ORIGINAL ARTICLE
Magnetic Resonance Imaging of Neuroendocrine Tumor Hepatic Metastases Does Hepatobiliary Phase Imaging Improve Lesion Conspicuity and Interobserver Agreement of Lesion Measurements? Brian Morse, MD,* Daniel Jeong, MD,* Kerry Thomas, MD,* Dalanda Diallo, MD,† and Jonathan R. Strosberg, MD‡
Objective: The aim of this study was to determine if magnetic resonance imaging (MRI) performed with hepatobiliary phase imaging results in higher lesion conspicuity and produces lesion measurements with higher interobserver agreement than other MRI sequences when imaging neuroendocrine hepatic metastases. Methods: Patients who had MRIs with both gadoxetate disodium and gadopentetate dimeglumine contrast within a 6-month span were identified, and 23 hepatic lesions were selected. Three radiologists and 1 oncologist measured the greatest diameter of each lesion on the following sequences: T2 weighted, T1 weighted, postcontrast (dynamic, delayed, and hepatobiliary phase), and diffusion weighted. Signal intensity ratio (SIlesion/SIliver) and contrast-to-noise ratio ([SIlesion – SIliver]/noise) were calculated for all lesions on each sequence. The interobserver agreement of measurements on each sequence was calculated using concordance correlation coefficient. Results: Diffusion-weighted sequences had the highest signal intensity ratio ranging from 147% to 187% (vs other sequences range of 19.6%– 130%). One hepatobiliary sequence had the highest contrast-to-noise ratio with a value of 41 (vs other sequences range of 3.2–28.1). Lesion measurements on all sequences showed high-interobserver agreement, with hepatobiliary sequences showing some of the highest levels of agreement. Conclusions: Our results support the use of contrast agents with hepatobiliary excretion when imaging neuroendocrine tumors metastatic to liver. Key Words: neuroendocrine tumors, hepatobiliary phase, magnetic resonance imaging, RECIST (Pancreas 2017;46: 1219–1224)
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euroendocrine tumors (NET) can originate in almost any organ system of the body and span a pathologic spectrum from indolent tumors to aggressive carcinomas. Approximately 60% to 70% of NET arise from the gastrointestinal tract, most commonly the rectum and small bowel.1 An analysis of Surveillance, Epidemiology, and End Results data of patients with NET spanning from 1973 to 2004 found that 50% of patients
From the *Department of Diagnostic Imaging, Moffitt Cancer Center; †Department of Radiology, University of South Florida; and ‡Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL. Received for publication January 8, 2017; accepted August 11, 2017. Address correspondence to: Brian Morse, MD, Moffitt Cancer Center, WCB-RAD MD/OPI, 12902 USF Magnolia Dr, Tampa, FL 33612 (e‐mail: [email protected]). No financial support was provided for this work. The authors declare no conflict of interest or funding relevant to this work. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MPA.0000000000000920
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have regional or distant metastases at initial diagnosis.2 Sites of metastatic disease vary based on the primary tumor, but the most common site of metastatic disease is the liver.1 Imaging of the liver is, therefore, critical for assessment of disease status. Previous work has shown that certain magnetic resonance imaging (MRI) sequences perform well in the evaluation of hepatic metastases from NET. For example, Dromain et al3 found that T2-weighted and arterial phase postcontrast sequences had the highest contrast-to-noise ratio of lesion versus normal liver and that arterial phase images identified the greatest number of metastases. d’Assignies et al4 found that diffusion-weighted imaging (DWI) sequences had a higher sensitivity than T2weighted or postcontrast sequences for NET hepatic metastases (Fig. 1). The DWI has also been found to be an independent predictor of response to therapy, that is, restricted diffusion decreases with successful therapy response.5–7 Previous work has also shown that DWI characteristics correlate with NET grade and can therefore be prognostic.8,9 Arterial phase images are produced using “dynamic” postcontrast imaging, acquiring multiple sequences in rapid succession after contrast administration, typically with timing to achieve arterial, portal venous, and a later portal venous or interstitial phase. Dynamic imaging is performed routinely for abdomen MRI because lesions in the liver, kidneys, and pancreas can be characterized based on their appearance at multiphase imaging. Standard MR contrast agents remain in the extracellular space and are cleared by the kidneys. There are newer MR contrast agents that are actively transported into hepatocytes and then excreted into the biliary system. These agents are capable of dynamic imaging, similar to a standard MR contrast agent, and they can produce delayed postcontrast images after the contrast is taken up by the hepatocytes, or “hepatobiliary phase” images. Lesions that do not contain functional hepatocytes (such as metastases) do not take up the contrast agent and are depicted with high-contrast relative to normal liver (Fig. 2). Over the past decade, the use of these contrast agents in abdominal imaging has increased, with gadoxetate disodium, which is the agent with hepatobiliary excretion in most widespread use. Although numerous studies have shown the use of gadoxetate disodium results in improved sensitivity for hepatic metastases (primarily studied in colon cancer), there is little data in the literature concerning the value of these agents in evaluation of NET liver metastases.10,11 Based on our institutional experience, we hypothesized that hepatobiliary phase images produced with gadoxetate disodium would achieve higher levels of lesion conspicuity compared with other MR sequences or postcontrast images obtained with a contrast agent, which lacks hepatobiliary excretion. Signal intensity ratio and contrast-to-noise ratio were used in this study to quantify lesion conspicuity. www.pancreasjournal.com
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FIGURE 1. A, Arterial phase dynamic postcontrast image. B, T2-weighted image. C, Diffusion-weighted image (b-value, 50). Magnetic resonance images of a typical hepatic metastasis (indicated by arrow) from neuroendocrine tumor (small bowel carcinoid in this example). The high contrast of lesion to liver achieved by these sequences is obvious in this example.
Tumor measurement accuracy is critical for assessment of progression and therapeutic response, particularly in protocols using Response Evaluation Criteria in Solid Tumors (RECIST). Ideally, tumors should be measured on sequences that minimize variability among different observers. We hypothesized that the higher lesion conspicuity achieved with hepatobiliary phase images would translate into higher interobserver agreement of lesion measurements. For this study, we used the concordance correlation coefficient (CCC) to quantify interobserver agreement of tumor measurements. We included a clinician observer in our study to determine if hepatobiliary phase images
produced higher interobserver agreement between radiologist and nonradiologist measurements.
MATERIALS AND METHODS This Health Insurance Portability and Accountability Act compliant, retrospective, chart review study was reviewed and approved by the local institutional review board. The radiology picture archiving communication system (Merge Radsuite v 8.30.7.385; Merge Healthcare, Chicago, Ill) was used to find patients with MRIs using gadoxetate disodium contrast ordered by the neuroendocrine tumor
FIGURE 2. A, Arterial phase postcontrast image. B, Portal venous phase postcontrast image. C, Late portal venous phase postcontrast image. D, Five-minute delayed postcontrast image with standard contrast agent. E, Hepatobiliary phase image with gadoxetate disodium. These are images of a small bowel carcinoid metastasis to the liver (indicated by arrow). Images A through C show dynamic postcontrast images of the lesion. This is a typical enhancement pattern for a NET metastasis, hyperenhancing to liver on arterial phase images with less enhancement (or wash-out) relative to normal liver on more delayed postcontrast images. Delayed postcontrast images obtained with a standard contrast agent (D) show the lesion enhances less than normal liver and is somewhat ill defined. Gadoxetate disodium allows acquisition of hepatobiliary phase images (E), which depict the lesion with high conspicuity.
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section at our hospital between September 2008 and September 2013. Those cases were reviewed to identify patients who also had previous abdomen MRIs performed within 6 months using gadopentetate dimeglumine contrast. Those MRIs were reviewed by the senior radiologist to determine if suitable target lesions were present. Target lesions had to measure at least 1 cm in diameter (as per RECIST guidelines) and be visualized on all sequences. Using these criteria, a total of 7 patients (5 male and 2 female; mean age, 58 years) with 23 suitable lesions were identified. The primary tumors consisted of 5 NET of distal small bowel, 1 gastric NET, and 1 pancreatic NET. All but one of the patients were on therapy with somatostatin analogs. The patients receiving somatostatin analogs were on therapy before acquisition of the initial MRI, and there was no change in therapy between MRIs. All cases had biopsyproven hepatic metastases. Four were biopsied using ultrasound guidance, and 3 had liver biopsies performed during surgery to remove the primary tumor. The MR imaging was performed using a 1.5-T MRI scanner using a standard 8-channel body coil (Siemens Medical Solutions, Erlangen, Germany). Sequences used in this study were acquired in the axial plane. The following MR sequences were acquired (TR = repetition time, TE = echo time, slice thickness of 6 mm unless otherwise noted): T2 weighted (TR, 1000; TE, 184), T1-weighted gradient echo, in and out of phase (TR, 155; TE, 4.48 and 2.17), fat-suppressed and T2-weighted sequence (TR, 3500; TE, 103), precontrast and postcontrast fat-suppressed T1-weighted sequence (TR, 4.3; TE, 1.83; slice thickness, 3 mm), and diffusion-weighted sequence (TR, 9500; TE, 88, b-values 50, 500, 800 s/mm2). Gadopentetate dimeglumine (Magnevist) (Bayer HealthCare, Whippany, NJ) (0.1 mmol/kg) was used for the “standard” contrast agent, and gadoxetate disodium (Eovist) (Bayer HealthCare, Whippany, NJ) (0.025 mmol/kg) was used as the contrast agent with hepatobiliary excretion. Postcontrast sequences consisted of dynamic postcontrast image acquisition (for both gadopentetate dimeglumine and gadoxetate disodium), 5-minute delayed postcontrast images (gadopentetate dimeglumine only), and 20-minute delayed postcontrast hepatobiliary phase images (gadoxetate disodium only). The first dynamic sequence (Dynamic 1) was timed to produce arterial phase images, with subsequent dynamic sequences (Dynamic 2 + 3) timed to produce early and late portal venous phase images. When using gadoxetate disodium, contrast dose was calculated using the patient's weight and contrast diluted with saline to a total volume of 20 mL. The dilution was used to combat motion artifact, which can be seen with dynamic postcontrast sequence acquisition using gadoxetate disodium.12 Two hepatobiliary phase sequences were acquired (denoted hepatobiliary 1 and hepatobiliary 2). The only difference between these 2 sequences was that hepatobiliary 2 had a slice thickness of 6 mm rather than 3 mm. Patients with examination results that met our inclusion criteria were reviewed by the senior radiologist to ensure that all sequences were free of significant artifact, and that potential target lesions were visible on all sequences. If these conditions were met, the senior radiologist selected target lesions and made a set of images of each target lesion on all sequences. Those images were placed into a folder on the picture archiving communication system for review by observers. If more than one lesion was present on the image, the lesion of interest was indicated with an arrow on the first sequence. Observers were instructed to view the image in a one-image per monitor screen layout and measure the longest diameter of the lesion (following RECIST guidelines).13 Observers were instructed to measure the maximum axial diameter of the lesion on every sequence and record their measurement on a worksheet. The signal intensity of the lesion, normal liver, and noise were made for every lesion on every sequence. The signal © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Hepatobiliary Phase Imaging of NET Metastases
intensity of the lesion was calculated by drawing a circular region of interest (ROI) on the lesion to encompass the maximum amount of lesion possible without suffering from volume averaging (aiming to encompass at least 75% of lesion bulk). The signal intensity of liver was made with an ROI comparable with the lesion ROI at a comparable vertical distance. The ROI for noise was measured outside the anterior abdominal wall. Signal intensity ratio was calculated using the following formula: (Signal Intensity Lesion)/(Signal Intensity Liver). The intensity of the lesion relative to the liver varied on each sequence. On some sequences, the lesion was hypointense relative to liver, and on others, the lesion was hyperintense. For the purposes of this project, the conspicuity of the lesion is of interest, so the signal intensity ratio is reported as percent change from liver parenchyma, not an absolute value. The contrast-to-noise ratio was calculated by the following formula: [(Signal Intensity Lesion)/ (Signal Intensity Liver)]/noise. All radiologist observers in this study had fellowship training in abdominal imaging. They consisted of 2 junior radiologists with a 2-year postfellowship experience and 1 senior radiologist with a 6-year postfellowship experience. The clinician observer is a medical oncologist who specializes in the treatment of NET. The agreement between subjects was evaluated by the CCC (SPSS v 20.0, IBM, Armonk, NY) by Lin.14,15 No multiplicity adjustment was considered. The CCC was calculated for each sequence and between each pair of junior radiologists, senior radiologist, and medical oncologist.
RESULTS Table 1 shows the signal intensity ratios of lesion to liver by sequence, and Table 2 shows contrast-to-noise ratio of lesion to liver by sequence. Diffusion weighted images outperformed other sequences with regard to signal intensity ratio. Signal intensity ratio of the hepatobiliary phase sequence was similar to arterialphase dynamic postcontrast and slightly less than T2-weighted sequences. The data for contrast-to-noise ratio showed that hepatobiliary phase and T2-weighted sequences outperformed other sequences. Hepatobiliary 2 had a larger slice thickness than hepatobiliary 1 (6 vs 3 mm). This explains the higher contrastto-noise ratio achieved with hepatobiliary phase 2 because the lower spatial resolution results in higher signal. Only the TABLE 1. Signal Intensity Ratio by Sequence Sequence DWI b 500 DWI b 50 DWI b 800 T2, fat-suppressed T2 T1 out-of-phase Dynamic 1 gadopentetate dimeglumine Hepatobiliary 1 Dynamic 1 gadoxetate disodium Hepatobiliary 2 T1, fat-suppressed Dynamic 3 gadoxetate disodium Dynamic 2 gadoxetate disodium Dynamic 2 gadopentetate dimeglumine Delayed gadopentetate dimeglumine T1 in-phase Dynamic 3 gadopentetate dimeglumine
Range, %
Average, %
34–380 20–470 12–370 30–410 10–440 10–230 28–220 10–130 10–100 10–50 16–120 5–50 3–90 12–80 12–70 5–40 15–70
187.1 184.2 147.1 130 103.3 51.7 48.3 46.3 40.4 37.9 30 23.8 23.3 22.1 21.3 20.8 19.6
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TABLE 2. Contrast-to-Noise Ratio by Sequence Sequence Hepatobiliary 2 T2, fat-suppressed Hepatobiliary 1 T2 T1 out-of-phase Dynamic 1 gadopentetate dimeglumine Dynamic 1 gadoxetate disodium Dynamic 3 gadoxetate disodium Dynamic 2 gadopentetate dimeglumine Dynamic 3 gadopentetate dimeglumine T1 in-phase T1, fat-suppressed Dynamic 2 gadoxetate disodium Delayed gadopentetate dimeglumine DWI b 50 DWI b 500 DWI b 800
Range
Average
10–77.3 7.4–97.5 5.3–53.7 1–106 1.2–66.5 6.3–57.3 1.8–28 0.3–39.2 3.1–45.7 4.5–47.2 1–49.5 0.4–22 0.7–21.7 4.3–14.5 0.5–21 0.5–11.5 0.3–10.5
41 28.1 24.1 20 17.3 14.2 10.7 10.6 10.5 10.5 9.9 7.3 7.1 6.6 6.5 4.6 3.2
hepatobiliary sequence with larger slice thickness significantly outperformed T2-weighted sequences. The DWI performed poorly with regards to contrast-to-noise ratio, but this is secondary to the larger noise relative to signal seen with DWI. The results for interobserver agreement show that the CCC of measurements was high for all sequences among radiologists (Table 3). The highest interobserver agreement among junior radiologists was obtained with the T2-weighted, fat-suppressed sequence. This was also true for junior versus senior radiologists (although this sequence tied with third dynamic phase using gadoxetate disodium). In general, the CCC data show that interobserver agreement does parallel lesion conspicuity, that is, lesions with the highest signal intensity ratio and contrast-tonoise ratio in general have higher values for CCC. Similar findings of interobserver agreement are observed when comparing the measurements of radiologists versus the clinician (Table 4). The
sequences with the highest lesion conspicuity produced the highest CCCs with DWI and hepatobiliary phase sequences resulting in the highest levels of interobserver agreement. Of note, there were several lesions (5 lesions on second gadopentetate dimeglumine dynamic postcontrast sequence, 3 lesions on third gadopentetate dimeglumine dynamic postcontrast sequence, 2 lesions on first gadoxetate disodium dynamic postcontrast sequence, 2 lesions on T2-weighted, and 2 lesions on T1-out-of-phase sequences), which the clinician could not visualize well enough to measure. All of these lesions were deemed to be visible and measureable by radiologist observers. A zero value was recorded for these lesions for the clinician.
DISCUSSION The evaluation of patients with NET relies heavily on crosssectional imaging. Of paramount importance in this evaluation is adequate contrast between lesion and normal liver. Our study is the first attempt to quantify lesion conspicuity of NET hepatic metastases using a contrast agent with hepatobiliary excretion. Previous work has shown the superiority of T2-weighted, arterial phase postcontrast, and DWI sequences for the evaluation of hepatic metastases from NET.3,4 We hypothesized that hepatobiliary phase sequences would outperform other sequences with regard to lesion conspicuity, and this was partially true. Hepatobiliary phase sequences had the highest contrast-to-noise ratio, and the signal intensity ratio was only slightly lower than DWI and T2weighted sequences (signal intensity ratio was comparable for arterial phase images). This is important because while DWI and T2-weighted images are part of most modern MR protocols, the choice of contrast agent (ie, whether to use a contrast agent with hepatobiliary excretion) will vary based on examination indication. When using a contrast agent without hepatobiliary excretion, one must rely on only dynamic and delayed postcontrast sequences. Our data shows that hepatobiliary phase sequences outperform these sequences with regard to lesion conspicuity. This makes sense, because while NET liver metastases should show the greatest enhancement on arterial phase images, this is not true in practice. Neuroendocrine tumors are a heterogeneous group of tumors, and not all NET liver metastases show arterial phase hyperenhancement, which helps explain the variable lesion conspicuity seen with dynamic postcontrast images in this study.3 In
TABLE 3. Interobserver Agreement by Sequence Among Radiologists Sequences T2, fat-suppressed Dynamic 1 gadoxetate disodium Hepatobiliary 2 DWI b 800 DWI b 500 T2 Dynamic 3 gadoxetate disodium Dynamic 3 gadopentetate dimeglumine DWI b 50 Hepatobiliary 1 Dynamic 2 gadoxetate disodium Dynamic 1 gadopentetate dimeglumine T1, fat-suppressed T1 out-of-phase T1 in-phase Dynamic 2 gadopentetate dimeglumine
CCC Jr Rad 1 vs Jr Rad 2
Sequences
CCC Jr Rads vs Sr Rad
0.97 0.959 0.951 0.95 0.947 0.946 0.944 0.943 0.935 0.934 0.929 0.928 0.928 0.923 0.896 0.862
T2, fat-suppressed Dynamic 3 gadoxetate disodium Dynamic 1 gadoxetate disodium Hepatobiliary 1 DWI b 500 Dynamic 3 gadopentetate dimeglumine T2 Hepatobiliary 2 DWI b 800 T1 out-of-phase DWI b 50 Dynamic 2 gadoxetate disodium Dynamic 1 gadopentetate dimeglumine T1 in-phase T1, fat-suppressed Dynamic 2 gadopentetate dimeglumine
0.981 0.981 0.979 0.977 0.976 0.975 0.973 0.972 0.971 0.969 0.967 0.965 0.964 0.956 0.956 0.939
Jr Rad indicates junior radiologist; Sr Rad, senior radiologist.
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Hepatobiliary Phase Imaging of NET Metastases
TABLE 4. Interobserver Agreement by Sequence Radiologists Versus Clinician Sequences
CCC Jr Rads vs Clinician
Sequences
CCC Sr Rad vs Clinician
0.976 0.968 0.968 0.967 0.964 0.961 0.936 0.909 0.899 0.890 0.884 0.876 0.866 0.846 0.823 0.710
DWI b 500 Dynamic 1 gadopentetate dimeglumine Hepatobiliary 1 Hepatobiliary 2 DWI b 50 T1 in-phase DWI b 800 Dynamic 3 gadoxetate disodium T1 out-of-phase T2, fat-suppressed Dynamic 2 gadoxetate disodium Dynamic 3 gadopentetate dimeglumine Dynamic 1 gadoxetate disodium T2 T1, fat-suppressed Dynamic 2 gadopentetate dimeglumine
0.983 0.98 0.979 0.977 0.97 0.968 0.951 0.914 0.897 0.892 0.89 0.886 0.878 0.842 0.8 0.708
DWI b 500 Hepatobiliary 2 Hepatobiliary 1 Dynamic 1 gadopentetate dimeglumine DWI b 50 T1 in-phase DWI b 800 Dynamic 3 gadoxetate disodium Dynamic 1 gadoxetate disodium Dynamic 2 gadoxetate disodium T1 out-of-phase T2, fat-suppressed T1, fat-suppressed Dynamic 3 gadopentetate dimeglumine T2 Dynamic 2 gadopentetate dimeglumine
Jr Rad indicates junior radiologist; Sr Rad, senior radiologist.
contrast, all NET liver metastases show hypoenhancement relative to liver on hepatobiliary phase images (Fig. 3). Contrast agents with hepatobiliary excretion are also capable of dynamic imaging
(ie, acquisition of arterial and portal venous phase images), so it makes sense to use these agents when imaging NET liver metastases. Another advantage of these agents is that hepatobiliary
FIGURE 3. A, Arterial phase postcontrast image. B, Late portal venous phase postcontrast image. C, Hepatobiliary phase image with gadoxetate disodium. This MRI shows 2 metastases to the liver from small bowel carcinoid (indicated by arrows). The lesions do not show the “classic” appearance of bright, homogenous enhancement on arterial phase images. One lesion is difficult to detect at all on the dynamic postcontrast images. All NET metastases will enhance less than normal liver on hepatobiliary phase images because they do not contain functioning hepatocytes.
FIGURE 4. A, Arterial phase postcontrast image affected by motion artifact. B, Hepatobiliary phase image with gadoxetate disodium. This is a hepatic metastasis from a pancreatic NET (indicated by arrow). The arterial phase image is degraded by motion artifact. The lesion is detected but accurate measurement would be difficult. The dynamic images cannot be repeated without administering another contrast bolus. Timing is not such a crucial consideration with hepatobiliary phase using gadoxetate disodium. After waiting for the hepatocytes to take up the contrast (10–20 minutes), the sequence can be acquired as many times as needed to ensure images are free of motion artifact. © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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phase sequences can be acquired at multiple time points after contrast administration without sacrificing their efficacy16 (Fig. 4). If dynamic images are ruined by motion artifact or poor timing, they cannot be repeated unless you administer another contrast bolus. We hypothesized that hepatobiliary phase sequences would result in interobserver agreement of lesion measurements that was higher than other sequences. Our results showed highinterobserver agreement for all sequences (almost all exceeding 0.9), so stratification of these results is difficult. However, the hepatobiliary phase sequences were among the sequences with the highest CCC values, whether comparing radiologists or radiologists versus clinician. Sequences with better lesion conspicuity resulted in the highest CCC values. For example, DWI and hepatobiliary phase sequences produced some of the highest values for signal intensity ratio and contrast-to-noise ratio, and these sequences also produced some of the highest values for CCC. This relationship correlated with reader experience, that is, the improvement in interobserver agreement using sequences with higher signal intensity ratio and contrast-to-noise ratio was more dramatic comparing clinician measurements to radiologists. It is possible the added experience of radiologists with MRI can compensate for the more subtle appearance of lesions with lower conspicuity and still maintain high CCC values. In clinical practice, lesion measurements are sometimes made by nonradiologists, although there is little in the literature to support this practice. There is also little data in the literature regarding the interobserver agreement of RECIST measurements with regard to abdomen MRI. It is reassuring that our data show that lesions can be measured by MRI with high-interobserver agreement, and that radiologist/clinician measurements also showed fairly uniform high-interobserver agreement. There are limitations to our study, most notably our small sample size. It was difficult to identify patients who underwent a change in MRI contrast agents without change in therapy or disease status. When these patients were identified, their MRI examinations had to be free of artifacts and display lesions, which could be measured in a reliable fashion. These criteria limited the number of patients and lesions. However, we wanted to conduct a head-to-head comparison of gadoxetate disodium and a standard contrast agent, and these strict criteria were the closest comparison we could achieve in a retrospective analysis. We obtained highinterobserver agreement of lesion measurements on essentially all sequences. This may not have been the case had we incorporated radiologists without specific training in abdominal imaging and body MRI. Moreover, all radiologists in this study work at a cancer center and are highly skilled and familiar with performing measurements for clinical trials using various protocols, which may not be the case in general practice. Almost all of the metastases measured for this study were from patients already being treated with somatostatin analogs. In general, this type of therapy does not cause dramatic changes in size or enhancement of metastases.17 However, there can be some alteration in enhancement from this therapy, and this may have adversely affected our measurements of lesion conspicuity for the dynamic postcontrast sequences. Our results do reflect what is commonly encountered in clinical practice, that is, most imaging in these patients is performed after therapy to monitor therapy response. Our data supports earlier work proving that T2-weighted and diffusion-weighted sequences perform well for the evaluation of NET hepatic metastases. Most MR examinations will include these sequences but the choice of contrast agent will vary based on indication. Our work shows that hepatobiliary phase sequences depict NET hepatic metastases with lesion conspicuity equal to or better than other sequences and produce measurements with high-interobserver agreement. In addition, there are numerous
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technical advantages to using a contrast agent with hepatobiliary excretion (ability to acquire dynamic and hepatobiliary phase sequences, less rigid timing requirements, less variable appearance of lesions, ability to repeat hepatobiliary phase at multiple time points). This supports the use of an MRI contrast agent with hepatobiliary excretion when imaging NET metastatic to liver. ACKNOWLEDGMENTS The authors wish to thank Jongphil Kim for his work on the statistical analysis for this article. REFERENCES 1. Ganeshan D, Bhosale P, Yang T, et al. Imaging features of carcinoid tumors of the gastrointestinal tract. AJR Am J Roentgenol. 2013;201:773–786. 2. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–3072. 3. Dromain C, de Baere T, Baudin E, et al. MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques. AJR Am J Roentgenol. 2003;180:121–128. 4. d’Assignies G, Fina P, Bruno O, et al. High sensitivity of diffusion-weighted MR imaging for the detection of liver metastases from neuroendocrine tumors: comparison with T2-weighted and dynamic gadolinium-enhanced MR imaging. Radiology. 2013;268:390–399. 5. Galbán CJ, Hoff BA, Chenevert TL, et al. Diffusion MRI in early cancer therapeutic response assessment. NMR Biomed. 2017;30:1–10. 6. Malayeri A, El Khouli R, Zaheer A, et al. Principles and applications of diffusion-weighted imaging in cancer detection, staging, and treatment follow-up. Radiographics. 2011;31:1773–1791. 7. Lambregts DM, Maas M, Stokkel MP, et al. Magnetic resonance imaging and other imaging modalities in diagnostic and tumor response evaluation. Semin Radiat Oncol. 2016;26:193–198. 8. Besa C, Ward S, Cui Y, et al. Neuroendocrine liver metastases: value of apparent diffusion coefficient and enhancement ratios for characterization of histopathologic grade. J Magn Reson Imaging. 2016;44:1432–1441. 9. Wang Y, Chen ZE, Yaghmai V, et al. Diffusion-weighted MR imaging in pancreatic endocrine tumors correlated with histopathologic characteristics. J Magn Reson Imaging. 2011;33:1071–1079. 10. Frydrychowicz A, Lubner MG, Brown JJ, et al. Hepatobiliary MR imaging with gadolinium-based contrast agents. J Magn Reson Imaging. 2012; 35:492–511. 11. Koh DM, Collins DJ, Wallace T, et al. Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI improves the detection of colorectal liver metastases. Br J Radiol. 2012;85:980–989. 12. Motosugi U, Ichikawa T, Sou H, et al. Dilution method of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)enhanced magnetic resonance imaging (MRI). J Magn Reson Imaging. 2009;30:849–854. 13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247. 14. Lin LI. Correction: a note on the concordance correlation coefficient. Biometrics. 2000;56:324–325. 15. Lin LI. A concordance correlation coefficient to evaluate reproducibility. Biometrics. 1989;45:255–268. 16. Seale MK, Catalano OA, Saini S, et al. Hepatobiliary-specific MR contrast agents: role in imaging the liver and biliary tree. Radiographics. 2009; 29:1725–1748. 17. Kim KW, Krajewski KM, Nishino M, et al. Update on the management of gastroenteropancreatic neuroendocrine tumors with emphasis on the role of imaging. AJR Am J Roentgenol. 2013;201:811–824.
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Magnetic Resonance Imaging of Neuroendocrine Tumor Hepatic Metastases Does Hepatobiliary Phase Imaging Improve Lesion Conspicuity and Interobserver Agreement of Lesion Measurements? Brian Morse, MD,* Daniel Jeong, MD,* Kerry Thomas, MD,* Dalanda Diallo, MD,† and Jonathan R. Strosberg, MD‡
Objective: The aim of this study was to determine if magnetic resonance imaging (MRI) performed with hepatobiliary phase imaging results in higher lesion conspicuity and produces lesion measurements with higher interobserver agreement than other MRI sequences when imaging neuroendocrine hepatic metastases. Methods: Patients who had MRIs with both gadoxetate disodium and gadopentetate dimeglumine contrast within a 6-month span were identified, and 23 hepatic lesions were selected. Three radiologists and 1 oncologist measured the greatest diameter of each lesion on the following sequences: T2 weighted, T1 weighted, postcontrast (dynamic, delayed, and hepatobiliary phase), and diffusion weighted. Signal intensity ratio (SIlesion/SIliver) and contrast-to-noise ratio ([SIlesion – SIliver]/noise) were calculated for all lesions on each sequence. The interobserver agreement of measurements on each sequence was calculated using concordance correlation coefficient. Results: Diffusion-weighted sequences had the highest signal intensity ratio ranging from 147% to 187% (vs other sequences range of 19.6%– 130%). One hepatobiliary sequence had the highest contrast-to-noise ratio with a value of 41 (vs other sequences range of 3.2–28.1). Lesion measurements on all sequences showed high-interobserver agreement, with hepatobiliary sequences showing some of the highest levels of agreement. Conclusions: Our results support the use of contrast agents with hepatobiliary excretion when imaging neuroendocrine tumors metastatic to liver. Key Words: neuroendocrine tumors, hepatobiliary phase, magnetic resonance imaging, RECIST (Pancreas 2017;46: 1219–1224)
N
euroendocrine tumors (NET) can originate in almost any organ system of the body and span a pathologic spectrum from indolent tumors to aggressive carcinomas. Approximately 60% to 70% of NET arise from the gastrointestinal tract, most commonly the rectum and small bowel.1 An analysis of Surveillance, Epidemiology, and End Results data of patients with NET spanning from 1973 to 2004 found that 50% of patients
From the *Department of Diagnostic Imaging, Moffitt Cancer Center; †Department of Radiology, University of South Florida; and ‡Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL. Received for publication January 8, 2017; accepted August 11, 2017. Address correspondence to: Brian Morse, MD, Moffitt Cancer Center, WCB-RAD MD/OPI, 12902 USF Magnolia Dr, Tampa, FL 33612 (e‐mail: [email protected]). No financial support was provided for this work. The authors declare no conflict of interest or funding relevant to this work. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MPA.0000000000000920
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have regional or distant metastases at initial diagnosis.2 Sites of metastatic disease vary based on the primary tumor, but the most common site of metastatic disease is the liver.1 Imaging of the liver is, therefore, critical for assessment of disease status. Previous work has shown that certain magnetic resonance imaging (MRI) sequences perform well in the evaluation of hepatic metastases from NET. For example, Dromain et al3 found that T2-weighted and arterial phase postcontrast sequences had the highest contrast-to-noise ratio of lesion versus normal liver and that arterial phase images identified the greatest number of metastases. d’Assignies et al4 found that diffusion-weighted imaging (DWI) sequences had a higher sensitivity than T2weighted or postcontrast sequences for NET hepatic metastases (Fig. 1). The DWI has also been found to be an independent predictor of response to therapy, that is, restricted diffusion decreases with successful therapy response.5–7 Previous work has also shown that DWI characteristics correlate with NET grade and can therefore be prognostic.8,9 Arterial phase images are produced using “dynamic” postcontrast imaging, acquiring multiple sequences in rapid succession after contrast administration, typically with timing to achieve arterial, portal venous, and a later portal venous or interstitial phase. Dynamic imaging is performed routinely for abdomen MRI because lesions in the liver, kidneys, and pancreas can be characterized based on their appearance at multiphase imaging. Standard MR contrast agents remain in the extracellular space and are cleared by the kidneys. There are newer MR contrast agents that are actively transported into hepatocytes and then excreted into the biliary system. These agents are capable of dynamic imaging, similar to a standard MR contrast agent, and they can produce delayed postcontrast images after the contrast is taken up by the hepatocytes, or “hepatobiliary phase” images. Lesions that do not contain functional hepatocytes (such as metastases) do not take up the contrast agent and are depicted with high-contrast relative to normal liver (Fig. 2). Over the past decade, the use of these contrast agents in abdominal imaging has increased, with gadoxetate disodium, which is the agent with hepatobiliary excretion in most widespread use. Although numerous studies have shown the use of gadoxetate disodium results in improved sensitivity for hepatic metastases (primarily studied in colon cancer), there is little data in the literature concerning the value of these agents in evaluation of NET liver metastases.10,11 Based on our institutional experience, we hypothesized that hepatobiliary phase images produced with gadoxetate disodium would achieve higher levels of lesion conspicuity compared with other MR sequences or postcontrast images obtained with a contrast agent, which lacks hepatobiliary excretion. Signal intensity ratio and contrast-to-noise ratio were used in this study to quantify lesion conspicuity. www.pancreasjournal.com
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FIGURE 1. A, Arterial phase dynamic postcontrast image. B, T2-weighted image. C, Diffusion-weighted image (b-value, 50). Magnetic resonance images of a typical hepatic metastasis (indicated by arrow) from neuroendocrine tumor (small bowel carcinoid in this example). The high contrast of lesion to liver achieved by these sequences is obvious in this example.
Tumor measurement accuracy is critical for assessment of progression and therapeutic response, particularly in protocols using Response Evaluation Criteria in Solid Tumors (RECIST). Ideally, tumors should be measured on sequences that minimize variability among different observers. We hypothesized that the higher lesion conspicuity achieved with hepatobiliary phase images would translate into higher interobserver agreement of lesion measurements. For this study, we used the concordance correlation coefficient (CCC) to quantify interobserver agreement of tumor measurements. We included a clinician observer in our study to determine if hepatobiliary phase images
produced higher interobserver agreement between radiologist and nonradiologist measurements.
MATERIALS AND METHODS This Health Insurance Portability and Accountability Act compliant, retrospective, chart review study was reviewed and approved by the local institutional review board. The radiology picture archiving communication system (Merge Radsuite v 8.30.7.385; Merge Healthcare, Chicago, Ill) was used to find patients with MRIs using gadoxetate disodium contrast ordered by the neuroendocrine tumor
FIGURE 2. A, Arterial phase postcontrast image. B, Portal venous phase postcontrast image. C, Late portal venous phase postcontrast image. D, Five-minute delayed postcontrast image with standard contrast agent. E, Hepatobiliary phase image with gadoxetate disodium. These are images of a small bowel carcinoid metastasis to the liver (indicated by arrow). Images A through C show dynamic postcontrast images of the lesion. This is a typical enhancement pattern for a NET metastasis, hyperenhancing to liver on arterial phase images with less enhancement (or wash-out) relative to normal liver on more delayed postcontrast images. Delayed postcontrast images obtained with a standard contrast agent (D) show the lesion enhances less than normal liver and is somewhat ill defined. Gadoxetate disodium allows acquisition of hepatobiliary phase images (E), which depict the lesion with high conspicuity.
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Pancreas • Volume 46, Number 9, October 2017
section at our hospital between September 2008 and September 2013. Those cases were reviewed to identify patients who also had previous abdomen MRIs performed within 6 months using gadopentetate dimeglumine contrast. Those MRIs were reviewed by the senior radiologist to determine if suitable target lesions were present. Target lesions had to measure at least 1 cm in diameter (as per RECIST guidelines) and be visualized on all sequences. Using these criteria, a total of 7 patients (5 male and 2 female; mean age, 58 years) with 23 suitable lesions were identified. The primary tumors consisted of 5 NET of distal small bowel, 1 gastric NET, and 1 pancreatic NET. All but one of the patients were on therapy with somatostatin analogs. The patients receiving somatostatin analogs were on therapy before acquisition of the initial MRI, and there was no change in therapy between MRIs. All cases had biopsyproven hepatic metastases. Four were biopsied using ultrasound guidance, and 3 had liver biopsies performed during surgery to remove the primary tumor. The MR imaging was performed using a 1.5-T MRI scanner using a standard 8-channel body coil (Siemens Medical Solutions, Erlangen, Germany). Sequences used in this study were acquired in the axial plane. The following MR sequences were acquired (TR = repetition time, TE = echo time, slice thickness of 6 mm unless otherwise noted): T2 weighted (TR, 1000; TE, 184), T1-weighted gradient echo, in and out of phase (TR, 155; TE, 4.48 and 2.17), fat-suppressed and T2-weighted sequence (TR, 3500; TE, 103), precontrast and postcontrast fat-suppressed T1-weighted sequence (TR, 4.3; TE, 1.83; slice thickness, 3 mm), and diffusion-weighted sequence (TR, 9500; TE, 88, b-values 50, 500, 800 s/mm2). Gadopentetate dimeglumine (Magnevist) (Bayer HealthCare, Whippany, NJ) (0.1 mmol/kg) was used for the “standard” contrast agent, and gadoxetate disodium (Eovist) (Bayer HealthCare, Whippany, NJ) (0.025 mmol/kg) was used as the contrast agent with hepatobiliary excretion. Postcontrast sequences consisted of dynamic postcontrast image acquisition (for both gadopentetate dimeglumine and gadoxetate disodium), 5-minute delayed postcontrast images (gadopentetate dimeglumine only), and 20-minute delayed postcontrast hepatobiliary phase images (gadoxetate disodium only). The first dynamic sequence (Dynamic 1) was timed to produce arterial phase images, with subsequent dynamic sequences (Dynamic 2 + 3) timed to produce early and late portal venous phase images. When using gadoxetate disodium, contrast dose was calculated using the patient's weight and contrast diluted with saline to a total volume of 20 mL. The dilution was used to combat motion artifact, which can be seen with dynamic postcontrast sequence acquisition using gadoxetate disodium.12 Two hepatobiliary phase sequences were acquired (denoted hepatobiliary 1 and hepatobiliary 2). The only difference between these 2 sequences was that hepatobiliary 2 had a slice thickness of 6 mm rather than 3 mm. Patients with examination results that met our inclusion criteria were reviewed by the senior radiologist to ensure that all sequences were free of significant artifact, and that potential target lesions were visible on all sequences. If these conditions were met, the senior radiologist selected target lesions and made a set of images of each target lesion on all sequences. Those images were placed into a folder on the picture archiving communication system for review by observers. If more than one lesion was present on the image, the lesion of interest was indicated with an arrow on the first sequence. Observers were instructed to view the image in a one-image per monitor screen layout and measure the longest diameter of the lesion (following RECIST guidelines).13 Observers were instructed to measure the maximum axial diameter of the lesion on every sequence and record their measurement on a worksheet. The signal intensity of the lesion, normal liver, and noise were made for every lesion on every sequence. The signal © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Hepatobiliary Phase Imaging of NET Metastases
intensity of the lesion was calculated by drawing a circular region of interest (ROI) on the lesion to encompass the maximum amount of lesion possible without suffering from volume averaging (aiming to encompass at least 75% of lesion bulk). The signal intensity of liver was made with an ROI comparable with the lesion ROI at a comparable vertical distance. The ROI for noise was measured outside the anterior abdominal wall. Signal intensity ratio was calculated using the following formula: (Signal Intensity Lesion)/(Signal Intensity Liver). The intensity of the lesion relative to the liver varied on each sequence. On some sequences, the lesion was hypointense relative to liver, and on others, the lesion was hyperintense. For the purposes of this project, the conspicuity of the lesion is of interest, so the signal intensity ratio is reported as percent change from liver parenchyma, not an absolute value. The contrast-to-noise ratio was calculated by the following formula: [(Signal Intensity Lesion)/ (Signal Intensity Liver)]/noise. All radiologist observers in this study had fellowship training in abdominal imaging. They consisted of 2 junior radiologists with a 2-year postfellowship experience and 1 senior radiologist with a 6-year postfellowship experience. The clinician observer is a medical oncologist who specializes in the treatment of NET. The agreement between subjects was evaluated by the CCC (SPSS v 20.0, IBM, Armonk, NY) by Lin.14,15 No multiplicity adjustment was considered. The CCC was calculated for each sequence and between each pair of junior radiologists, senior radiologist, and medical oncologist.
RESULTS Table 1 shows the signal intensity ratios of lesion to liver by sequence, and Table 2 shows contrast-to-noise ratio of lesion to liver by sequence. Diffusion weighted images outperformed other sequences with regard to signal intensity ratio. Signal intensity ratio of the hepatobiliary phase sequence was similar to arterialphase dynamic postcontrast and slightly less than T2-weighted sequences. The data for contrast-to-noise ratio showed that hepatobiliary phase and T2-weighted sequences outperformed other sequences. Hepatobiliary 2 had a larger slice thickness than hepatobiliary 1 (6 vs 3 mm). This explains the higher contrastto-noise ratio achieved with hepatobiliary phase 2 because the lower spatial resolution results in higher signal. Only the TABLE 1. Signal Intensity Ratio by Sequence Sequence DWI b 500 DWI b 50 DWI b 800 T2, fat-suppressed T2 T1 out-of-phase Dynamic 1 gadopentetate dimeglumine Hepatobiliary 1 Dynamic 1 gadoxetate disodium Hepatobiliary 2 T1, fat-suppressed Dynamic 3 gadoxetate disodium Dynamic 2 gadoxetate disodium Dynamic 2 gadopentetate dimeglumine Delayed gadopentetate dimeglumine T1 in-phase Dynamic 3 gadopentetate dimeglumine
Range, %
Average, %
34–380 20–470 12–370 30–410 10–440 10–230 28–220 10–130 10–100 10–50 16–120 5–50 3–90 12–80 12–70 5–40 15–70
187.1 184.2 147.1 130 103.3 51.7 48.3 46.3 40.4 37.9 30 23.8 23.3 22.1 21.3 20.8 19.6
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TABLE 2. Contrast-to-Noise Ratio by Sequence Sequence Hepatobiliary 2 T2, fat-suppressed Hepatobiliary 1 T2 T1 out-of-phase Dynamic 1 gadopentetate dimeglumine Dynamic 1 gadoxetate disodium Dynamic 3 gadoxetate disodium Dynamic 2 gadopentetate dimeglumine Dynamic 3 gadopentetate dimeglumine T1 in-phase T1, fat-suppressed Dynamic 2 gadoxetate disodium Delayed gadopentetate dimeglumine DWI b 50 DWI b 500 DWI b 800
Range
Average
10–77.3 7.4–97.5 5.3–53.7 1–106 1.2–66.5 6.3–57.3 1.8–28 0.3–39.2 3.1–45.7 4.5–47.2 1–49.5 0.4–22 0.7–21.7 4.3–14.5 0.5–21 0.5–11.5 0.3–10.5
41 28.1 24.1 20 17.3 14.2 10.7 10.6 10.5 10.5 9.9 7.3 7.1 6.6 6.5 4.6 3.2
hepatobiliary sequence with larger slice thickness significantly outperformed T2-weighted sequences. The DWI performed poorly with regards to contrast-to-noise ratio, but this is secondary to the larger noise relative to signal seen with DWI. The results for interobserver agreement show that the CCC of measurements was high for all sequences among radiologists (Table 3). The highest interobserver agreement among junior radiologists was obtained with the T2-weighted, fat-suppressed sequence. This was also true for junior versus senior radiologists (although this sequence tied with third dynamic phase using gadoxetate disodium). In general, the CCC data show that interobserver agreement does parallel lesion conspicuity, that is, lesions with the highest signal intensity ratio and contrast-tonoise ratio in general have higher values for CCC. Similar findings of interobserver agreement are observed when comparing the measurements of radiologists versus the clinician (Table 4). The
sequences with the highest lesion conspicuity produced the highest CCCs with DWI and hepatobiliary phase sequences resulting in the highest levels of interobserver agreement. Of note, there were several lesions (5 lesions on second gadopentetate dimeglumine dynamic postcontrast sequence, 3 lesions on third gadopentetate dimeglumine dynamic postcontrast sequence, 2 lesions on first gadoxetate disodium dynamic postcontrast sequence, 2 lesions on T2-weighted, and 2 lesions on T1-out-of-phase sequences), which the clinician could not visualize well enough to measure. All of these lesions were deemed to be visible and measureable by radiologist observers. A zero value was recorded for these lesions for the clinician.
DISCUSSION The evaluation of patients with NET relies heavily on crosssectional imaging. Of paramount importance in this evaluation is adequate contrast between lesion and normal liver. Our study is the first attempt to quantify lesion conspicuity of NET hepatic metastases using a contrast agent with hepatobiliary excretion. Previous work has shown the superiority of T2-weighted, arterial phase postcontrast, and DWI sequences for the evaluation of hepatic metastases from NET.3,4 We hypothesized that hepatobiliary phase sequences would outperform other sequences with regard to lesion conspicuity, and this was partially true. Hepatobiliary phase sequences had the highest contrast-to-noise ratio, and the signal intensity ratio was only slightly lower than DWI and T2weighted sequences (signal intensity ratio was comparable for arterial phase images). This is important because while DWI and T2-weighted images are part of most modern MR protocols, the choice of contrast agent (ie, whether to use a contrast agent with hepatobiliary excretion) will vary based on examination indication. When using a contrast agent without hepatobiliary excretion, one must rely on only dynamic and delayed postcontrast sequences. Our data shows that hepatobiliary phase sequences outperform these sequences with regard to lesion conspicuity. This makes sense, because while NET liver metastases should show the greatest enhancement on arterial phase images, this is not true in practice. Neuroendocrine tumors are a heterogeneous group of tumors, and not all NET liver metastases show arterial phase hyperenhancement, which helps explain the variable lesion conspicuity seen with dynamic postcontrast images in this study.3 In
TABLE 3. Interobserver Agreement by Sequence Among Radiologists Sequences T2, fat-suppressed Dynamic 1 gadoxetate disodium Hepatobiliary 2 DWI b 800 DWI b 500 T2 Dynamic 3 gadoxetate disodium Dynamic 3 gadopentetate dimeglumine DWI b 50 Hepatobiliary 1 Dynamic 2 gadoxetate disodium Dynamic 1 gadopentetate dimeglumine T1, fat-suppressed T1 out-of-phase T1 in-phase Dynamic 2 gadopentetate dimeglumine
CCC Jr Rad 1 vs Jr Rad 2
Sequences
CCC Jr Rads vs Sr Rad
0.97 0.959 0.951 0.95 0.947 0.946 0.944 0.943 0.935 0.934 0.929 0.928 0.928 0.923 0.896 0.862
T2, fat-suppressed Dynamic 3 gadoxetate disodium Dynamic 1 gadoxetate disodium Hepatobiliary 1 DWI b 500 Dynamic 3 gadopentetate dimeglumine T2 Hepatobiliary 2 DWI b 800 T1 out-of-phase DWI b 50 Dynamic 2 gadoxetate disodium Dynamic 1 gadopentetate dimeglumine T1 in-phase T1, fat-suppressed Dynamic 2 gadopentetate dimeglumine
0.981 0.981 0.979 0.977 0.976 0.975 0.973 0.972 0.971 0.969 0.967 0.965 0.964 0.956 0.956 0.939
Jr Rad indicates junior radiologist; Sr Rad, senior radiologist.
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Hepatobiliary Phase Imaging of NET Metastases
TABLE 4. Interobserver Agreement by Sequence Radiologists Versus Clinician Sequences
CCC Jr Rads vs Clinician
Sequences
CCC Sr Rad vs Clinician
0.976 0.968 0.968 0.967 0.964 0.961 0.936 0.909 0.899 0.890 0.884 0.876 0.866 0.846 0.823 0.710
DWI b 500 Dynamic 1 gadopentetate dimeglumine Hepatobiliary 1 Hepatobiliary 2 DWI b 50 T1 in-phase DWI b 800 Dynamic 3 gadoxetate disodium T1 out-of-phase T2, fat-suppressed Dynamic 2 gadoxetate disodium Dynamic 3 gadopentetate dimeglumine Dynamic 1 gadoxetate disodium T2 T1, fat-suppressed Dynamic 2 gadopentetate dimeglumine
0.983 0.98 0.979 0.977 0.97 0.968 0.951 0.914 0.897 0.892 0.89 0.886 0.878 0.842 0.8 0.708
DWI b 500 Hepatobiliary 2 Hepatobiliary 1 Dynamic 1 gadopentetate dimeglumine DWI b 50 T1 in-phase DWI b 800 Dynamic 3 gadoxetate disodium Dynamic 1 gadoxetate disodium Dynamic 2 gadoxetate disodium T1 out-of-phase T2, fat-suppressed T1, fat-suppressed Dynamic 3 gadopentetate dimeglumine T2 Dynamic 2 gadopentetate dimeglumine
Jr Rad indicates junior radiologist; Sr Rad, senior radiologist.
contrast, all NET liver metastases show hypoenhancement relative to liver on hepatobiliary phase images (Fig. 3). Contrast agents with hepatobiliary excretion are also capable of dynamic imaging
(ie, acquisition of arterial and portal venous phase images), so it makes sense to use these agents when imaging NET liver metastases. Another advantage of these agents is that hepatobiliary
FIGURE 3. A, Arterial phase postcontrast image. B, Late portal venous phase postcontrast image. C, Hepatobiliary phase image with gadoxetate disodium. This MRI shows 2 metastases to the liver from small bowel carcinoid (indicated by arrows). The lesions do not show the “classic” appearance of bright, homogenous enhancement on arterial phase images. One lesion is difficult to detect at all on the dynamic postcontrast images. All NET metastases will enhance less than normal liver on hepatobiliary phase images because they do not contain functioning hepatocytes.
FIGURE 4. A, Arterial phase postcontrast image affected by motion artifact. B, Hepatobiliary phase image with gadoxetate disodium. This is a hepatic metastasis from a pancreatic NET (indicated by arrow). The arterial phase image is degraded by motion artifact. The lesion is detected but accurate measurement would be difficult. The dynamic images cannot be repeated without administering another contrast bolus. Timing is not such a crucial consideration with hepatobiliary phase using gadoxetate disodium. After waiting for the hepatocytes to take up the contrast (10–20 minutes), the sequence can be acquired as many times as needed to ensure images are free of motion artifact. © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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phase sequences can be acquired at multiple time points after contrast administration without sacrificing their efficacy16 (Fig. 4). If dynamic images are ruined by motion artifact or poor timing, they cannot be repeated unless you administer another contrast bolus. We hypothesized that hepatobiliary phase sequences would result in interobserver agreement of lesion measurements that was higher than other sequences. Our results showed highinterobserver agreement for all sequences (almost all exceeding 0.9), so stratification of these results is difficult. However, the hepatobiliary phase sequences were among the sequences with the highest CCC values, whether comparing radiologists or radiologists versus clinician. Sequences with better lesion conspicuity resulted in the highest CCC values. For example, DWI and hepatobiliary phase sequences produced some of the highest values for signal intensity ratio and contrast-to-noise ratio, and these sequences also produced some of the highest values for CCC. This relationship correlated with reader experience, that is, the improvement in interobserver agreement using sequences with higher signal intensity ratio and contrast-to-noise ratio was more dramatic comparing clinician measurements to radiologists. It is possible the added experience of radiologists with MRI can compensate for the more subtle appearance of lesions with lower conspicuity and still maintain high CCC values. In clinical practice, lesion measurements are sometimes made by nonradiologists, although there is little in the literature to support this practice. There is also little data in the literature regarding the interobserver agreement of RECIST measurements with regard to abdomen MRI. It is reassuring that our data show that lesions can be measured by MRI with high-interobserver agreement, and that radiologist/clinician measurements also showed fairly uniform high-interobserver agreement. There are limitations to our study, most notably our small sample size. It was difficult to identify patients who underwent a change in MRI contrast agents without change in therapy or disease status. When these patients were identified, their MRI examinations had to be free of artifacts and display lesions, which could be measured in a reliable fashion. These criteria limited the number of patients and lesions. However, we wanted to conduct a head-to-head comparison of gadoxetate disodium and a standard contrast agent, and these strict criteria were the closest comparison we could achieve in a retrospective analysis. We obtained highinterobserver agreement of lesion measurements on essentially all sequences. This may not have been the case had we incorporated radiologists without specific training in abdominal imaging and body MRI. Moreover, all radiologists in this study work at a cancer center and are highly skilled and familiar with performing measurements for clinical trials using various protocols, which may not be the case in general practice. Almost all of the metastases measured for this study were from patients already being treated with somatostatin analogs. In general, this type of therapy does not cause dramatic changes in size or enhancement of metastases.17 However, there can be some alteration in enhancement from this therapy, and this may have adversely affected our measurements of lesion conspicuity for the dynamic postcontrast sequences. Our results do reflect what is commonly encountered in clinical practice, that is, most imaging in these patients is performed after therapy to monitor therapy response. Our data supports earlier work proving that T2-weighted and diffusion-weighted sequences perform well for the evaluation of NET hepatic metastases. Most MR examinations will include these sequences but the choice of contrast agent will vary based on indication. Our work shows that hepatobiliary phase sequences depict NET hepatic metastases with lesion conspicuity equal to or better than other sequences and produce measurements with high-interobserver agreement. In addition, there are numerous
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technical advantages to using a contrast agent with hepatobiliary excretion (ability to acquire dynamic and hepatobiliary phase sequences, less rigid timing requirements, less variable appearance of lesions, ability to repeat hepatobiliary phase at multiple time points). This supports the use of an MRI contrast agent with hepatobiliary excretion when imaging NET metastatic to liver. ACKNOWLEDGMENTS The authors wish to thank Jongphil Kim for his work on the statistical analysis for this article. REFERENCES 1. Ganeshan D, Bhosale P, Yang T, et al. Imaging features of carcinoid tumors of the gastrointestinal tract. AJR Am J Roentgenol. 2013;201:773–786. 2. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–3072. 3. Dromain C, de Baere T, Baudin E, et al. MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques. AJR Am J Roentgenol. 2003;180:121–128. 4. d’Assignies G, Fina P, Bruno O, et al. High sensitivity of diffusion-weighted MR imaging for the detection of liver metastases from neuroendocrine tumors: comparison with T2-weighted and dynamic gadolinium-enhanced MR imaging. Radiology. 2013;268:390–399. 5. Galbán CJ, Hoff BA, Chenevert TL, et al. Diffusion MRI in early cancer therapeutic response assessment. NMR Biomed. 2017;30:1–10. 6. Malayeri A, El Khouli R, Zaheer A, et al. Principles and applications of diffusion-weighted imaging in cancer detection, staging, and treatment follow-up. Radiographics. 2011;31:1773–1791. 7. Lambregts DM, Maas M, Stokkel MP, et al. Magnetic resonance imaging and other imaging modalities in diagnostic and tumor response evaluation. Semin Radiat Oncol. 2016;26:193–198. 8. Besa C, Ward S, Cui Y, et al. Neuroendocrine liver metastases: value of apparent diffusion coefficient and enhancement ratios for characterization of histopathologic grade. J Magn Reson Imaging. 2016;44:1432–1441. 9. Wang Y, Chen ZE, Yaghmai V, et al. Diffusion-weighted MR imaging in pancreatic endocrine tumors correlated with histopathologic characteristics. J Magn Reson Imaging. 2011;33:1071–1079. 10. Frydrychowicz A, Lubner MG, Brown JJ, et al. Hepatobiliary MR imaging with gadolinium-based contrast agents. J Magn Reson Imaging. 2012; 35:492–511. 11. Koh DM, Collins DJ, Wallace T, et al. Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI improves the detection of colorectal liver metastases. Br J Radiol. 2012;85:980–989. 12. Motosugi U, Ichikawa T, Sou H, et al. Dilution method of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)enhanced magnetic resonance imaging (MRI). J Magn Reson Imaging. 2009;30:849–854. 13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247. 14. Lin LI. Correction: a note on the concordance correlation coefficient. Biometrics. 2000;56:324–325. 15. Lin LI. A concordance correlation coefficient to evaluate reproducibility. Biometrics. 1989;45:255–268. 16. Seale MK, Catalano OA, Saini S, et al. Hepatobiliary-specific MR contrast agents: role in imaging the liver and biliary tree. Radiographics. 2009; 29:1725–1748. 17. Kim KW, Krajewski KM, Nishino M, et al. Update on the management of gastroenteropancreatic neuroendocrine tumors with emphasis on the role of imaging. AJR Am J Roentgenol. 2013;201:811–824.
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