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In vivo 1H MR spectroscopy of thyroid carcinoma
European Journal of Radiology 54 (2005) 112–117
In vivo 1H MR spectroscopy of thyroid carcinoma Ann D. Kinga,∗ , David K.W. Yeunga , Anil T. Ahujaa , Gary M.K. Tseb , Amy B.W. Chanb , Sherlock S.L. Lamc , Andrew C. van Hasseltd a
Department of Diagnostic Radiology and Organ Imaging, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China b Department of Anatomical and Cellular Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China c Department of Chemistry, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China d Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China Received 2 February 2004; received in revised form 28 April 2004; accepted 3 May 2004
Abstract To determine if proton magnetic resonance spectroscopy (1 H MRS) of thyroid carcinoma is feasible and to determine if 1 H MRS spectra of malignant tumors differ from that of normal thyroid tissue. We performed 1 H MRS at 1.5 T at echo-times (TE) 136 and 272 ms to examine eight patients with thyroid cancer (primary tumour or nodal metastasis) larger than 1 cm3 in size and five volunteers with normal thyroids. Spectra acquired from six primary tumors (three anaplastic carcinomas, two papillary carcinomas and one follicular carcinoma) and two nodes (two papillary carcinoma metastases) were analyzed in the time-domain using a non-linear least squares fitting algorithm with incorporation of prior knowledge. Choline (3.2 ppm) was identified in all solid carcinomas with a mean choline/creatine of 4.3 at TE 136 ms and 5.4 at TE 272 ms. Ratios for malignant tumors at TE 136 ms ranged from 1.6 in well differentiated follicular carcinoma to 9.4 in anaplastic carcinoma. No choline was detected in normal thyroid tissues. Our results showed that 1 H MRS is a feasible technique for the evaluation of malignant thyroid tumors larger than 1 cm3 and that proton spectra of malignant tumors differ from that of normal thyroid tissue. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Thyroid neoplasms; Magnetic resonance (MR); Spectroscopy; Head and neck neoplasms; Metabolism; Magnetic resonance (MR) tissue characterization
1. Introduction Thyroid nodules are common. Fortunately, the vast majority of these thyroid nodules are benign but they have to be distinguished from the much rarer malignant nodule. At present, we believe that fine needle aspiration cytology (FNAC) + or − ultrasound are the best method for investigating thyroid nodules. However, even in experienced hands there are cases in which the aetiology of the nodule remains uncertain and surgery has to be performed for diagnostic purposes. Even though the percentage of indeterminate nodules may be small, ∗
Corresponding author. Tel.: +852 2632 2290; fax: +852 2636 0012. E-mail address: [email protected] (A.D. King).
0720-048X/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2004.05.003
in those centers where goiter is common, it can lead to a significant number of patients undergoing surgery for benign disease. In order to decrease the risk of unnecessary surgery, as well as the financial burden to the community, there is a need for a new non-invasive pre-surgical diagnostic test. At present proton magnetic resonance spectroscopy (1 H MRS) is being used to evaluate cancers in many regions of the body, but the neck poses many technical difficulties such as shimming and subject motion for in vivo spectroscopy. The aim of the study is to take the first step in the evaluation of the role of in vivo 1 H MRS in thyroid nodules by determining if the technique is feasible for examining the thyroid gland and if so to document the preliminary findings of 1 H spectra associated with thyroid cancer.
A.D. King et al. / European Journal of Radiology 54 (2005) 112–117
2. Subjects and methods Patients underwent neck ultrasound for a neck mass. Those patients in whom the ultrasound found a lesion suspicious of thyroid cancer were recruited for in vivo 1 H MRS in this prospective study with informed consent. In vivo 1 H MRS was performed on thyroid tumors larger than 1 cm3 , or lymph nodes larger than 1 cm3 when the thyroid tumor was too small for spectroscopic examination. Biopsy was performed after spectroscopy. Only data from those patients in whom there was histological confirmation of thyroid malignancy were included in the study. The study group comprised of eight patients (four males, four females, age range 18–76 years, mean 58 years) with thyroid cancers. 1 H MRS was performed on six primary tumors (three anaplastic carcinomas, two papillary carcinomas and one follicular carcinoma) and two metastatic nodes from papillary carcinoma. In addition, five volunteers undergoing MRI of the neck for a non-thyroid related problem and with a normal thyroid gland were recruited as controls (three males, two females, age range 45–62 years, mean 52 years). The local ethics committee granted ethical approval for the study. The examinations were performed on a 1.5 T whole-body MR imaging system (Gyroscan ACS-NT, Philips, Best, The Netherlands). A standard volume neck coil was used for the conventional imaging of the neck and a 14 cm circular receive-only surface coil was placed over the tumor to improve the signal-to-noise ratio when performing MR spectroscopy. The body coil was used to generate a homogeneous B1 excitation field in all MR examinations. MR imaging was performed in the transverse and coronal planes and with image guidance, the volume of interest was positioned within each lesion, carefully excluding normal structures. Using the point-resolved spectroscopic (PRESS) sequence (repetition time [TR]/echo time [TE] 2000/136 and 2000/272 ms; 64 signal acquisitions) with the circular surface-coil selected as signal receiver, two water-suppressed spectra were acquired for each volume of interest. Pre-acquisition optimization procedures consisted of receiver gain and frequency adjustment, shimming and gradient tuning. Water suppression was achieved by selective inversion recovery, starting the measurement at the zero crossing of the water signal. Data were acquired at a spectral bandwidth of 1000 Hz and the averaged water-suppressed spectra were exported and processed on an off-line computer. Spectra were visually assessed for the presence or absence of peaks including choline (Cho) (3.2 ppm), creatine (Cr) (3.03 ppm), fatty acids (FA) ( CH2 ) (2.02 ppm), FA ( CH2 ) (1.30 ppm) and FA ( CH3 ) (0.90 ppm). Spectral analysis was performed in the time-domain with the use of a fitting routine known as advanced method for accurate, robust and efficient spectral fitting, or AMARES [1] implemented in the magnetic resonance user interface (MRUI) software package (available at http://www.mrui.uab.es/mrui/mruiHomePage.html). Both residual water (4.65 ppm) and the broad FA peaks in the
113
chemical shift range of 0.5–2.1 ppm were first removed from the measured free induction decay by means of the time domain Hankel–Lanczos singular value decomposition filtering [2] to enable a more precise estimation of Cho and Cr peak amplitudes. The resonance frequency and line-width of Cho and Cr were selected manually; these parameters were used as the starting values in the non-linear least squares fitting algorithm. The following prior knowledge was incorporated into the fitting procedure: line-widths of Cr equal to that of Cho; resonance frequencies were constrained to lie in the range plus or minus 0.05 ppm of the peaks’ known resonance frequencies; the first-order phase correction estimated by AMARES was fixed to zero, and the resonances relative to phase was also set to zero. A Gaussian line-shape was assumed for both Cho and Cr resonances. The calculated peak amplitude for Cho and Cr peaks were used to determine the Cho/Cr ratio for each thyroid lesion. The calculated line-width of Cho peak as determined by the spectral fitting procedure was used to evaluate the quality of the spectra. 3. Results The voxel volume used to obtain 1 H MRS on the six primary tumors was 3–45 cm3 (mean, 22.3 cm3 ), on the two nodes was 2.1–7.8 cm3 and on the normal thyroids was 2.3–3.4 cm3 (mean, 3.2 cm3 ). Table 1 summarizes the 1 H MRS results for primary tumors, metastatic nodes, and normal thyroid tissue acquired at TEs 136 and 272 ms. An example of 1 H MRS for a primary tumor is shown in Fig. 1a and b. The mean Cho/Cr for tumor (primary tumors and metastatic nodes) was 4.3 at TE 136 ms and 5.4 at TE 272 ms. Normal thyroid spectra obtained from the four control subjects did not show the presence of Cho and Cr; broad FA peaks were observed in the range 0.90–1.30 ppm on all the spectra acquired at both TEs. An example of spectrum obtained from the normal thyroid is shown in Fig. 2. The range of Cho peak line-width in patients with malignancy at TE 136 ms was from 3.7 to 8.3 Hz (mean, 5.8 Hz) and at TE 272 ms was from 3.2 to 5.22 Hz (mean, 4.1 Hz). 4. Discussion Fine needle aspiration cytology and ultrasound have made a major impact on the pre-surgical characterization of thyroid nodules, but diagnostic difficulties remain, particularly in distinguishing benign follicular adenomas from minimally invasive follicular carcinomas. This has led to recent research into the role of in vitro 1 H MRS of tissue specimens obtained from thyroid nodules at surgery [3–6]. The results of these studies show spectral differences between normal thyroid tissue, benign thyroid nodules and malignant tumors. These findings include an increase in amino acids in carcinomas [3–5], and a progressive increase in lipid peaks (assigned to diglycerides and triglycerides), from colloid/hyperplastic nodules to follicular adenomas to invasive carcinomas [5].
Note: (+): positive presence of metabolite; (−): absence of metabolite; F: spectrum not interpretable; ND: not determined; NA: not applicable; Ca: carcinoma. Numbers shown with the metabolites are the chemical shift values in parts per million (ppm).
+ + + + F + + − + + + + + + − − − F − − − − − − − + + − − − F + + − − − − − − + + + + F + + − − − − − − 8.9 ND ND ND F 2.7 4.5 ND ND ND ND ND ND + + + + − + + − + + + + + + + + + − + + − + + + + + + − − − − − − − − − − − + + − − + + + + − − − − − −
FA 1.30 FA 2.02 Cr 3.03 Cho 3.2
+ + − + + + + − − − − − − 9.4 ND ND 3.9 1.6 3.9 2.6 ND ND ND ND ND ND 36 45 8.5 36 5.5 3 7.8 2.1 3.4 2.3 3.4 3.4 3.4 Anaplastic Ca Anaplastic Ca Anaplastic Ca Follicular Ca Papillary Ca Papillary Ca Papillary Ca Papillary Ca NA NA NA NA NA Thyroid Thyroid Thyroid Thyroid Thyroid Thyroid Node Node Normal thyroid Normal thyroid Normal thyroid Normal thyroid Normal thyroid 1 2 3 4 5 6 7 8 9 10 11 12 13
FA 1.30 FA 2.02 Cr 3.03 Cho 3.2 Cho/Cr Cho/Cr
FA 0.90
TE 272 ms TE 136 ms VOI (cm3 ) Histopathology Tissue
Table 1 MRS for primary thyroid carcinomas, metastatic nodes and normal thyroid 1H
+ + + + F + + − + + + + +
A.D. King et al. / European Journal of Radiology 54 (2005) 112–117 FA 0.90
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The main drawback to in vitro 1 H MRS is that it only samples a small volume of the tumor and does not provide pre-surgical diagnosis so preventing unnecessary surgery for benign lesions. In vivo 1 H MRS has the advantage that it allows pre-operative evaluation, samples a greater volume of tissue, and the spectra are not influenced by the potential effects of oxygen disruption once the tissue is removed. While in vivo techniques cannot resolve the same number of spectral peaks that are identifiable with the higher field magnets that are used for in vitro techniques, in vivo 1 H MRS has been successfully used to evaluate other cancers of the body [7]. There are also a small number of series reporting results of in vivo 1 H MRS in the head and neck where the emphasis has been on the evaluation of squamous cell carcinomas [8–10]. This study was performed also to assess the feasibility of performing in vivo 1 H MRS of thyroid cancer and to document its spectral profile. It did not, however, set out to distinguish malignant from benign tumors. There are technical difficulties when performing spectroscopy of the thyroid. These problems include movement of the tumor as a result of swallowing and breathing, shimming difficulties arising from large magnetic susceptibility differences between neck tissues and air in the trachea, and contamination of the spectra by adjacent fat. In addition, at present, spectroscopy can only be performed on relatively large tumors, as a result many of the more common types of thyroid cancer are too small for evaluation, hence the relatively large number of anaplastic carcinomas in this study. However, with these limitations in mind this study has shown that it is possible to perform in vivo 1 H MRS on tumors greater than 1 cm3 . In this study Cho peaks were detected in 87% of thyroid carcinomas (Fig. 1), being found in primary tumors and metastatic nodes but not in normal thyroid tissue. Choline has also been reported in thyroid cancers in early work [11] where Cho/water ratios were higher in neoplasms than non-neoplasms. However, using water as an internal reference requires the assumption that the concentration of water in normal and pathologic tissues is equal. Since we were not able to obtain evidence to support such assumption, we therefore chose to use Cho/Cr ratio instead in our data analysis. The use of prior knowledge in the spectra analysis and the removal of intense broad peaks arising FA (Fig. 1) enabled a more precise estimation of Cho and Cr. Choline and Cr were not detected in normal thyroid tissue (Fig. 2) but were detected in most cases of carcinoma allowing Cho/Cr ratios to be calculated. While one might expect to detect Cho in normal thyroid tissues, its concentration is probably too low to be detected at 1.5 T. In 1 H MRS of the breast, for instance, Cho is usually not detectable in normal breast tissues in vivo at 1.5 T but becomes detectable at higher field strengths [14,15]. At a TE of 136 ms Cho/Cr ratios ranged from 1.6 in well-differentiated follicular carcinoma to 9.4 in anaplastic carcinoma. High Cho/Cr ratios have been shown in both in vivo and in vitro studies of cancers of the body including squamous cell carcinoma of the head and neck [8,9,12,13]. In two cases of malignant thyroid tumors the
A.D. King et al. / European Journal of Radiology 54 (2005) 112–117
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Fig. 1. (a) Proton MR spectrum acquired at TE 136 ms from the primary tumor in a patient with an anaplastic carcinoma of the right lobe of the thyroid. The nominal voxel volume was 36 cm3 . Prominent peaks detected were Cho (3.2 ppm), Cr (3.03 ppm), FA ( CH2 ) (1.30 ppm) and FA ( CH3 ) (0.90 ppm). (b) Transverse T1-weighted MR image shows the position of the volume of interest for spectroscopy represented by the white square box placed within the primary tumor.
Cr could not be detected and this may represent a failure in the technique. However, in both cases the tumors were the highly aggressive anaplastic carcinomas and the low Cr in these cases may reflect an increase in metabolism which has been associated with more aggressive tumors [16]. Both in vitro and ex vivo 1 H MR spectroscopy reports on human thyroid have documented the presence of lipids [3,16]. Similar observations have been made in brain tumors where the presence of lipids has been shown to be related to the degree of vascular proliferation [17]. Mackinnon et al.
[5] found that there is a progressive increase in the amount of lipids moving from benign to increasingly malignant thyroid lesion types. In our study, we also found intense FA peaks in most thyroid lesions mainly at 1.30 and 0.90 ppm and to a lesser degree at 2.02 ppm. However, these FA peaks were too broad for quantitative analysis and the difficulties in measuring them may be compounded by the presence of other macromolecular species such as proteins [18] or signal contamination from subcutaneous fat. In one patient no Cho, Cr or FA peaks were identified at either TE, in this case the tumor
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A.D. King et al. / European Journal of Radiology 54 (2005) 112–117
Fig. 2. (a) Proton MR spectrum acquired at TE 136 ms from a normal thyroid gland. The nominal voxel volume was 2.04 cm3 . No peaks detected for Cho (3.2 ppm) or Cr (3.03 ppm), prominent peaks detected for FA ( CH2 ) (1.30 ppm) and FA ( CH3 ) (0.90 ppm). (b) Transverse T1-weighted MR image shows the position of the volume of interest for spectroscopy represented by the white square box placed within the normal right lobe of the thyroid gland.
was a cystic papillary carcinoma in a node suggesting that 1 H MRS may prove to be of limited value in cystic tumors.
evaluating the potential diagnostic role of in vivo 1 H MRS, further research is required to validate these findings and to determine if the spectra from carcinomas differ not only from normal thyroid tissue but also from benign thyroid nodules.
5. Conclusion Our results show that 1 H MRS of thyroid carcinoma larger than 1 cm3 is feasible. Elevated Cho is detected in thyroid carcinomas but not in normal thyroid tissue. Creatine also can be detected frequently in malignant lesions allowing calculation of Cho/Cr ratios, which in this study ranged from 1.6 to 9.4. These preliminary findings are only a small step towards
References [1] Vanhamme L, van den Boogaart A, van Huffel S. Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. J Magn Reson 1997;129:35–43. [2] Van den Boogaart A, van Ormondt D, Pijnappel WWF, de Beer R, Ala-Korpela M. Removal of the water resonance from H-1 magnetic
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resonance spectra. In: McWhirter JG, editor. Mathematics in signal processing III. Oxford, England: Clarendon; 1994. p. 175–95. Russell P, Lean CL, Delbridge L, May GL, Dowd S, Mountford CE. Proton magnetic resonance and human thyroid neoplasia. I: Discrimination between benign and malignant neoplasms. Am J Med 1994;4:383–8. Delbridge L, Lean CL, Russell P, et al. Proton magnetic resonance and human thyroid neoplasia. II: Potential avoidance of surgery for benign follicular neoplasms. World J Surg 1994;18:512–7. Mackinnon WB, Delbridge L, Russell P, et al. Two-dimensional proton magnetic resonance spectroscopy for tissue characterization of thyroid neoplasms. World J Surg 1996;20:841–7. Johnson M, Selinsky B, Davis M, et al. In vitro NMR evaluation of human thyroid lesions. Invest Radiol 1989;24:666–71. Smith ICP, Stewart LC. Magnetic resonance spectroscopy in medicine: clinical impact. Progr Nucl Magn Reson Spectrosc 2002;40:1–34. Star-Lack JM, Adalsteinsson E, Adam MF, et al. In vivo 1 H MR spectroscopy of human head and neck lymph node metastasis and comparison with oxygen tension measurements. AJNR Am J Neuroradiol 2000;21:183–93. Mukherji SK, Schiro S, Castillo M, Kwock L, Muller KE, Blackstock W. Proton MR spectroscopy of squamous cell carcinoma of the extracranial head and neck: in vitro and in vivo studies. AJNR Am J Neuroradiol 1997;18:1057–72. Maheshwari SR, Mukherji SK, Neelon B, et al. The choline/creatine ratio in five benign neoplasms: comparison with squamous cell carcinoma by use of in vitro MR spectroscopy. AJNR Am J Neuroradiol 2000;21:1930–5. Huang W, Roche P, Button T, Shindo M. In vivo 1 H MR spectroscopic study of thyroid lesions: correlation with pathology. In: Book
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of Abstracts: Tenth Annual Meeting of the International Society for Magnetic Resonance in Medicine. ISMRM, Berkeley, CA, vol. 10; 2002. p. 570. Yeung DK, Yang WT, Tse GM. Breast cancer: in vivo proton MR spectroscopy in the characterization of histopathologic subtypes and preliminary observations in axillary node metastases. Radiology 2002;225:190–7. Bolan PJ, Meisamy S, Baker EH, et al. In vivo quantification of choline compounds in the breast with 1 H MR spectroscopy. Magn Reson Med 2003;50:1134–43. Mukherji SK, Schiro S, Castillo M, et al. Proton MR spectroscopy of squamous cell carcinoma of the upper aerodigestive tract: in vitro characteristics. AJNR Am J Neuroradiol 1996;17:1485– 90. EI-Sayed S, Bezabeh T, Odlum O, et al. An ex vivo study exploring the diagnostic potential of 1 H magnetic resonance spectroscopy in squamous cell carcinoma of the head and neck region. Head Neck 2002;24:766–72. Bezabeh T, El-Sayed S, Odlum O, et al. Grading of head and neck tumors by 1 H MRS: an approach with potential clinical utility. In: Book of Abstracts: Ninth Annual Meeting of the International Society for Magnetic Resonance in Medicine. ISMRM, Berkeley, CA, vol. 9; 2001. p. 2345. Yoshioka Y, Sasaki J, Yamamoto M, et al. Quan1 H-NMR tification by of dolichol, cholesterol and choline-containing lipids in extracts of normal and phathological thyroid tissue. NMR Biomed 2000;3:377– 83. Tugnoli V, Tosi MR, Tinti A, et al. Characterization of lipids from human brain tissues by multinuclear magnetic resonance spectroscopy. Biospectroscopy 2001;62:297–306.
In vivo 1H MR spectroscopy of thyroid carcinoma Ann D. Kinga,∗ , David K.W. Yeunga , Anil T. Ahujaa , Gary M.K. Tseb , Amy B.W. Chanb , Sherlock S.L. Lamc , Andrew C. van Hasseltd a
Department of Diagnostic Radiology and Organ Imaging, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China b Department of Anatomical and Cellular Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China c Department of Chemistry, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China d Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR China Received 2 February 2004; received in revised form 28 April 2004; accepted 3 May 2004
Abstract To determine if proton magnetic resonance spectroscopy (1 H MRS) of thyroid carcinoma is feasible and to determine if 1 H MRS spectra of malignant tumors differ from that of normal thyroid tissue. We performed 1 H MRS at 1.5 T at echo-times (TE) 136 and 272 ms to examine eight patients with thyroid cancer (primary tumour or nodal metastasis) larger than 1 cm3 in size and five volunteers with normal thyroids. Spectra acquired from six primary tumors (three anaplastic carcinomas, two papillary carcinomas and one follicular carcinoma) and two nodes (two papillary carcinoma metastases) were analyzed in the time-domain using a non-linear least squares fitting algorithm with incorporation of prior knowledge. Choline (3.2 ppm) was identified in all solid carcinomas with a mean choline/creatine of 4.3 at TE 136 ms and 5.4 at TE 272 ms. Ratios for malignant tumors at TE 136 ms ranged from 1.6 in well differentiated follicular carcinoma to 9.4 in anaplastic carcinoma. No choline was detected in normal thyroid tissues. Our results showed that 1 H MRS is a feasible technique for the evaluation of malignant thyroid tumors larger than 1 cm3 and that proton spectra of malignant tumors differ from that of normal thyroid tissue. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Thyroid neoplasms; Magnetic resonance (MR); Spectroscopy; Head and neck neoplasms; Metabolism; Magnetic resonance (MR) tissue characterization
1. Introduction Thyroid nodules are common. Fortunately, the vast majority of these thyroid nodules are benign but they have to be distinguished from the much rarer malignant nodule. At present, we believe that fine needle aspiration cytology (FNAC) + or − ultrasound are the best method for investigating thyroid nodules. However, even in experienced hands there are cases in which the aetiology of the nodule remains uncertain and surgery has to be performed for diagnostic purposes. Even though the percentage of indeterminate nodules may be small, ∗
Corresponding author. Tel.: +852 2632 2290; fax: +852 2636 0012. E-mail address: [email protected] (A.D. King).
0720-048X/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2004.05.003
in those centers where goiter is common, it can lead to a significant number of patients undergoing surgery for benign disease. In order to decrease the risk of unnecessary surgery, as well as the financial burden to the community, there is a need for a new non-invasive pre-surgical diagnostic test. At present proton magnetic resonance spectroscopy (1 H MRS) is being used to evaluate cancers in many regions of the body, but the neck poses many technical difficulties such as shimming and subject motion for in vivo spectroscopy. The aim of the study is to take the first step in the evaluation of the role of in vivo 1 H MRS in thyroid nodules by determining if the technique is feasible for examining the thyroid gland and if so to document the preliminary findings of 1 H spectra associated with thyroid cancer.
A.D. King et al. / European Journal of Radiology 54 (2005) 112–117
2. Subjects and methods Patients underwent neck ultrasound for a neck mass. Those patients in whom the ultrasound found a lesion suspicious of thyroid cancer were recruited for in vivo 1 H MRS in this prospective study with informed consent. In vivo 1 H MRS was performed on thyroid tumors larger than 1 cm3 , or lymph nodes larger than 1 cm3 when the thyroid tumor was too small for spectroscopic examination. Biopsy was performed after spectroscopy. Only data from those patients in whom there was histological confirmation of thyroid malignancy were included in the study. The study group comprised of eight patients (four males, four females, age range 18–76 years, mean 58 years) with thyroid cancers. 1 H MRS was performed on six primary tumors (three anaplastic carcinomas, two papillary carcinomas and one follicular carcinoma) and two metastatic nodes from papillary carcinoma. In addition, five volunteers undergoing MRI of the neck for a non-thyroid related problem and with a normal thyroid gland were recruited as controls (three males, two females, age range 45–62 years, mean 52 years). The local ethics committee granted ethical approval for the study. The examinations were performed on a 1.5 T whole-body MR imaging system (Gyroscan ACS-NT, Philips, Best, The Netherlands). A standard volume neck coil was used for the conventional imaging of the neck and a 14 cm circular receive-only surface coil was placed over the tumor to improve the signal-to-noise ratio when performing MR spectroscopy. The body coil was used to generate a homogeneous B1 excitation field in all MR examinations. MR imaging was performed in the transverse and coronal planes and with image guidance, the volume of interest was positioned within each lesion, carefully excluding normal structures. Using the point-resolved spectroscopic (PRESS) sequence (repetition time [TR]/echo time [TE] 2000/136 and 2000/272 ms; 64 signal acquisitions) with the circular surface-coil selected as signal receiver, two water-suppressed spectra were acquired for each volume of interest. Pre-acquisition optimization procedures consisted of receiver gain and frequency adjustment, shimming and gradient tuning. Water suppression was achieved by selective inversion recovery, starting the measurement at the zero crossing of the water signal. Data were acquired at a spectral bandwidth of 1000 Hz and the averaged water-suppressed spectra were exported and processed on an off-line computer. Spectra were visually assessed for the presence or absence of peaks including choline (Cho) (3.2 ppm), creatine (Cr) (3.03 ppm), fatty acids (FA) ( CH2 ) (2.02 ppm), FA ( CH2 ) (1.30 ppm) and FA ( CH3 ) (0.90 ppm). Spectral analysis was performed in the time-domain with the use of a fitting routine known as advanced method for accurate, robust and efficient spectral fitting, or AMARES [1] implemented in the magnetic resonance user interface (MRUI) software package (available at http://www.mrui.uab.es/mrui/mruiHomePage.html). Both residual water (4.65 ppm) and the broad FA peaks in the
113
chemical shift range of 0.5–2.1 ppm were first removed from the measured free induction decay by means of the time domain Hankel–Lanczos singular value decomposition filtering [2] to enable a more precise estimation of Cho and Cr peak amplitudes. The resonance frequency and line-width of Cho and Cr were selected manually; these parameters were used as the starting values in the non-linear least squares fitting algorithm. The following prior knowledge was incorporated into the fitting procedure: line-widths of Cr equal to that of Cho; resonance frequencies were constrained to lie in the range plus or minus 0.05 ppm of the peaks’ known resonance frequencies; the first-order phase correction estimated by AMARES was fixed to zero, and the resonances relative to phase was also set to zero. A Gaussian line-shape was assumed for both Cho and Cr resonances. The calculated peak amplitude for Cho and Cr peaks were used to determine the Cho/Cr ratio for each thyroid lesion. The calculated line-width of Cho peak as determined by the spectral fitting procedure was used to evaluate the quality of the spectra. 3. Results The voxel volume used to obtain 1 H MRS on the six primary tumors was 3–45 cm3 (mean, 22.3 cm3 ), on the two nodes was 2.1–7.8 cm3 and on the normal thyroids was 2.3–3.4 cm3 (mean, 3.2 cm3 ). Table 1 summarizes the 1 H MRS results for primary tumors, metastatic nodes, and normal thyroid tissue acquired at TEs 136 and 272 ms. An example of 1 H MRS for a primary tumor is shown in Fig. 1a and b. The mean Cho/Cr for tumor (primary tumors and metastatic nodes) was 4.3 at TE 136 ms and 5.4 at TE 272 ms. Normal thyroid spectra obtained from the four control subjects did not show the presence of Cho and Cr; broad FA peaks were observed in the range 0.90–1.30 ppm on all the spectra acquired at both TEs. An example of spectrum obtained from the normal thyroid is shown in Fig. 2. The range of Cho peak line-width in patients with malignancy at TE 136 ms was from 3.7 to 8.3 Hz (mean, 5.8 Hz) and at TE 272 ms was from 3.2 to 5.22 Hz (mean, 4.1 Hz). 4. Discussion Fine needle aspiration cytology and ultrasound have made a major impact on the pre-surgical characterization of thyroid nodules, but diagnostic difficulties remain, particularly in distinguishing benign follicular adenomas from minimally invasive follicular carcinomas. This has led to recent research into the role of in vitro 1 H MRS of tissue specimens obtained from thyroid nodules at surgery [3–6]. The results of these studies show spectral differences between normal thyroid tissue, benign thyroid nodules and malignant tumors. These findings include an increase in amino acids in carcinomas [3–5], and a progressive increase in lipid peaks (assigned to diglycerides and triglycerides), from colloid/hyperplastic nodules to follicular adenomas to invasive carcinomas [5].
Note: (+): positive presence of metabolite; (−): absence of metabolite; F: spectrum not interpretable; ND: not determined; NA: not applicable; Ca: carcinoma. Numbers shown with the metabolites are the chemical shift values in parts per million (ppm).
+ + + + F + + − + + + + + + − − − F − − − − − − − + + − − − F + + − − − − − − + + + + F + + − − − − − − 8.9 ND ND ND F 2.7 4.5 ND ND ND ND ND ND + + + + − + + − + + + + + + + + + − + + − + + + + + + − − − − − − − − − − − + + − − + + + + − − − − − −
FA 1.30 FA 2.02 Cr 3.03 Cho 3.2
+ + − + + + + − − − − − − 9.4 ND ND 3.9 1.6 3.9 2.6 ND ND ND ND ND ND 36 45 8.5 36 5.5 3 7.8 2.1 3.4 2.3 3.4 3.4 3.4 Anaplastic Ca Anaplastic Ca Anaplastic Ca Follicular Ca Papillary Ca Papillary Ca Papillary Ca Papillary Ca NA NA NA NA NA Thyroid Thyroid Thyroid Thyroid Thyroid Thyroid Node Node Normal thyroid Normal thyroid Normal thyroid Normal thyroid Normal thyroid 1 2 3 4 5 6 7 8 9 10 11 12 13
FA 1.30 FA 2.02 Cr 3.03 Cho 3.2 Cho/Cr Cho/Cr
FA 0.90
TE 272 ms TE 136 ms VOI (cm3 ) Histopathology Tissue
Table 1 MRS for primary thyroid carcinomas, metastatic nodes and normal thyroid 1H
+ + + + F + + − + + + + +
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The main drawback to in vitro 1 H MRS is that it only samples a small volume of the tumor and does not provide pre-surgical diagnosis so preventing unnecessary surgery for benign lesions. In vivo 1 H MRS has the advantage that it allows pre-operative evaluation, samples a greater volume of tissue, and the spectra are not influenced by the potential effects of oxygen disruption once the tissue is removed. While in vivo techniques cannot resolve the same number of spectral peaks that are identifiable with the higher field magnets that are used for in vitro techniques, in vivo 1 H MRS has been successfully used to evaluate other cancers of the body [7]. There are also a small number of series reporting results of in vivo 1 H MRS in the head and neck where the emphasis has been on the evaluation of squamous cell carcinomas [8–10]. This study was performed also to assess the feasibility of performing in vivo 1 H MRS of thyroid cancer and to document its spectral profile. It did not, however, set out to distinguish malignant from benign tumors. There are technical difficulties when performing spectroscopy of the thyroid. These problems include movement of the tumor as a result of swallowing and breathing, shimming difficulties arising from large magnetic susceptibility differences between neck tissues and air in the trachea, and contamination of the spectra by adjacent fat. In addition, at present, spectroscopy can only be performed on relatively large tumors, as a result many of the more common types of thyroid cancer are too small for evaluation, hence the relatively large number of anaplastic carcinomas in this study. However, with these limitations in mind this study has shown that it is possible to perform in vivo 1 H MRS on tumors greater than 1 cm3 . In this study Cho peaks were detected in 87% of thyroid carcinomas (Fig. 1), being found in primary tumors and metastatic nodes but not in normal thyroid tissue. Choline has also been reported in thyroid cancers in early work [11] where Cho/water ratios were higher in neoplasms than non-neoplasms. However, using water as an internal reference requires the assumption that the concentration of water in normal and pathologic tissues is equal. Since we were not able to obtain evidence to support such assumption, we therefore chose to use Cho/Cr ratio instead in our data analysis. The use of prior knowledge in the spectra analysis and the removal of intense broad peaks arising FA (Fig. 1) enabled a more precise estimation of Cho and Cr. Choline and Cr were not detected in normal thyroid tissue (Fig. 2) but were detected in most cases of carcinoma allowing Cho/Cr ratios to be calculated. While one might expect to detect Cho in normal thyroid tissues, its concentration is probably too low to be detected at 1.5 T. In 1 H MRS of the breast, for instance, Cho is usually not detectable in normal breast tissues in vivo at 1.5 T but becomes detectable at higher field strengths [14,15]. At a TE of 136 ms Cho/Cr ratios ranged from 1.6 in well-differentiated follicular carcinoma to 9.4 in anaplastic carcinoma. High Cho/Cr ratios have been shown in both in vivo and in vitro studies of cancers of the body including squamous cell carcinoma of the head and neck [8,9,12,13]. In two cases of malignant thyroid tumors the
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Fig. 1. (a) Proton MR spectrum acquired at TE 136 ms from the primary tumor in a patient with an anaplastic carcinoma of the right lobe of the thyroid. The nominal voxel volume was 36 cm3 . Prominent peaks detected were Cho (3.2 ppm), Cr (3.03 ppm), FA ( CH2 ) (1.30 ppm) and FA ( CH3 ) (0.90 ppm). (b) Transverse T1-weighted MR image shows the position of the volume of interest for spectroscopy represented by the white square box placed within the primary tumor.
Cr could not be detected and this may represent a failure in the technique. However, in both cases the tumors were the highly aggressive anaplastic carcinomas and the low Cr in these cases may reflect an increase in metabolism which has been associated with more aggressive tumors [16]. Both in vitro and ex vivo 1 H MR spectroscopy reports on human thyroid have documented the presence of lipids [3,16]. Similar observations have been made in brain tumors where the presence of lipids has been shown to be related to the degree of vascular proliferation [17]. Mackinnon et al.
[5] found that there is a progressive increase in the amount of lipids moving from benign to increasingly malignant thyroid lesion types. In our study, we also found intense FA peaks in most thyroid lesions mainly at 1.30 and 0.90 ppm and to a lesser degree at 2.02 ppm. However, these FA peaks were too broad for quantitative analysis and the difficulties in measuring them may be compounded by the presence of other macromolecular species such as proteins [18] or signal contamination from subcutaneous fat. In one patient no Cho, Cr or FA peaks were identified at either TE, in this case the tumor
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Fig. 2. (a) Proton MR spectrum acquired at TE 136 ms from a normal thyroid gland. The nominal voxel volume was 2.04 cm3 . No peaks detected for Cho (3.2 ppm) or Cr (3.03 ppm), prominent peaks detected for FA ( CH2 ) (1.30 ppm) and FA ( CH3 ) (0.90 ppm). (b) Transverse T1-weighted MR image shows the position of the volume of interest for spectroscopy represented by the white square box placed within the normal right lobe of the thyroid gland.
was a cystic papillary carcinoma in a node suggesting that 1 H MRS may prove to be of limited value in cystic tumors.
evaluating the potential diagnostic role of in vivo 1 H MRS, further research is required to validate these findings and to determine if the spectra from carcinomas differ not only from normal thyroid tissue but also from benign thyroid nodules.
5. Conclusion Our results show that 1 H MRS of thyroid carcinoma larger than 1 cm3 is feasible. Elevated Cho is detected in thyroid carcinomas but not in normal thyroid tissue. Creatine also can be detected frequently in malignant lesions allowing calculation of Cho/Cr ratios, which in this study ranged from 1.6 to 9.4. These preliminary findings are only a small step towards
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