The added diagnostic value of complementary gadoxetic acid-enhanced MRI to 18F-DOPA-PET/CT for liver staging in medullary thyroid carcinoma

Background A high proportion of patients with advanced stages of medullary thyroid carcinoma (MTC) present with liver metastasis metastases. The aim of our study was to investigate the added diagnostic value of complementary gadoxetic acid-enhanced MRI to 18F-DOPA-PET/CT for liver staging in MTC. Methods Thirty-six patients (14 female, median age 55 years) with histologically confirmed MTC undergoing gadoxetic acid-enhanced liver MRI within 1 month of matching contrast-enhanced 18F-DOPA-PET/CT between 2010 and 2016 were selected for this IRB-approved retrospective study. 18F-DOPA-PET/CT and multiparametric MRI data sets were read consecutively and liver lesions were categorised on a 5-point Likert scale (1–definitely benign; 2–probably benign; 3–intermediate risk for metastasis; 4–probably metastasis; 5–definitely metastasis). It was noted if gadoxetic acid-enhanced MRI detected additional, 18F-DOPA-PET/CT-occult metastases (category 5) or if gadoxetic acid-enhanced MRI allowed for a definite classification (categories 1 and 5) of lesions for which 18F-DOPA-PET/CT remained inconclusive (categories 2–4). Follow-up PET/CT and MRI examinations were used as a reference standard. Results A total of 207 liver lesions (18F-DOPA-PET/CT 149, MRI 207; 152 metastases, 37 benign cysts, 18 hemangiomas) were analysed. Fifty-eight additional lesions were detected by MRI, of which 54 were metastases (median diameter 0.5 cm [interquartile range 0.4–0.7 cm]) occult on 18F-DOPA-PET/CT. MRI allowed for a definite lesion classification (categories 1 and 5) in 92% (190/207) whereas 18F-DOPA-PET/CT allowed for a definite lesion classification in 76% (113/149). MRI lead to a change in lesion categorisation in 14% (21/149). Conclusion Gadoxetic acid-enhanced MRI allows for a more precise liver staging in MTC patients compared to 18F-DOPA-PET/CT alone, particularly for 18F-DOPA-negative metastases and lesions < 1 cm.


Key points
Combining gadoxetic acid-enhanced MRI and 18 F-DOPA-PET/CT optimises liver staging in MTC patients. Gadoxetic acid-enhanced MRI is particularly helpful for the detection and characterisation of small (< 1 cm) liver lesions.

Background
Medullary thyroid carcinoma (MTC) accounts for 1-2% of all thyroid malignancies and causes up to 13% of all thyroid disease-related deaths [1,2]. Sporadic occurrence encompasses 75% of all MTC cases while the remaining 25% are associated with hereditary tumour syndromes (e.g., multiple endocrine neoplasia (MEN) 2A and 2B). MTC-related lethality is mostly due to distant metastases and the median 10-year survival upon advanced stages of the disease is reported to be 10% [3,4]. 13 to 15% of patients present with distant metastases at the time of diagnosis [5]. Medullary thyroid carcinoma is a malignant neuroendocrine tumour with the capability to take up amine precursors, such as dopamine, for decarboxylation (Amine Precursor Uptake and Decarboxylation system), thereby allowing the use of 18 F-DOPA as a radiotracer for the detection of metastases. Particularly 18 F-DOPA-PET/CT has been recognized as a highly sensitive and specific imaging modality for the detection of metastatic MTC [6][7][8][9][10].
The liver is the most frequently affected organ, with liver metastases in 45% of patients with advanced MTC [1]. However, liver staging in MTC remains challenging, as small metastases may remain 18 F-DOPA-negative. A timely and comprehensive liver staging is of major importance to evaluate potential treatment options with a growing oncological toolbox including local ablative treatment, surgical, or systemic therapy [11][12][13][14][15][16][17][18][19]. Recent studies have shown that contrast-enhanced liver magnetic resonance imaging (MRI) is best suited for the detection of malignant liver lesions, particularly small metastases < 1.0 cm [20][21][22][23][24]. Gadoxetic acid is a contrast medium which specifically distributes into hepatocytes and the biliary tract system in a late, hepatobiliary phase. This allows for a differentiation of hepatocytes from neoplastic cells, which do not show a gadoxetic acid storage, thereby rendering gadoxetic acid a valuable contrast agent in patients with suspected hepatocellular carcinoma [25][26][27] or suspected liver metastases [28][29][30]. However, the value of contrast-enhanced liver MRI in patients with metastatic MTC was not yet investigated and the current guidelines do not recommend gadoxetic acid-enhanced MRI as routine liver staging in MTC. Therefore, the aim of the present study was to investigate the added diagnostic value of complementary gadoxetic acid-enhanced liver MRI to 18 F-DOPA-PET/ CT for liver staging in MTC.
We hypothesised that gadoxetic acid-enhanced liver MRI (a) provides a higher liver metastasis detection rate than 18 F-DOPA-PET/CT, and (b) allows for a definite liver lesion classification when 18 F-DOPA-PET/CT remains inconclusive in patients with histologically confirmed MTC.

Methods
This retrospective study was approved by the Institutional Review Board and the requirement for informed consent was waived. Written informed consent for the diagnostic 18 F-DOPA PET/CT scan and the contrastenhanced MRI scan was obtained from all patients prior to the examination.

Study population
Patients with histologically confirmed MTC who underwent gadoxetic acid-enhanced liver MRI and 18 F-DOPA-PET/CT for whole-body tumour staging within 30 days between 2010 and 2016 were included in the analysis. Detailed inclusion and exclusion criteria are provided in Table 1, (Fig. 1) visualises the process of patient selection.  Table 2.

Blinded reading
First, two blinded radiologists (C. C. C. and P. M. K., 10 and 6 years of experience in oncological whole-body imaging and MRI reading; C. C. C. is additionally certified in diagnostic nuclear medicine) independently evaluated the co-registered contrast-enhanced CT and PET datasets side by side on a clinical workstation using dedicated image postprocessing software (syngo.via; Siemens Healthineers). Second, the readers analysed the liver MRI datasets on a clinical workstation (first reading: comprehensive, multi-sequence MRI protocol including all sequences; second reading: DWI). For each modality, any detectable liver lesions were systematically classified on a 5-point Likert scale applying the following lesion classification: 1definitely benign; 2probably benign; 3intermediate risk for malignancy; 4probably malignant; 5definitely malignant.
The following malignancy criteria were applied: 1. 18 F-DOPA-avidity 2. Hyperenhancement on multiphasic MRI 3. Hyperenhancement on 18 F-DOPA-PET/CT 4. MRI: Wash-out on the late dynamic phase 5. MRI: Presence of a capsule or pseudocapsule 6. Restricted diffusion as supporting co-feature [28,31] Target parameters were a change in lesion category based on gadoxetic acid-enhanced MRI and the detection of 18 F-DOPA PET/CT-occult metastases. A consensus reading was performed in case of divergent results. Combined 18 F-DOPA-PET/CT and MRI follow-up scans were used as reference standard.

Clinical data analysis
The following clinical parameters were documented for each patient: age and sex, presence of hereditary tumour  Table 3 shows the patient characteristics for patients included in the retrospective analysis.

Statistical analysis
The statistical analysis was performed using SPSS 21 for Windows (IBM Corp.). The Wilcoxon signed-rank test for related groups was used to detect differences in the number of detected lesions or in lesion categorisation between 18 F-DOPA PET/CT scans and gadoxetic acid-enhanced MRI scans. Statistical significance was assumed for p-values < 0.05.

Results
In total, 207 liver lesions were detected and classified in 36 patients. The number of lesions detected with 18 F-DOPA-PET/CT and gadoxetic acid-enhanced MRI is shown in Table 4. 18  All lesions could be characterized as benign (category 1 or 2) or malignant (category 4 or 5). Differences between the number of detected lesions with 18 F-DOPA-PET/CT and gadoxetic acid-enhanced MRI can be seen in (Fig. 2). MRI detected significantly more lesions than 18    provided added diagnostic value. MRI detected significantly more category 5 lesions than 18 F-DOPA-PET/CT (p < 0.001) (Fig. 6).
On MRI, no definite lesion characterisation (categories 2-4) was rare (8% of all lesions, 17/207) whereas 18 F-DOPA-PET/CT did not allow for a definite lesion categorisation in 36 lesions (24% of all lesions detected by 18 F-DOPA-PET/CT, 36/149). Changes in lesion categorisation based on the MRI scan can be obtained from Table 4. Of note, all liver metastases could successfully be diagnosed using the multiphase contrast-enhanced sequences, the T2-weighted sequences, and the DWI. The hepatobiliary phase did not lead to the detection of additional metastases but added significantly to the level of confidence in lesion characterisation.
Of note, one patient in the investigated cohort did not show any metastatic lesions on 18 F-DOPA-PET/CT but one metastasis (category 5 lesion) on multiparametric liver MRI. Of the 152 metastases detected on multiparametric MRI, 84 (55% of all detected metastases) demonstrated a diffusion restriction. However, a significant proportion (56/152, 37%) of the detected metastases demonstrated a brisk arterial rim enhancement and a cystic centre, resulting in T2-shine through (Fig. 7). ADC quantification was possible for 28 lesions with a

Discussion
In the present study, we investigated the added diagnostic value of gadoxetic acid-enhanced MRI to 18 F-DOPA-PET/CT for liver staging in patients with MTC. Complementary gadoxetic acid-enhanced MRI allowed for the detection of significantly more lesions compared to 18 F-DOPA-PET/CT alone. In addition, liver lesion categorisation as benign or malignant was more conclusive at a significantly higher frequency, especially for small lesions with a diameter < 1 cm.
Our results are supported by a study that investigated ultrasound, CT, whole-body and liver MRI, and 18 F-FDG-PET/CT for the detection of tumour recurrence and metastases in MTC patients with elevated serum calcitonin levels after initial treatment [32]. They found MRI to detect more liver metastases than the other imaging modalities, with MRI being the only modality to detect very small metastases (millimeter range) in two patients. The combination of MRI and CT detected significantly more metastases than 18 F-FDG-PET/CT. However, the authors do not detail on the type of intravenous contrast agent and the comprehensive liver MRI protocol did not include DWI sequences. Our study extends the literature as it provides evidence for the use of multi-phase liver MRI with an intravenous, hepatobiliary contrast agent for liver staging in MTC including a late, hepatobiliary phase and diffusion-weighted images for the detection of liver metastases and for appropriate characterisation of liver lesions.
In line with our results, previous studies have shown a significant benefit of multi-phase contrast enhanced MRI for the detection of metastatic liver disease. In a head-to-head comparison of somatostatin receptor scintigraphy, multi-phase CT, and MRI in patients with neuroendocrine tumours for liver staging, MRI with intravenous Gd-DOTA administration allowed for the detection of significantly more metastases than CT and scintigraphy [33]. In addition, it was shown, that for the detection of liver metastases in patients with neuroendocrine tumours, the use of liver MRI using hepatobiliary contrast agent gadoxetic acid yields significant additional diagnostic value to nuclear imaging techniques [22]. Recent studies have also demonstrated that gadoxetic acid-enhanced MRI is superior for the detection of liver metastases to MRI with non-specific contrast agent or CT with contrast enhancement [29,34]. In our cohort, DWI was an important co-feature for metastasis detection and characterisation. However, a significant proportion of MTC liver metastases showed a brisk arterial rim enhancement and a cystic centre, resulting in T2-shine through. As a consequence, our results suggest that DWI alone is not sufficient for liver metastasis detection and characterisation in MTC. Therefore, MTC liver staging should be performed based on all sequences of the comprehensive liver MRI protocol.
In our institution, 18 F-DOPA-PET/CT is performed for whole-body tumour staging in MTC since numerous studies demonstrated superiority to 18 F-FDG hybrid imaging [6,[8][9][10]35]. The detection of liver metastases in MTC patients, however, is difficult due to the typically small size with correspondingly low 18 F-DOPA uptake or size below the spatial resolution of PET imaging. Taken together, there is no existing consensus on imaging modalities for liver staging in patients with MTC. Our results strongly suggest that hepatobiliary contrast-enhanced liver MRI should be performed as routine part of whole-body tumour staging protocols in MTC. The hepatobiliary phase enabled by the use of the hepatocyte-specific contrast agent added significantly to the level of confidence in lesion characterisation. Future studies should further investigate the impact of multiphase liver MRI on clinical patient management, with regard to the various treatment options for metastatic liver disease as well as clinical endpoints such as progression-free and overall patient survival. Even in patients with multifocal liver metastases, the exact number and localisation of individual metastases may play a major role for therapy guidance, for instance to determine resectablility or eligibility for locoregional treatment options.
We acknowledge several limitations of the study. First, MRI was performed on two different 1.5 Tesla MRI scanners. Although imaging protocols were standardised, slight differences in image acquisition with potential impact on image reading cannot be fully excluded. Second, 18 F-DOPA-PET/CT and gadoxetic acid enhanced MRI were performed within 30 days. Despite this relatively short interval, it is possible that patients with highly aggressive tumours experienced rapid tumor progression with new liver metastases between the two scans. However, the actual median time interval between gadoxetic acid-enhanced MRI and 18 F-DOPA-PET/CT was 3 days (interquartile range 0-12 days), making short-term tumour progression unlikely. Third, a reading bias may be present since reading of one modality potentially influences the sensitivity of the reader for lesion detection on images of the other modality. To limit this bias, the reading order was randomised. Fourth, follow-up imaging was used as reference standard as no patient from the investigated population underwent liver biopsy. Fifth, the CT part of the 18 F-DOPA-PET/ CT scan was only performed in portal venous phase. Appending an unenhanced, an arterial, and a late dynamic phase may further improve the diagnostic Fig. 7 Lesion detection on contrast enhanced images compared to DWI and ADC maps. a, b T1 GRE fs with arterial and hepatobiliary phase. c, d DWI, b800 and ADC map. Contrast enhanced T1 images show a centrally hypointense lesion (arrow) with a hyperenhancing rim in the arterial phase and no contrast uptake in the hepatobiliary phase, indicating a partially cystic metastasis (a and b). Note the T2-shine through on DWI due to its cystic character (c and d) performance of 18 F-DOPA-PET/CT for the detection of (hypervascular) liver metastases. However, acquisition of additional CT phases increases radiation exposure and potentially requires a higher injection volume of iodinated contrast agent, which limits the applicability especially in young patients and chronic kidney disease.

Conclusion
Gadoxetic acid-enhanced liver MRI significantly increases the detection rate for liver metastases in patients with MTC, particularly of small lesions with a diameter < 1 cm. In addition, gadoxetic acid-enhanced MRI allows for a definite lesion categorisation when 18 F-DOPA-PET/CT remains inconclusive, with potential impact on clinical patient management and therapy guidance. Our results provide evidence for the routine use of gadoxetic acid-enhanced MRI as part of comprehensive staging protocols in MTC patients.