 3 T with acceptable spectral quality and good signal-to-noise ratio. They concluded that, although initial results from this small cohort are promising, further experience with a larger and more biologically variable range of tumours must be undertaken to determine the final clinical utility of this technique. 6. Limitations The application of 1 H-MRSI in the assessment and monitoring of cancerous disease can be limited by several factors. One limitation is the size of the voxel required to obtain an adequate signal-to-noise (SNR) ratio to detect the presence of malignancy. In very small lesions, the sensitivity of 1 H-MRSI to discriminate between benign and malignant lesions deteriorates due to partial volume effects. To overcome this limitation, 1 H-MRSI could be performed at higher field strengths with increased SNR and smaller voxel sizes. Another limitation is the anatomic location of the lesion. Breathing and peristaltic motion and large air–tissue interfaces cause magnetic susceptibility difficulties, which affect magnetic field homogeneity, and thus, lead to line-broadening and loss of signal. Therefore, cancers of the chest, abdomen, and gastrointestinal structures are often not sufficiently assessable by 1 H-MRSI. Another limitation of 1 H-MRSI is of an intrinsic biochemical origin. At the clinically used field strengths of 1.5 and 3 T, the detec-

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Fig. 7. Fifty-eight-year-old patient with invasive ductal carcinoma G2 of the left breast. (A) Colour-coded diffusion-weighted image (DWI) (b = 850 s/mm2 ) overlaid on high-spatial resolution morphologic T1-weighted MR image demonstrating restricted diffusion and (B) low ADC values on a colour-coded ADC map. ADC map derived from b = 50 and 850 s/mm2 (mean ± SD = 0.78 ± 0.16 × 10−3 mm2 /s) in the same region as a marker of lesion malignancy.

tion of metabolites other than Cho that are indicative of cancer are limited due to the much lower concentrations of the compounds (0.01 mol/L for Cho vs. 0.00001 mol/L or lower for other tumour associated compounds). A solution to this problem could be the utilization of higher field strengths (7 T or higher) and phosphorus MR spectroscopy (31 P MRSI), as 31 P MRSI can detect some of these compounds and is more sensitive at higher field strengths. 7.

1 H-MRSI

and beyond. . .

7.1. Phosphorus MR spectroscopy (31 P MRSI) Most MR imaging is performed on the 1 H nucleus; however, other nuclei can be imaged as well. Phosphorus MR spectroscopy (31 P MRSI) provides a window for assessing tissue bioenergetics and the metabolism of membrane phospholipids. Indeed, the significance of signal derived from phospholipid precursors and catabolites as biochemical markers for tumour progression and treatment response has been demonstrated [16,101]. It has been proven in vitro and in vivo 31 P MRSI studies that high levels of phosphocholine (PC)/phosphoethanolamine (PE) can be detected in several cancers, whereas low levels are found in healthy

Fig. 8. The combination of PET and MRI offers a multitude of functional information, which can be acquired at the same time. PET and functional MR data complement each other, along with high-resolution anatomy. (Modified from Wehrl et al., EJNMMI 2009).

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parenchyma. A significant decrease in the PE/PC ratio in malignant, compared with benign tumours, has been reported [102], and changes in PE/PC ratios (significant increase in the PE peak relative to the PC peak) have been observed during and after chemotherapy or radiation therapy. In animal studies, Mahmood et al. [103,104] studied the effects of chemotherapy, radiation therapy, and combined radio–chemotherapy in soft tissue and in murine mammary carcinoma using 31 P MRSI. The authors found that the in vivo changes detected by 31 P MRSI in phospholipid precursors and catabolites occur directly at the cellular level and may reflect cell death or growth inhibition after antineoplastic therapy, thus sufficient therapy monitoring should be feasible. Dixon et al. [105] investigated hepatic infiltration by lymphoma with 31 P MRSI in 22 patients and compared the results with the clinical staging and assessment of liver involvement by computed tomography, ultrasound, and liver function tests. They concluded that an accurate assessment of hepatic lymphoma infiltration and assessment of response to chemotherapy with 31 P MRSI is possible. Shukla-Dave et al. evaluated the prediction of treatment response of head and neck cancers with 31 P MRSI from pretreatment, relative phosphomonoester levels, and concluded that 31 P MRSI may prove to be a useful predictor of therapeutic response in head and neck cancers [106]. Although several clinical and experimental studies have reported alterations in phospholipid metabolism energetics and pH in tumours, the low sensitivity of 31 P MRSI restricts its clinical application to relatively large and primarily superficial tumours in the clinical setting [107,108]. Further studies and significant improvements in MR hardware and software are warranted to reveal the true potential of 31 P MRSI in cancer imaging.

7.2. Sodium MR imaging (23 Na MRI) Sodium MRI (23 Na MRI) is a further promising MR imaging technique beyond anatomical imaging that provides information on physiology and cellular metabolism [109–112]. Sodium imaging yields information that reflects the physiological and biochemical state of diseased tissue, and the sodium concentration is a sensitive indicator of cellular and metabolic integrity and ion homeostasis [112–116]. In normal cells, a low intracellular sodium concentration is maintained by actively pumping sodium out of the cell with the Na+ /K+ ATP-ase pump against a concentration gradient formed by the much higher extracellular sodium concentration. If ATP supply is insufficient due to an impaired cellular energy metabolism or due to a compromised cellular integrity, the intracellular sodium levels rise sharply. 23 Na MRI can detect these elevated sodium levels after exhaustive exercise, but also in various diseases, such as myocardial infarction and cancer. Ouwerkerk et al. [112] demonstrated that 23 Na MRI with short echo times can be used to quantify absolute sodium tissue concentration in patients with primary brain tumours, however up to date there are no reliable means to exclusively quantify intracellular sodium. Nevertheless, we can still use 23 Na MRI of the total tissue sodium to our advantage. The observed so called tissue sodium concentration (TSC) is composed of the weighted average of extracellular sodium content and intracellular sodium in the tissue being examined. Ouwerkerk et al. showed increased TSC in human brain tumours relative to that in normal brain structures [112]. In another study, Ouwerkerk et al. [114] investigated the potential of 23 Na MRI for the differentiation of benign and malignant breast lesions and concluded that elevated TSC in breast lesions appears to be a cellular-level indicator associated with malignancy, and thus, may have the potential to increase the specificity of breast MRI. However, further studies, as well as improvements in MR hardware and software, are warranted to elucidate the true potential of 23 Na MRI in cancer imaging.

7.3. Diffusion-weighted imaging (DWI) DWI provides information about the local micro-structural characteristics of the diffusivity of water molecules in tissues, which is quantified using the apparent diffusion coefficient (ADC). Decreased diffusivity in the tissue correlates with a low ADC value. DWI is primarily used in clinical routine for the early detection of cerebral ischemia [117]; however, changes in tissue water diffusion properties can be helpful for detection and characterization of pathologic processes in any part of the body [118]. In general, cancer tends to have a more restricted diffusion and low ADC values than does normal tissue because of the high cell densities and abundance of intra- and intercellular membranes in cancer [83,119,120]. In recent years, the application of DWI in the clinical routine was limited to examinations of the brain [117] because of technical difficulties, but, due to new developments in imaging techniques (e.g., parallel imaging) and hardware (e.g., stronger gradient systems and multi-channel coils), these limitations (e.g., susceptibility and respiratory motion artefacts) can be overcome [121]. Hence, in the last several years, the potential of DWI for clinical diagnostics, especially for tumour identification, has been shown for several organs, e.g. liver, kidneys, pancreas, prostate, breast, etc. [122,123], and whole body [124–129]. Numerous investigators have evaluated DWI of primary brain tumours [117,130,131] and it has been demonstrated that DWI can be used to demarcate enhancing and non-enhancing tumours from surrounding vasogenic edema, which has significantly higher indices of diffusion anisotropy. This may be important in determining radiation ports, surgical margins, and biopsy sites. In addition, DWI of the brain can be helpful in the postoperative setting to differentiate between acute infarction and postoperative edema, as cytotoxic edema is characterized by low ADC values, whereas vasogenic edema has high ADC values. In recent years, the application of DWI in breast cancer imaging has been evaluated by several studies [132–134], and it was demonstrated that breast cancer showed lower ADC values for breast cancer compared to healthy breast tissue (Fig. 7). Guo et al. showed the statistical difference in ADC values between malignant and benign lesions, and a high accuracy of ADC in the differentiation of breast tumours, with a sensitivity of 93% and a specificity of 88% [133]. In another study, Woodhams et al. used breast diffusionweighted imaging (DWI) to diagnose breast cancer and identify cancer extension. They concluded that DWI has the potential for clinical application in the detection of breast cancer, and can be easily inserted into a standard MR imaging protocol [135,136]. Several studies at both 1.5 and 3 T have investigated DWI in prostate cancer assessment and the results suggest that ADC values calculated from DWI may have clinical utility in cancer detection, as cancerous tissue had significantly lower ADC values than benign prostatic tissue [129,137–139]. However, in order to facilitate routine clinical use, further studies and technical improvement (e.g., spatial resolution) will be needed. In conclusion DWI is a promising adjunct tool in cancer assessment that provides additional functional information to the information from routine MRI and MRS, as well.

8. Conclusion MRS techniques are accurate, safe, and allow a non-invasive assessment of cancer. In combination with morphologic and dynamic MRI, MRSI should be routinely used for the staging, assessment of response to treatment, and therapy monitoring in brain, breast, and prostate cancer. Additional evolving applications for MRSI include the assessment of head and neck tumours, gynaecological and gastrointestinal cancer, as well as lymph node

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involvement in malignant disease. However, 1 H-MRSI, 31 P MRSI, sodium imaging, and DWI are not stand-alone techniques in cancer assessment. It can be assumed that, in the future, the combination of MRI, MRSI, and other molecular imaging techniques, such as Positron Emission Tomography (PET), will be state of the art (Fig. 8). Due to this hybrid imaging, information on tumour biology, such as neo-vascularity, apoptosis, and necrosis, will be able to be acquired, and thus, an improvement in pre-therapeutic diagnosis, assessment, and monitoring of response to treatment will be possible. Contributors All authors have substantially contributed to this paper and take full responsibility for its content. Conflict of interest All authors state that both the author and the authors’ institutions have no conflicts of interest. Acknowledgement Funding provided by the Austrian Nationalbank Jubilaeumsfonds Nr.13652 and the Austrian Society of Senology. References [1] Kwock L, Smith JK, Castillo M, Ewend MG, Collichio F, Morris DE, et al. Clinical role of proton magnetic resonance spectroscopy in oncology: brain, breast, and prostate cancer. Lancet Oncol 2006;7(10):859–68. [2] Kwock L, Smith JK, Castillo M, Ewend MG, Cush S, Hensing T, et al. Clinical applications of proton MR spectroscopy in oncology. Technol Cancer Res Treat 2002;1(1):17–28. [3] Gruber S, Stadlbauer A, Mlynarik V, Gatterbauer B, Roessler K, Moser E. Proton magnetic resonance spectroscopic imaging in brain tumor diagnosis. Neurosurg Clin N Am 2005;16(1):101–14, vi. [4] Al-Okaili RN, Krejza J, Wang S, Woo JH, Melhem ER. Advanced MR imaging techniques in the diagnosis of intraaxial brain tumors in adults. Radiographics 2006;26(Suppl 1):S173–89. [5] Castillo M, Kwock L. Proton MR spectroscopy of common brain tumors. Neuroimaging Clin N Am 1998;8(4):733–52. [6] Castillo M, Kwock L. Clinical applications of proton magnetic resonance spectroscopy in the evaluation of common intracranial tumors. Top Magn Reson Imaging 1999;10(2):104–13. [7] Castillo M, Kwock L, Mukherji SK. Clinical applications of proton MR spectroscopy. AJNR Am J Neuroradiol 1996;17(1):1–15. [8] Galanaud D, Chinot O, Nicoli F, et al. Use of proton magnetic resonance spectroscopy of the brain to differentiate gliomatosis cerebri from low-grade glioma. J Neurosurg 2003;98(2):269–76. [9] Ganslandt O, Stadlbauer A, Fahlbusch R, et al. Proton magnetic resonance spectroscopic imaging integrated into image-guided surgery: correlation to standard magnetic resonance imaging and tumor cell density. Neurosurgery 2005;56(Suppl 2):291–8, discussion – 8. [10] Bartella L, Morris EA. Advances in breast imaging: magnetic resonance imaging. Curr Oncol Rep 2006;8(1):7–13. [11] Bartella L, Morris EA, Dershaw DD, et al. Proton MR spectroscopy with choline peak as malignancy marker improves positive predictive value for breast cancer diagnosis: preliminary study. Radiology 2006;239(3): 686–92. [12] Bartella L, Thakur SB, Morris EA, et al. Enhancing nonmass lesions in the breast: evaluation with proton (H-1) MR spectroscopy. Radiology 2007;245(1):80–7. [13] Gruber SBW, Chmelik M, Pinker K, Stadlbauer A, Trattnig S. High spatial resolution three-dimensional spectroscopic imaging in breast cancer in 12–15 min as part of a multimodal concept at 3 T. In: RSNA 2008. 2008. [14] Gruber SPK, Bogner W, Grabner G, Stadlbauer A, Helbich TH, Trattnig S. Three dimensional spectroscopic imaging in breast cancer at 3 T: A pilot study. In: ISMRM 2008. 2008. [15] Carroll PR, Coakley FV, Kurhanewicz J. Magnetic resonance imaging and spectroscopy of prostate cancer. Rev Urol 2006;8(Suppl 1):S4–10. [16] Ackerstaff E, Pflug BR, Nelson JB, Bhujwalla ZM. Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res 2001;61(9):3599–603. [17] Akin O, Hricak H. Imaging of prostate cancer. Radiol Clin North Am 2007;45(1):207–22.

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