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DOI: 10.1148/radiol.2453061854
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(Radiology 2007;245:788-797.)
© RSNA, 2007

Genitourinary Imaging

Adrenal Masses: Characterization with in Vivo Proton MR Spectroscopy—Initial Experience1

Juliano F. Faria, MD, Suzan M. Goldman, MD, PhD, Jacob Szejnfeld, MD, PhD, Homero Melo, MSc, Cláudio Kater, MD, PhD, Philip Kenney, MD, Martha P. Huayllas, MD, MSc, Guilherme Demarchi, MD, Viviane V. Francisco, MD, Cássio Andreoni, MD, PhD, Miguel Srougi, MD, PhD, Valdemar Ortiz, MD, PhD, and Nitamar Abdalla, MD, PhD

1 From the Department of Diagnostic Imaging, Federal University of São Paulo, Napoleão de Barros, 800, Vila Clementino, São Paulo, SP, Brazil 04024-002. From the 2005 RSNA Annual Meeting. Received October 28, 2006; revision requested January 10, 2007; revision received March 6; accepted April 11; final version accepted April 18. Address correspondence to J.F.F. (e-mail: drjulianounifesp{at}hotmail.com).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Purpose: To prospectively determine the accuracy of in vivo proton (1H) magnetic resonance (MR) spectroscopy in distinguishing adrenal adenomas, pheochromocytomas, adrenocortical carcinomas, and metastases, with histologic or computed tomographic findings and follow-up data as the reference standards.

Materials and Methods: This study was approved by the institutional ethics committee, and informed consent was obtained. Sixty consecutive patients (24 male and 36 female patients; mean age, 53 years) harboring adrenal tumors larger than 2 cm in diameter (mean diameter, 4.6 cm ± 3.4 [standard deviation]) entered the study and were examined with a 1.5-T MR imaging system and point-resolved multivoxel 1H MR spectroscopy. Thirty-eight patients had adenomas; 10, pheochromocytomas; five, carcinomas; and seven, metastases. Amplitude values for choline, creatine, lipid, and a metabolite peak at precession frequency of 4.0–4.3 ppm were measured. Metabolite ratios (choline-creatine, choline-lipid, lipid-creatine, and 4.0–4.3 ppm/creatine) and cutoff values (obtained by using receiver operating characteristic analyses) were obtained and compared for each type of adrenal mass, which was identified previously on the basis of clinical, hormonal, and pathologic evidence. Results were evaluated with {chi}2 and Student t tests. Significance was inferred at P < .05.

Results: Cutoff values of 1.20 for the choline-creatine ratio (92% sensitivity, 96% specificity; P < .01), 0.38 for the choline-lipid ratio (92% sensitivity, 90% specificity; P < .01), and 2.10 for the lipid-creatine ratio (45% sensitivity, 100% specificity) enabled adenomas and pheochromocytomas to be distinguished from carcinomas and metastases. A 4.0–4.3 ppm/creatine ratio greater than 1.50 enabled distinction of pheochromocytomas and carcinomas from adenomas and metastases (87% sensitivity, 98% specificity; P < .01). The best distinction was obtained by comparing choline-creatine and 4.0–4.3 ppm/creatine ratios.

Conclusion: 1H MR spectroscopy can be used to characterize adrenal masses on the basis of spectral findings for benign adenomas, carcinomas, pheochromocytomas, and metastases.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Computed tomography (CT) and magnetic resonance (MR) imaging are well-established methods used to differentiate adenomas from nonadenomatous adrenal lesions (1–3). Adrenal imaging techniques include unenhanced and contrast material–enhanced CT, MR imaging, and fluorine 18 fluorodeoxyglucose positron emission tomography (PET) (4–9). However, difficulties associated with use of adrenal imaging remain not only for diagnosis of atypical adenomas but also for detection of other adrenal alterations, such as metastases, pheochromocytomas, and adrenocortical carcinomas (10–13). The appearance of benign pheochromocytomas generally overlaps that of carcinomas and metastases on CT and MR images. There is no signal intensity decrease on MR images, and benign pheochromocytomas have inconsistent, often extremely vascular behavior (14).

Proton (1H) MR spectroscopy is a noninvasive imaging technique that is used to measure the biochemical nature of living tissues. It can be performed with most 1.5-T MR imaging instruments, and the information it yields may represent additional data on tumor metabolism that can be useful for diagnosis. Several studies have been performed to evaluate 1H MR spectroscopy of brain tumors (15–23), and this modality has been used to characterize hepatocellular, colorectal, breast, cervical, neck, ovarian, prostate, salivary gland, bone, and soft-tissue tumors (24–33).

There is no tumor-specific metabolite that can be detected with 1H MR spectroscopy (34). It is possible, however, to detect specific patterns in changes in metabolite concentrations. Choline is a compound metabolite that participates in cellular membrane synthesis and breakdown and can be used as a tumor marker. The creatine level yields information on cell energy status, and this compound may be used as a standard metabolite. The importance of lipid peaks is uncertain because they are frequently associated with benign cellular processes (eg, the intracellular lipid seen in benign adenomas).

To our knowledge, only one study has been performed to evaluate in vivo 1H MR spectroscopy for characterization of adrenal tumors (35). Adrenal cortical lesions differ in their lipid content, and this difference can be appraised with 1H MR spectroscopy. Evidence from in vivo measurements is used to confirm that the percentage of lipid content is significantly lower in carcinomas than in adenomas. However, the question remains: Is 1H MR spectroscopy able to generate new information in addition to the high-quality anatomic data provided by conventional MR imaging, and could this information be used to replace or complement biopsy findings in the evaluation and clinical care of patients? Given the differences in biochemical activity among adrenal adenomas, pheochromocytomas, carcinomas, and metastases, 1H MR spectroscopy may be used to make this distinction. Thus, the purpose of our study was to prospectively determine the accuracy of in vivo 1H MR spectroscopy in distinguishing adrenal adenomas, pheochromocytomas, adrenocortical carcinomas, and metastases, with histologic or CT findings and follow-up data as the reference standards.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Patients, Masses, and Reference Standards
This study was approved by the institutional ethics committee, and informed consent was obtained from all patients. Sixty-four consecutive patients (25 male and 39 female patients; mean age, 54 years) with adrenal masses who met our study criteria and had undergone previous imaging with either abdominal CT protocol (densitometry or washout) were prospectively evaluated with a dedicated 1H MR spectroscopy protocol. The endocrinology and urology services referred patients to the department of diagnostic imaging between August 2004 and January 2006. We did not include patients with malignant tumors who already were involved in therapeutic chemotherapy protocols, those who had undergone previous adrenal biopsy, or those with an adrenal mass smaller than 2.0 cm in diameter. We excluded four adenomas with diameters of approximately 2 cm since it was impossible to obtain voxels eligible for analysis. Two patients had bilateral adrenal lesions. In each case, only the larger lesion was included in the study. Sixty patients (24 male and 36 female patients; mean age, 53 years) harboring adrenal tumors larger than 2 cm in diameter (mean, 4.6 cm ± 3.4 [standard deviation]) entered the study (Fig 1).


Figure 1
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  		Figure 1: Flowchart of study enrollment.

 
We used a previously reported threshold (unenhanced CT attenuation ≤ 10 HU, enhancement washout ≥ 60%) as a reference standard to classify adrenal masses as adenomas. Criteria for adenoma diagnosis also included stable size for at least 12 months and surgical resection of functioning adenomas or atypical masses. Thirty-eight patients with adenomas were included in the study: 26 adenomas had an attenuation of no more than 10 HU on unenhanced CT images (–10 to 8 HU; mean, 3 HU), 24 had stable size (mean duration of follow-up, 22 months; range, 12–48 months), and two had been surgically resected (both had refractory hyperaldosteronism at presentation). Of the 38 adenomas, 12 had an attenuation of more than 10 HU at unenhanced CT (18–30 HU; mean, 23 HU). Two adenomas were surgically resected. At imaging, one patient had an adenoma with a mass diameter of 4 cm and washout of less than 60%, and the other patient had refractory hyperaldosteronism. The other 10 adenomas had washout of at least 60% (range, 60%–86%; mean, 67%) and stable size (mean duration of follow-up, 25 months; range, 14–46 months).

Evaluation of pheochromocytomas and carcinomas included histopathologic analysis of surgical specimens (reference standard). Five carcinomas and 10 pheochromocytomas were included. Eight pheochromocytomas were diagnosed biochemically, and two were not diagnosed. Metastasis evaluation included histopathologic proof by means of biopsy or surgery. Seven metastases were included: surgically resected lung carcinosarcoma (n = 1) and lung adenocarcinoma (n = 1) and biopsy-sampled lung carcinoma (n = 2), lymphoma (n = 1), germ cell carcinoma (n = 1), and mesenchymal tumor (n = 1).

The mean diameters, with standard deviations, and diameter ranges (in parentheses) for the adenomas, pheochromocytomas, carcinomas, and metastases were 2.8 cm ± 0.7 (2.1–4.4 cm), 5.5 cm ± 1.3 (3.4–8.4 cm), 10.1 cm ± 5.6 (4.7–18.4 cm), and 8.5 cm ± 4.7 (3.1–16.0 cm), respectively. Forty-eight masses were located in the right gland, and 12 were located in the left gland.

MR Imaging and 1H MR Spectroscopic Imaging
Examinations were performed with a 1.5-T (43 mT/m) MR unit (Sonata MC; Siemens, Erhlund, Germany) equipped with a phased-array coil. MR imaging performed at the level of the adrenal mass consisted of a T2-weighted sequence and chemical shift imaging. Localization images, which consisted of transverse, coronal, and sagittal T2-weighted sections, were obtained by using a half-Fourier rapid acquisition with relaxation enhancement (RARE) sequence with 4.4-msec echo space, repetition time msec/echo time msec of 900/90 (effective), 3-mm section thickness, 37 x 37-cm field of view, and 167 x 256 matrix. Localization sequences could be any breath-hold sequence with adequate time-space resolution.

Chemical shift MR imaging was performed by using a fast low-angle shot sequence with a repetition time of 100 msec (coronal plane) or 170 msec (transverse plane), double echo times of 2.4 and 4.8 msec, a 90° flip angle, 4-mm maximum section thickness, 167 x 256 matrix, 35 x 35-cm field of view, and one signal acquired. Half-Fourier RARE sequences were performed in transverse, coronal, and sagittal planes for three-dimensional mass localization and 1H MR spectroscopy planning. To determine the correct insertion for the volume of interest, we used three localizing half-Fourier RARE sagittal sequences: at maximum inspiration, at maximum expiration, and at free breathing. In this way, we determined the range of positioning, from the highest to the lowest point, where the gland could be located during the acquisition of 1H MR spectroscopic images during free breathing. There would be a high probability that the adrenal gland and mass would be located in this interval. This allowed one of the authors (J.F.F., H.M.; each with 4 years of MR experience) to carefully position the multivoxel volume of interest grids in the center of the lesion, with use of all three sagittal sequences, to include as much of the lesion area as possible or, preferentially, to include all of the lesion and part of the adjacent fat tissue. The volume of interest grid was composed of 256 voxels, with a nominal voxel size of 0.75 x 0.75 x 1.0 cm (0.56 cm3), within a 16 x 12 x 0.75-cm field of view. The field homogeneity was optimized automatically over the selected grid of interest by observing the water signal intensity (Fig 2).


Figure 2
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  		Figure 2: Planning for the 1H MR spectroscopy sequence (1000/88) used to examine the pheochromocytoma. A, B, Half-Fourier RARE sagittal image at maximum inspiration (A) and maximum expiration (B). The horizontal lines represent the maximum adrenal mobility during patient respiration, which was 1.8 cm in this case. C, Half-Fourier RARE sagittal, coronal, and transverse images obtained during free breathing show eight saturation region bands, the multivoxel grid, and the intersection lines. The volume of interest grid is composed of 256 voxels, with a nominal voxel size of 0.75 x 0.75 x 1.0 cm (0.56 cm3) within a 16 x 12 x 0.75-cm field of view.

 
Three-dimensional 1H MR spectroscopy was performed by using a point-resolved spatially localized spectroscopy sequence with a two-dimensional chemical shift imaging sequence, multivoxel localization, 1500/135, and an acquisition time of approximately 6 minutes. Eight saturation region bands were used. Water suppression was achieved prior to the point-resolved spatially localized spectroscopic examination. One signal was acquired for each water suppression spectrum. The total amount of time needed for spectroscopy, including planning and data acquisition, was, on average, 20 minutes.

1H MR Spectroscopic Data Analysis
After data acquisition, an author (J.F.F.) processed the 1H MR spectroscopy data by using a protocol specifically designed for that purpose at a workstation (Leonardo; Siemens) with spectral analysis software, a 1000-Hz Gaussian line-broadening filter, and zero filling of Hanning (approximately 4-msec center and 200-msec width). Fourier transformation and automatic phase correction were also incorporated in this order.

1H MR spectroscopy images were overlaid on the corresponding T2-weighted images and evaluated to determine which voxels were eligible for analysis. Individual voxels were considered eligible if they consisted of 100% lesion tissue. Voxels located in the adjacent fat were not included in the analysis. 1H MR spectroscopy images were interpreted by means of visual inspection and metabolite peak amplitude measurements. Analysis time varied according to the number of evaluated voxels and lasted up to 50 minutes. All spectral fits were performed in an analysis window from 0.50 to 5.0 ppm. Metabolites with a standard deviation of more than 20% were not included in the statistical analysis. Metabolite amplitude peaks from each eligible voxel were measured and used to calculate the mean mass ratio. Lipid-positive peaks were determined in the chemical shift range of 0.90–2.02 ppm. Creatine- and choline-positive peaks were determined with chemical shifts of 3.08 and 3.22 ppm, respectively. All amplitudes were determined for each metabolite of interest for every lesion; subsequently, all means, medians, and ranges were calculated for every metabolite ratio (choline to creatine, choline to lipid, and lipid to creatine). We noted a peak in the frequency range of 4.0–4.3 ppm, mainly in pheochromocytomas and carcinomas. A retrospective evaluation was performed, and a 4.0–4.3 ppm/creatine ratio was calculated.

Statistical Analysis
Differences in ratios between lesion types were correlated by using the {chi}2 test with Yates correction or the Fisher exact test when a cell value was less than 5. Two-sample paired Student t tests were used to compare mean metabolite ratios for different mass groups. A P value of less than .05 indicated significance for all tests. Estimated power analysis for comparison of proportions was performed for all tables.

Receiver operating characteristics curve analyses were used for different ratio thresholds to ascertain the best cutoff values for sensitivity and specificity. Sensitivity, specificity, positive predictive value (PPV), and accuracy were determined for each mass metabolite ratio cutoff value.

Analyses were conducted by using a software program (Epi Info, version 3.3.2, 2005; Centers for Disease Control and Prevention, Atlanta, Ga). Receiver operating characteristics curve analysis was performed with statistical software (SPSS for Windows, version 10; SPSS, Chicago, Ill). Power analysis was performed with other software (Stata, version 8.2; Stata, College Station, Tex).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
Eligible Voxels
On average, there were 9 eligible voxels (range, 3–52 voxels) in adenomas, 46 (range, 16–144 voxels) in pheochromocytomas, 76 (range, 48–144 voxels) in carcinomas, and 39 (range, 14–144 voxels) in metastases.

Visual Inspection and Metabolite Ratios
We observed different spectral patterns for different types of adrenal masses (Table 1). Adenomas had relatively homogeneous spectra, with low variability among each of the eligible voxels, and, in general, they had only positive lipid peaks in the spectra. We did not find significant differences (P > .05) in metabolite peaks between lipid-rich and lipid-poor adenomas (Fig 3). Conversely, pheochromocytomas, carcinomas, and metastases commonly revealed marked spectral variability at visual inspection (Figs 4–7).


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  		Table 1. Metabolite Ratio Values Obtained with 1H MR Spectroscopy

 

Figure 3A
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  		Figure 3a: Point-resolved multivoxel 1H MR spectroscopy (1500/135) performed in (a) 48-year-old man with right adrenal lipid-rich adenoma and (b) 25-year-old man with left adrenal lipid-poor adenoma. Spectroscopy revealed an eligible internal voxel for each lesion. Reference images (1000/88) are located to the right of each spectrum and were acquired in the coronal (top), sagittal (middle), and transverse (bottom) planes in a and in the sagittal (top), coronal (middle), and transverse (bottom) planes in b. These images reveal the location of the analyzed voxel inside each lesion (voxel size, 0.56 cm3). The metabolite ratios are as follows: choline-creatine ratio, 0.76 in a and 0.69 in b; lipid-creatine ratio, 6.72 in a and 5.0 in b; choline-lipid ratio, 0.11 in a and 0.14 in b; and 4.0–4.3 ppm/creatine ratio, 0.71 in a and 0.68 in b. A = amplitude, AU = arbitrary units, Cho = choline, Cr = creatine, and LIP = lipid.

 

Figure 3B
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  		Figure 3b: Point-resolved multivoxel 1H MR spectroscopy (1500/135) performed in (a) 48-year-old man with right adrenal lipid-rich adenoma and (b) 25-year-old man with left adrenal lipid-poor adenoma. Spectroscopy revealed an eligible internal voxel for each lesion. Reference images (1000/88) are located to the right of each spectrum and were acquired in the coronal (top), sagittal (middle), and transverse (bottom) planes in a and in the sagittal (top), coronal (middle), and transverse (bottom) planes in b. These images reveal the location of the analyzed voxel inside each lesion (voxel size, 0.56 cm3). The metabolite ratios are as follows: choline-creatine ratio, 0.76 in a and 0.69 in b; lipid-creatine ratio, 6.72 in a and 5.0 in b; choline-lipid ratio, 0.11 in a and 0.14 in b; and 4.0–4.3 ppm/creatine ratio, 0.71 in a and 0.68 in b. A = amplitude, AU = arbitrary units, Cho = choline, Cr = creatine, and LIP = lipid.

 

Figure 4
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  		Figure 4: Point-resolved multivoxel 1H MR spectroscopy performed in 32-year-old woman with right adrenal pheochromocytoma. Reference images acquired in the transverse (top), sagittal (middle), and coronal (bottom) planes (1000/88) show the location of the analyzed voxel (voxel size, 0.56 cm3). The metabolite ratios are as follows: choline-creatine ratio, 1.41; lipid-creatine ratio, 0.53; choline-lipid ratio, 2.62; and 4.0–4.3 ppm/creatine ratio, 2.69. A = amplitude, AU = arbitrary units, Cho = choline, Cr = creatine, and LIP = lipid.

 

Figure 5
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  		Figure 5: Point-resolved multivoxel 1H MR spectroscopy performed in 46-year-old woman with right adrenocortical carcinoma. Reference images acquired in the sagittal (1000/88) (top), coronal (4.3/2.1) (middle), and transverse (90/2.4) (bottom) planes show the location of the analyzed voxel (voxel size, 0.56 cm3). The metabolite ratios are as follows: choline-creatine ratio, 1.90; lipid-creatine ratio, 6.90; choline-lipid ratio, 0.27; and 4.0–4.3 ppm/creatine ratio, 5.3. A = amplitude, AU = arbitrary units, Cho = choline, Cr = creatine, and LIP = lipid.

 

Figure 6
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  		Figure 6: Point-resolved multivoxel 1H MR spectroscopy performed in 24-year-old woman with right adrenal metastases of high-grade lung carcinosarcoma. Reference images acquired in the transverse (top), coronal (middle), and sagittal (bottom) planes (1000/88) show the location of the analyzed voxel (voxel size, 0.56 cm3). The metabolite ratios are as follows: choline-creatine ratio, 4.13; lipid-cre-atine ratio, 0.29; choline-lipid ratio, 14.09; and 4.0–4.3 ppm/creatine ratio, 0.87. A = amplitude, AU = arbitrary units, Cho = choline, Cr = creatine, and LIP = lipid.

 

Figure 7A
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  		Figure 7a: Receiver operating characteristic curves. (a) 1H MR spectroscopy choline-creatine ratio for use in differentiation of carcinomas and metastases versus adenomas and pheochromocytomas. The area under the receiver operating characteristics curve was 0.91 (95% confidence interval, 0.81, 1.01). When the choline-creatine ratio was greater than 1.20, the best combination of sensitivity (92%) and specificity (96%) was provided. (b) 1H MR spectroscopy 4.0–4.3 ppm/creatine ratio for use in differentiation of carcinomas and pheochromocytomas versus adenomas and metastases. The area under the receiver operating characteristics curve was 0.97 (95% confidence interval: 0.92, 1.01). When the 4.0–4.3 ppm/creatine ratio was greater than 1.50, the best combination of sensitivity (87%) and specificity (98%) was provided.

 

Figure 7B
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  		Figure 7b: Receiver operating characteristic curves. (a) 1H MR spectroscopy choline-creatine ratio for use in differentiation of carcinomas and metastases versus adenomas and pheochromocytomas. The area under the receiver operating characteristics curve was 0.91 (95% confidence interval, 0.81, 1.01). When the choline-creatine ratio was greater than 1.20, the best combination of sensitivity (92%) and specificity (96%) was provided. (b) 1H MR spectroscopy 4.0–4.3 ppm/creatine ratio for use in differentiation of carcinomas and pheochromocytomas versus adenomas and metastases. The area under the receiver operating characteristics curve was 0.97 (95% confidence interval: 0.92, 1.01). When the 4.0–4.3 ppm/creatine ratio was greater than 1.50, the best combination of sensitivity (87%) and specificity (98%) was provided.

 
Metastases had the most heterogeneous spectra, with many different metabolite peaks, a predominance of positive choline peaks, and no positive lipid peaks. Carcinomas had high variability of spectra within the mass. Positive lipid peaks were seen frequently, while positive choline peaks were present in only a few (at least four) eligible voxels. Positive 4.0–4.3-ppm peaks were also present. There was little variability in the spectra of pheochromocytomas, with positive lipid and 4.0–4.3-ppm peaks. Few positive choline peaks were detected (less than two spectra). There were particular voxels in some of the lesions that had lipid and 4.0–4.3-ppm peaks with too wide a base, and these were confused with the adjacent creatine and choline peaks.

The results enabled us to differentiate the masses and group them (Tables 2–5). Carcinomas and metastases had choline-creatine ratios greater than 1.20 in 11 (92%) of 12 masses, while adenomas and pheochromocytomas had choline-creatine ratios equal to or less than 1.20 in 46 of 48 masses (92% sensitivity, 96% specificity, 86% PPV, 95% accuracy, P < .01). The areas under the receiver operating characteristics curve for the choline-creatine ratio and 4.0–4.3 ppm/creatine ratio were 0.91 (95% confidence interval: 0.81, 1.01) and 0.97 (95% confidence interval: 0.92, 1.01), respectively. High-grade tumors had higher choline-creatine ratios than did low-grade tumors. A choline-lipid ratio greater then 0.38 enabled distinction of carcinomas and metastases from pheochromocytomas or adenomas (92% sensitivity, 90% specificity, 69% PPV, 90% accuracy, P < .01). A lipid-creatine ratio of less than 2.10 enabled clear distinction of carcinomas, metastases, and pheochromocytomas from adenomas (45% sensitivity, 100% specificity, 100% PPV, 80% accuracy). There were no significant differences (P > .05) in the lipid-creatine ratios between lipid-rich and lipid-poor adenomas.


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  		Table 2. Comparison of 1H MR Spectroscopy Choline-Creatine Ratio Results

 

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  		Table 3. Comparison of 1H MR Spectroscopy Choline-Lipid Ratio Results

 

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  		Table 4. Comparison of 1H MR Spectroscopy Lipid-Creatine Ratio Results

 

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  		Table 5. Comparison of 1H MR Spectroscopy 4.0–4.3 ppm/Creatine Ratio Results

 
A 4.0–4.3 ppm/creatine ratio greater than 1.50 enabled distinction of carcinomas and pheochromocytomas from metastases and adenomas (87% sensitivity, 98% specificity, 98% PPV, 95% accuracy, P < .01). A 4.0–4.3 ppm/creatine ratio greater than 1.50 proved to be useful for differentiating pheochromocytomas from adenomas (80% sensitivity, 100% specificity). In our sample, only three adenomas had rare 4.0–4.3-ppm peaks in eligible voxels. However, discrimination was possible even in these cases, since the average 4.0–4.3 ppm/creatine ratio in the eligible voxels was still lower than 1.50. There were no significant differences (P > .05) in the 4.0–4.3 ppm/creatine ratios between pheochromocytomas and carcinomas. Estimated power for two-sample comparison of proportions for all results in the tables was 1.0. Although these relationships are more informative than the mean metabolite values, only groups of tissues could be differentiated. Consequently, we decided to compare the information from the two most informative relations. This comparison, performed with use of a scatterplot, allowed us to differentiate the four tissue types in 54 of 60 patients (Fig 8).


Figure 8
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  		Figure 8: Two-dimensional scatterplot based on the results obtained with the receiver operating characteristic curves for choline-creatine and 4.0–4.3 ppm/creatine ratios. Simultaneous use of these analyses for each type of adrenal mass enabled 54 of 60 masses to be sorted into four distinct groups. {circ} = adenoma, bullet = pheochromocytoma, {square} = carcinoma, and {blacksquare} = metastases.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 
With use of 1H MR spectroscopy visual inspection, important differences that enabled us to distinguish benign from malignant adrenal masses were observed only in the presence of a positive choline peak. However, the accuracy of 1H MR spectroscopy visual inspection was worse than that of 1H MR spectroscopy metabolite ratio analyses, which enabled distinction of benign adenomas, pheochromocytomas, carcinomas, and metastases.

In our sample, the choline-creatine ratio was the most useful metabolite ratio for differentiation of metastases and carcinomas from pheochromocytomas and adenomas, and the 4.0–4.3 ppm/creatine ratio was best for differentiation of pheochromocytomas and carcinomas from metastases and adenomas. It was useful to include the other ratios, even though there was some overlap in the differentiation between pheochromocytomas, adenomas, and carcinomas.

Lipid-rich adenomas contain more intracytoplasmic lipids than do lipid-poor adenomas; however, lipid-creatine ratios of lipid-poor and lipid-rich adenomas were not significantly different. Lipid-creatine ratios had low sensitivity but high specificity and PPV for adenoma diagnosis. The 4.0–4.3 ppm/creatine ratios of carcinomas and pheochromocytomas were not significantly different, but the choline-creatine ratio helped with the differentiation of them. Because of the frequent presence of a 4.0–4.3 ppm positive peak in pheochromocytomas and carcinomas, we decided to use this metabolite to create a new ratio: 4.0–4.3 ppm/creatine. To our surprise, this ratio turned out to be one of the most useful for differentiation. To our knowledge, this peak still has not been completely described and defined in the literature, but it may represent blood breakdown products (36). Rarely, adenomas may contain hemorrhage foci (37). Small pheochromocytomas tend to be solid, whereas hemorrhagic and cystic areas become more common with increasing size (38).

Evidence that high-grade tumors had higher choline-creatine ratios than did low-grade tumors has also been found in studies on malignant central nervous system and neck tumors (39,40). The usefulness of information generated from cell proliferation studies performed with healthy and diseased adrenal tissues is still controversial. A group of authors (41) found no significant difference in proliferation fractions between benign lesions and carcinomas. We noticed significant differences in the choline-creatine ratios between benign and malignant adrenal lesions; however, in carcinomas, the average limits were close to those of adenomas and pheochromocytomas. Because of the marked heterogeneity, the procedure used to detect a positive choline peak in large carcinomas is not simple. This is not true for adrenal metastases, as positive choline peaks frequently were found in eligible voxels, particularly in high-grade lesions.

There were limitations to our study. Lesions smaller than 2 cm in diameter are generally unsuitable for analysis because of the absence of eligible voxels. This is due to artifacts caused by respiratory movements, which do not allow insertion of the volume of interest in the three acquisitions in the sagittal plane—at inspiration and expiration and during free breathing. Use of 1H MR spectroscopy sequences during apnea could reduce this problem. Use of higher-field-strength MR imagers allows acquisition of reliable spectra from smaller lesions with faster imaging times and makes differentiation between the various metabolite peaks studied more accurate; further investigation of our technique with such instruments would be useful (42). Also, development of specific software for use with this analysis method would help to simplify measurements. Another problem was the possibility that a curve made at the edge of the lesion could have been contaminated by adjacent fat. However, we tested several peripheral noneligible voxels, compared them with spectra that were considered eligible, and found important differences in the curves. Our findings about the usefulness of this technique need to be validated by the findings of further studies. Such studies should include additional types of adrenal lesions, including nodular hyperplasia, myelolipomas, cysts, hematomas, pediatric neoplasms, and inflammatory processes. The information provided by 1H MR spectroscopy could complement the findings of other modalities, such as CT, MR imaging, and fluorodeoxyglucose PET.

In conclusion, multivoxel 1H MR spectroscopy can be used to characterize and distinguish the various adrenal masses, yielding different spectral findings for adenomas, pheochromocytomas, carcinomas, and metastases. Choline-creatine ratios greater than 1.20 yielded 92% sensitivity and 96% specificity, and choline-lipid ratios greater than 0.38 yielded 92% sensitivity and 90% specificity; both were sufficient for differentiation of adenomas and pheochromocytomas from carcinomas and metastases. In the differentiation of carcinomas and pheochromocytomas from adenomas and metastases, a 4.0–4.3 ppm/creatine ratio greater than 1.50 yielded 87% sensitivity and 98% specificity. Simultaneous use of these two analyses for each type of adrenal mass made it possible to sort 54 of 60 masses into four distinct groups.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATION FOR PATIENT CARE
 References
 


   IMPLICATION FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
References
 


   FOOTNOTES
 

Abbreviations: PPV = positive predictive value • RARE = rapid acquisition with relaxation enhancement

Author contributions: Guarantors of integrity of entire study, J.F.F., S.M.G., J.S., H.M., C.K., P.K., M.P.H., V.V.F., C.A., N.A.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, J.F.F., S.M.G., J.S., P.K., C.A.; clinical studies, J.F.F., S.M.G., J.S., M.P.H.; experimental studies, J.F.F., S.M.G., J.S., H.M., C.K., M.P.H., V.V.F., C.A., N.A.; statistical analysis, J.F.F., S.M.G., J.S., H.M., C.K., N.A.; and manuscript editing, J.F.F., S.M.G., J.S., H.M., C.K., P.K., M.P.H., G.D., V.V.F., M.S., V.O., N.A.

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATION FOR PATIENT CARE
 References
 

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