Thyroid ultrasound is the gold-standard diagnostic tool to identify thyroid nodules at the highest risk for malignancy. However, it lacks the specificity to accurately detect medullary thyroid carcinoma (MTC), thereby delaying treatment initiation. According to the available data, thyroid ultrasound can identify a malignant lesion in the correct thyroid lobe with a 90% sensitivity, but sensitivity decreases to 71% when localizing a microcarcinoma.
“Unfortunately, current thyroid ultrasound classification criteria are skewed toward classifying papillary thyroid carcinoma rather than MTC due to its rarity,” Leimbach et al explain in a review article published in Oncology. In addition, the rarity of MTC compromises the identification of differentiating features between the 2 diseases since the results of the studies rarely meet the criteria for statistical significance.
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In a recent study published in Ultrasound Quarterly, the authors reported relatively large nodules, aspect ratio less than 1, smooth edge, solid hypoechoic, microcalcification, and rich blood flow as ultrasonic features of MTC. According to Lei et al, “It is necessary to combine multiple ultrasonic features for the differential diagnosis of MTC, PTC, and benign thyroid nodules.”
The Roles of CT of MRI
Other imaging approaches have been applied, but not without limitations. For instance, computed tomography (CT) is widely available, but studies on its applicability in MTC are still scarce. Therefore, it is not considered a primary diagnostic tool for MTC. Instead, it is currently used to evaluate cervical and mediastinal lymph nodes and lung parenchyma for the presence of metastases, surgical planning, and targeted biopsies.
In a study published in Technology in Cancer Research & Treatment, Wang et al compared the diagnostic value of CT with that of ultrasound in MTC. They concluded, “Ultrasound can be used to observe the location, number, size, shape, border, internal echo, calcification, and blood flow of the lesion. It is a convenient, inexpensive, and nonradiative method with higher accuracy than enhanced [CT].”
Nonenhanced CT also enables the characterization of bony changes secondary to metastases, but the evaluation of bone marrow infiltration, the spinal canal, and soft tissues requires additional approaches.
Magnetic resonance imaging (MRI) is currently applied along with 3-phase contrast CT when liver metastasis is suspected, due to their sensitivities. MRI is an excellent option to visualize metastasis in soft tissues, intra-abdominal lymph nodes, bones, and the liver. It can therefore be used for initial staging of the disease and assessment of the treatment response.
There are several new MRI techniques, including whole-body MRI, dynamic contrast-enhanced, diffusion-weighted imaging, and a hybrid imaging system with positron emission tomography (PET). However, few have been explored in the context of MTC.
As stated by Kushchayev et al, “Although a number of new imaging modalities evolved over the last decades and are effectively used in different oncological applications, the clinical and research use of these novel techniques are still limited in the comprehensive evaluation of MTC.” They added that “new studies focusing on MRI techniques are needed.”
Nuclear Medicine Use Remains Controversial
Several conventional and advanced nuclear medicine techniques may add value to MTC diagnosis, but their use in clinical practice remains controversial.
One of the approaches is to use radiotracers for PET/CT in patients with suspected recurrent MTC. Castinetti and Taïeb stated in Thyroid, “The recent 2020 [European Association of Nuclear Medicine] guidelines recommend in particular to carry out 18F-FDOPA (6-18F-fluoro-L-3,4-dihydroxyphenylalanine) [PET/CT] scan in MTC patients with persistent disease.” In contrast, the American Thyroid Association 2015 guidelines do not recommend its use or the use of 18F-FDG PET/CT to detect distant metastasis due to decreased sensitivity.
18F-FDOPA PET/CT is the single best modality for detecting whole-body metastasis in patients with MTC, including small metastatic lymph nodes (around 6 mm). In addition, this is a sensitive technique to identify liver metastasis as well as metastatic lesions in unusual localizations. The sensitivity for metastatic/recurrent MTC is calculated to be between 79% and 100% using the calcitonin cut-off values proposed by the American Thyroid Association. Additionally, the detection rates of 18F-FDOPA PET/CT are considerably better than those of other imaging techniques in patients with rising tumor markers.
In a comparison between 18F-FDOPA PET/CT and 18F-FDG PET/CT, 18F-FDOPA performed better in evaluating metastatic/recurrent MTC, showing higher patient-based sensitivity (64% vs 48%) and lesion-based sensitivity (72% vs 52%). The sensitivity further increased when both methods were used.
“18F-FDG accumulates in neoplastic cells using glucose as an energy source mainly according to their proliferative activity. However, neuroendocrine tumors, including MTC, frequently show an indolent course and, consequently, a low 18F-FDG uptake,” Kushchayev et al explained. The best sensitivity was observed in MTC patients with serum calcitonin levels greater than 1000 pg/mL. Hence, experts believe that 18F-FDG PET/CT may be useful for detecting recurrence in patients with suspected aggressive disease, but not as a first-line diagnostic method in recurrent MTC.
Studies with somatostatin receptor tracers showed poorer results than those obtained for 18F-FDOPA PET/CT and 18F-FDG PET/CT. This can be explained, at least in part, by the lower density and inhomogeneous expression of somatostatin receptors in MTC, compared to other neuroendocrine tumors. In addition, the amount of information regarding somatostatin receptor tracers in MTC is even more limited.
One of the somatostatin receptor tracers, 68Ga-DOTATATE, showed promising results in detecting bone metastasis. Kushchayev et al stated, “Although 68Ga-DOTATATE PET/CT is not an optimal whole-body imaging technique as a single imaging modality in patients with MTC, it detects 100% for bone metastases and it was found to be superior to bone scan that identified 44% of osseous lesions.”
Additional strategies may include cholecystokinin receptor subtype/gastrin receptors and gastrin receptor scintigraphy, MIBG, 11C-methionine, immunoimaging, and bone scan. However, further studies are of utmost importance to clarify their role and accuracy in MTC diagnosis.
Hence, despite the recent advances in diagnostic imaging, Leimbach et al affirm that “imaging studies other than thyroid ultrasound have limited applicability in the initial diagnosis and management of MTC.”
Leimbach RD, Hoang TD, Shakir MKM. Diagnostic challenges of medullary thyroid carcinoma. Oncology. 2021;99(7):422-432. doi:10.1159/000515373
Kushchayev SV, Kushchayeva YS, Tella SH, Glushko T, Pacak K, Teytelboym OM. Medullary thyroid carcinoma: an update on imaging. J Thyroid Res. 2019;2019:1893047. doi:10.1155/2019/1893047
Lei R, Wang Z, Qian L. Ultrasonic characteristics of medullary thyroid carcinoma: differential from papillary thyroid carcinoma and benign thyroid nodule. Ultrasound Q. Published online April 10, 2021. doi:10.1097/RUQ.0000000000000508
Wang L, Kou H, Chen W, Lu M, Zhou L, Zou C. The diagnostic value of ultrasound in medullary thyroid carcinoma: a comparison with computed tomography. Technol Cancer Res Treat. 2020;19:153303382090583. doi:10.1177/1533033820905832
Castinetti F, Taïeb D. Positron emission tomography imaging in medullary thyroid carcinoma: time for reappraisal? Thyroid. 2021;31(2):151-155. doi:10.1089/thy.2020.0674