Ultrasound characteristics of medullary thyroid carcinoma and prognostic significance

Abstract

Purpose:

To investigate the ultrasound characteristics of medullary thyroid carcinoma and their relationship with prognosis.

Materials and methods:

A retrospective analysis was conducted on 133 medullary thyroid carcinoma nodules, encompassing their ultrasound findings and relevant clinical data. Based on the ultrasound characteristics, medullary thyroid carcinoma nodules were categorised into a benign feature group or malignant feature group, followed by a comparative assessment of disparities in ultrasound features and prognostic indicators between these two groups.

Results:

Among the 133 medullary thyroid carcinoma nodules analysed, there were 92 cases of malignant feature group (69.2%) and 41 cases of benign feature group (30.8%). The ultrasound characteristics of the benign feature group included well-defined borders (65.9%), hypo echogenicity (87.8%), rich blood flow (48.8%) or abundant blood flow (31.7%), and the absence of calcification (51.2%), or the presence of coarse calcification (36.6%). In contrast, the ultrasound characteristics of the malignant feature group revealed indistinct borders in the majority of cases (96.7%), hypoechogenicity in most cases (82.6%) or very low echogenicity in some cases (16.3%), and relatively rich blood flow in a significant number out of 92 patients (78.3%), with coarse calcification present in 66 cases (71.7%). Compared to the benign feature group, the malignant feature group demonstrated significantly higher rates of lymph node metastasis (69.6% vs 12.2%), distant metastasis (28.3% vs 9.8%), and recurrence (41.3% vs 9.8%). Moreover, the malignant feature group exhibited elevated preoperative calcitonin levels and its ultrasound features were found to be atypical in comparison with the benign feature group. A comprehensive understanding of the ultrasound characteristics of the benign feature group holds substantial clinical significance for diagnosing suspicious cases of medullary thyroid carcinoma. Furthermore, the ultrasound features of medullary thyroid carcinoma can serve as prognostic indicators, with the benign feature group having a more favorable prognosis than the malignant feature group.

Conclusion:

Medullary thyroid carcinoma demonstrates two distinct sonographic patterns. The benign feature group, often exhibiting benign-appearing features, is associated with a significantly more favorable prognosis than the malignant feature group. Recognising the benign feature group pattern is crucial to avoid misdiagnosis, and preoperative ultrasound features serve as valuable prognostic indicators.

Keywords

Medullary thyroid carcinoma undifferentiated thyroid malignancy ultrasound features prognosis calcitonin

Introduction

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasm originating from the parafollicular C cells of the thyroid gland, characterized by calcitonin secretion.¹ MTC represents 3%–10% of all thyroid malignancies.^1,2 It is recognised for its heightened invasiveness and unfavorable prognosis compared to other types of thyroid cancer, contributing to approximately 13.4% of deaths related to thyroid malignancy.^3
–5

The most prevalent pathological type of thyroid cancer is papillary thyroid carcinoma (PTC), and there have been reports suggesting that preoperative ultrasound features can predict the biological behavior of PTC. Specifically, PTC exhibiting “benign ultrasound features” has a more favorable prognosis compared to those displaying “malignant ultrasound features.”⁶ However, limited studies^7
–9 have reported on the ultrasound characteristics of MTC and their prognostic implications, with no similar research found worldwide. Due to the low incidence and clinical rarity of MTC, our understanding of its ultrasound features remains restricted. While prior studies predominantly focused on ultrasound-prognosis correlations in PTC,⁶ data on MTC remain limited and inconsistent.^7
–9 Recent evidence¹⁰ highlights the impact of operator-dependent variables on MTC sonographic features, yet standardised protocols are lacking. While the classification of MTC into types with benign (B-MTC) and malignant (M-MTC) ultrasound features has been previously described,^8,9 existing studies are limited by smaller sample sizes and inconsistent criteria. Our study contributes by (1) validating this classification in a larger, well-defined cohort; (2) employing a modified TI-RADS approach to improve feature assessment consistency; and (3) providing a more robust analysis of the correlation between these sonographic patterns and key prognostic outcomes such as lymph node metastasis, distant metastasis, recurrence, and calcitonin levels. Therefore, our study aims to comprehensively investigate the ultrasound characteristics of MTC and their correlation with tumour prognosis. This study systematically classifies MTC into B-MTC and M-MTC subtypes, rigorously addressing methodological gaps to establish prognostic correlations.

Methods

Ethics statement

The study protocol was approved by the Ethics Review Board of our Hospital (NSFC-AE-2022018) and followed the Declaration of Helsinki. All patients agreed to participate in the study and provided written informed consent.

Patients

This study consecutively enrolled 133 patients diagnosed with MTC via postoperative histopathology who underwent preoperative ultrasound examinations at our institution between January 2014 and January 2019. All patients met the inclusion criteria, with no exclusions.

Inclusion criteria were as follows: (1) confirmation of MTC through postoperative histopathology and performance of preoperative ultrasound examination; (2) selection of the nodule with the most malignant ultrasound features for patients with multiple nodules. Among them, 23 patients (17.3%) had two or more lesions, and we chose one nodule for analysis. Nodules under 1 cm were included in our analysis as they were identified during routine ultrasound screening or investigated due to clinical suspicion (e.g. elevated calcitonin, family history, or suspicious lymph nodes), leading to subsequent diagnostic confirmation.

Exclusion criteria were as follows: (1) patients who underwent subsequent surgery at another medical facility and were subsequently referred to our hospital for surgical treatment; (2) patients lost to follow-up after undergoing surgery.

A total of 133 nodules were included in the study, comprising 74 females and 59 males, with a mean age of 50.9 ± 12.3 years and an age range of 14–74 years. Prior to surgery, calcitonin levels were measured in 84 patients (63.16%), within upper limit of normal: 10 pg/mL. Calcitonin was only measured in 84 cases primarily due to retrospective data collection; for some patients referred with already confirmed diagnoses or undergoing surgery emergently, calcitonin levels were not part of the initial workup available in their records. Postoperative follow-up involved regular systemic imaging examinations such as thyroid ultrasound, computed tomography (CT) scan, or PET-CT conducted every six months or annually. In cases where recurrence or distant metastasis was detected through imaging examinations, regardless of pathological confirmation, it was classified as either local tumour recurrence or distant metastasis. The average duration of post-surgery follow-up was 33.13 months (range: 12–70 months).

Data acquisition

The Philips iU22 high-resolution ultrasound diagnostic system, equipped with a linear array transducer (5–12 MHz), was utilised in this study. Ultrasound examinations were performed using preset parameters: gain at 50 dB, depth adjusted to cover the entire thyroid gland and cervical lymph nodes, and dynamic range at 60 dB. All scans were conducted by one of two sonographers with over ten years of experience in thyroid ultrasound, utilising the same equipment. Each patient was scanned once preoperatively. Probe pressure was standardised using a mechanical arm (⩽2 N) to minimize artefactual echogenicity alterations. Ultrasound images were independently analysed by two board-certified radiologists (15 and 12 years of thyroid ultrasound experience, respectively). Discrepancies (which occurred in approximately 15% of cases, primarily related to calcification classification and margin assessment) were resolved through consensus discussion; a third senior radiologist was available but not required as all cases were resolved between the initial two reviewers. Interobserver reliability before consensus was good (kappa = 0.75 for calcifications, 0.78 for margins)

The nodules were assessed using a modified Thyroid Imaging Reporting and Data System (TI-RADS) developed at our institution, which incorporates features from both ACR TI-RADS and Korean TI-RADS to better capture the sonographic spectrum of MTC.^11,12 The analysis of nodules classifies the ultrasound characteristics of malignant thyroid nodules into six primary features: solid hypoechogenicity, marked hypoechoic appearance, ill-defined margins, an A/T ratio ⩾1 (i.e. taller-than-wide), presence of microcalcifications, and abundant vascularity. MTC cases were divided into the “Benign Ultrasonic Feature Group” (B-MTC) and the “Malignant Ultrasonic Feature Group” (M-MTC).⁸ MTC nodules demonstrating two or fewer ultrasonic features were classified as B-MTC, while those exhibiting more than two features were categorized as M-MTC.

The ultrasonic features of the B-MTC and M-MTC groups were comparatively analysed. This analysis included (1) the characteristics of nodules can be categorised as solid (consisting of more than 90% solid component), cystic (with over 90% cystic component), or mixed (falling between the spectrum of solid and cystic). (2) Echogenicity of the nodules, classified as markedly hypoechoic (lower than the surrounding strap muscle), hypoechoic (lower than the thyroid tissue), or mixed echogenicity (including two or more types such as hypoechoic, isoechoic, and hyperechoic). Mixed echogenicity was defined as ⩾20% heterogeneity in nodule composition (e.g. 80% hypoechoic and 20% isoechoic regions). (3) Margins, defined as clear or unclear. (4) The A/T ratio, calculated as the ratio of the anteroposterior diameter to the transverse diameter. (5) Calcifications, categorised as microcalcifications (maximum diameter < 1 mm) and macrocalcifications (maximum diameter ⩾ 1 mm), with additional classification of rim calcifications as per ACR TI-RADS criteria.¹ (6) Blood flow, assessed according to Rago’s recommended method,¹³ and classified as absent, moderate, or abundant flow. Blood flow was quantified via Rago’s method,¹³ with peak systolic velocity (PSV) ⩾ 20 cm/s defining “abundant flow.” Intraobserver reliability was excellent (ICC = 0.89). Abnormal characteristics of lymph nodes were assessed based on the following criteria: (1) having a round or oval shape with a well-defined contour; (2) displaying uneven echogenicity without normal lymph node architecture and exhibiting focal hyperechogenicity; (3) showing irregular fluid-filled areas within the lymph nodes (fluid-filled areas ⩾2 mm); (4) containing microcalcifications within the lymph nodes; (5) demonstrating abundant and disorganised blood flow within the lymph nodes. Abnormal lymph nodes were defined as short-axis diameter ⩾5 mm, loss of fatty hilum, internal focal hyperechogenicity, or cystic changes.

The histopathological findings were based on the pathology reports, encompassing an assessment of the tumour’s unifocality/multifocality, extrathyroidal invasion, and lymph node metastasis. All pathological specimens were independently reviewed by two head and neck pathologists with over 20 years of experience, adhering to the 2022 WHO Classification of Thyroid Tumours. In addition, a correlation analysis was conducted between abnormal lymph nodes detected on ultrasound images and postoperative pathological evidence of lymph node metastasis.

Statistical analysis

The statistical analyses were performed using SPSS version 20.0. Continuous variables were analysed using the t-test, while categorical variables were assessed using either the chi-square test or Fisher’s exact test. A significance level of less than 0.05 was considered statistically significant.

Results

Ultrasound characteristics between B-MTC and M-MTC

The ultrasound characteristics of B-MTC and M-MTC patients are compared in Table 1. Out of the 133 MTC nodules, 92 (69.2%) were classified as M-MTC and 41 (30.8%) as B-MTC. Unifocality was determined based on surgical records, while multifocality required confirmation via postoperative histopathology. When comparing the M-MTC group with the B-MTC group, there were no statistically significant differences observed in terms of tumour size or unifocality/multifocality. Specifically, for tumours larger than 1 cm, there was no statistically significant difference found between B-MTC and M-MTC (p = 0.836).

Table 1.

Analysis of clinical data and ultrasound features of B-MTC and M-MTC.

Characteristic	B-MTCs (n = 41)	M-MTCs (n = 92)	χ²/Z/t	p
SEX, n (%)			9.577	0.002**
Female	31 (75.6%)	43 (46.7%)
Male	10 (24.4%)	49 (53.3%)
Age	50.07 ± 14.15	51.26 ± 11.49	0.512	0.610
Tumour size (cm)⩽1 cm>1 cm	2.00 ± 1.3210 (24.4%)31 (75.6%)	1.86 ± 1.4824 (26.1%)68 (73.9%)	0.5230.043	0.6020.836
Multifocal (%)	8 (19.5%)	31 (33.7%)	2.753	0.097
Lymph node metastasis (pathology)	5 (12.2%)	62 (69.6%)	34.564	<0.001***
Distant metastasis	4 (9.8%)	26 (28.3%)	5.559	0.018*
Recurrence	4 (9.8%)	38 (41.3%)	13.046	<0.001***
Nodule characteristicsSolidMixed	38 (92.7%)3 (7.3%)	91 (98.9%)1 (1.1%)	3.745	0.053
EchogenicityMarkedly hypoechoicHypoechoicMixed echogenicity	2 (4.9%)36 (87.8%)3 (7.3%)	15 (16.3%)76 (82.6%)1 (1.1%)	5.915	0.015*
MarginClearUnclear	27 (65.9%)14 (34.1%)	3 (3.3%)89 (96.7%)	63.608	<0.001***
Longitudinal-to-transverse ratio⩾1<1	8 (19.5%)33 (80.5%)	33 (35.9%)59 (64.1%)	3.559	0.059
CalcificationsNoMicrocalcificationsMacrocalcifications	21 (51.2%)5 (12.2%)15 (36.6%)	13 (14.1%)13 (14.1%)66 (71.7%)	21.094	<0.001***
Blood flowAbsentModerateAbundant blood flow	8 (19.5%)20 (48.8%)13 (31.7%)	10 (10.9%)72 (78.3%)10 (10.9%)	12.250	0.002**
Abnormal lymph nodesPositiveNegative	0 (0%)41 (100%)	57 (62.0%)35 (38.0%)	44.454	<0.001***

Compared with non-osteoporosis group, p < 0.05.

Compared with non-osteoporosis group, p < 0.01.

***

Compared with non-osteoporosis group, p < 0.001.

In the B-MTC group, certain features were found to be more prevalent (p < 0.05), as depicted in Figures 1 and 2. These features included well-defined margins (65.9%), hypoechogenicity (87.8%), moderate blood flow (48.8%) or abundant blood flow (31.7%), and the absence of calcifications (51.2%) or the presence of macrocalcifications (36.6%). Microcalcifications were observed in 4.9% (2/41) of B-MTC and 18.5% (17/92) of M-MTC nodules, with a statistically significant difference (p = 0.021). Conversely, the M-MTC group exhibited more frequent findings of indistinct margins (96.7%), hypoechoic (82.6%) to markedly hypoechoic (16.3%) characteristics, the presence of macrocalcifications (71.7%), and abundant blood flow (78.3%), as demonstrated in Figures 3 and 4.

In addition, a higher proportion of nodules in the M-MTC group demonstrated taller-than-wide features compared to the B-MTC group; however, this difference did not reach statistical significance (p = 0.059). Among the 133 cases of MTC

Prognosis between B-MTC and M-MTC

The prognosis comparison between B-MTC and M-MTC patients is presented in Table 1. In the B-MTC group, approximately 75% of the patients were female, while around 50% of the M-MTC patients were female. Compared to B-MTC, M-MTC exhibited a significantly higher prevalence of lymph node metastasis (p < 0.001), distant metastasis (p = 0.018), and recurrence (p < 0.001).

Furthermore, among the 84 patients who underwent preoperative calcitonin testing, elevated calcitonin levels were observed in 79 individuals (94%), with 23 cases in the B-MTC group and 61 cases in the M-MTC group. Notably, M-MTC was associated with significantly higher preoperative calcitonin levels compared to B-MTC (p = 0.018).

Correlation between ultrasound-detected lymph node abnormalities and pathology in MTC

The correlation between ultrasound detection of lymph node abnormalities in MTC and surgical pathology was assessed by McNemar’s test for consistency analysis, revealing a moderate level of agreement (p = 0.064, kappa = 0.64).

Discussion

MTC is categorised into sporadic and hereditary forms. In comparison with differentiated thyroid cancer, MTC demonstrates a heightened degree of malignancy, an inclination for early metastasis, and a relatively unfavorable prognosis.¹⁴ Prognostic factors encompass tumour size, lymph node invasion, the genetic classification of the tumour (sporadic vs hereditary), clinical staging, and calcitonin doubling time.¹⁵

Currently, ultrasound remains the preferred diagnostic tool for MTC. It allows for a preliminary diagnosis based on the characteristics of thyroid nodules, such as their morphology, internal echogenicity, blood flow, calcification, and cervical lymph nodes, guiding surgical intervention and post-operative follow-up.⁴

In this study, we employed the modified TI-RADS system developed by our institution (published in 2015)¹⁶ for several key reasons: (1) Simplicity and clinical feasibility: the modified TI-RADS is based on counting six high-suspicion ultrasonic features for malignant thyroid nodules (solid composition, marked hypoechogenicity, ill-defined margins, microcalcifications, taller-than-wide, and enhanced blood flow), at the same time, checking for any abnormal lymph nodes in the neck. This straightforward counting method allows for rapid risk stratification without complex scoring or calculations, making it highly practical for routine clinical use. (2) Inclusion of vascularity: unlike some other systems (including ACR TI-RADS¹⁷ and Korean TI-RADS),¹⁸ the modified TI-RADS incorporates vascularisation as a key criteria. This is particularly relevant for MTC, which often presents with hypervascularity. These features are not emphasised in the same way in other systems, which may limit their sensitivity for MTC. (3) Tailored for MTC evaluation: given that MTC exhibits unique sonographic characteristics (e.g. oval shape, well-defined margins, hypervascularity) that differ from PTC,¹⁹ we believed that a system incorporating vascular features would be more suitable. The modified TI-RADS allowed us to capture these nuances effectively. We acknowledge that both the ACR TI-RADS and the Korean TI-RADS are valuable systems, particularly for PTC.²⁰ However, our focus was on evaluating a system that could be easily applied in clinical practice while also addressing the specific features of MTC.

In our ultrasound examinations, we have observed that while MTC is a malignant tumour, certain ultrasound features can resemble those of benign nodules. As a result, we have classified MTC into two categories based on ultrasound characteristics: M-MTC and B-MTC. Notable differences have been observed between the two groups. B-MTC often exhibits similarities to benign thyroid nodules,⁸ appearing as oval-shaped, well-defined hypoechoic solid masses with occasional mixed cystic-solid features. Blood flow is typically abundant and disorganised in B-MTC cases, and abnormal lymph nodes may be visible in the drainage area. On the other hand, M-MTC demonstrates classic malignant characteristics including solid hypoechogenicity, irregular morphology, indistinct borders, and associated abnormal lymph nodes.⁹

Our findings align with Kim et al,⁸ who reported associations between ultrasound features and prognosis in MTC. However, our study included a larger cohort (133 vs 62 cases), potentially enhancing statistical robustness. Notably, B-MTC demonstrated a higher female predominance (75% vs 60% in Fukushima et al²¹), suggesting gender may influence sonographic phenotypes. Macrocalcifications predominated in M-MTC (71.7%), consistent with ACR TI-RADS criteria.¹ However, amyloid deposits in MTC may confound calcification classification, warranting cautious interpretation.

Although taller-than-wide is characteristic of PTC, malignant tumours tend to exhibit a “spherical” or “standing” shape, which maximises nutrient absorption. Previous studies²² have indicated that PTC demonstrates extensive fibrosis, resulting in reduced compressibility compared to benign tumours. However, the taller-than-wide lacks high sensitivity for diagnosing malignancies other than PTC. Reports suggest that MTC rarely exhibits taller-than-wide characteristics when compared to PTC.²³

The calcifications in MTC can manifest as either microcalcifications or coarse calcifications, with the latter being more prevalent. Histological analysis indicates that calcifications in MTC typically arise from three causes: (1) hemorrhage and necrosis, which usually present as benign calcifications; (2) minute calcifications within tumour cells, resembling granular bodies commonly observed in PTC; and (3) amyloid deposits in the stroma. Amyloid deposits primarily contribute to the formation of calcifications in MTC, facilitating their substantial and homogeneous distribution throughout the nodular structure.

MTC typically demonstrates a more abundant blood supply in comparison with PTC, although the degree of vascularity overlaps between B-MTC and M-MTC and correlates with nodule size and internal echo characteristics. MTC shares certain blood flow characteristics with thyroid adenomas, such as peripheral vascularity, which can potentially lead to misdiagnosis. However, MTC often exhibits disorganised vascular patterns with chaotic internal blood flow, while the surrounding flow tends to be discontinuous, unlike the more regular vascular patterns observed in adenomas.

Some studies²¹ have suggested a significant difference in tumour size between B-MTC and M-MTC tumours, whereas our findings indicated that this difference lacks statistical significance (p = 0.602). Consistent with the findings of Kim et al,⁸ we also observed no significant disparity in tumour size between the B-MTC and M-MTC groups, nor did we find any notable variation in the proportion of nodules larger than 1 cm. Furthermore, our study revealed a higher proportion of females in the B-MTC group compared to the M-MTC group, highlighting the importance of thorough clinical evaluations for suspicious nodules particularly among female patients.

Current research suggests that specific ultrasound features are associated with the malignancy risk of tumours, although the majority of available data pertains to PTC. Limited and inconsistent research exists regarding the ultrasound characteristics and prognosis of MTC. Fukushima et al.²¹ discovered that 70% of MTC nodules exhibit malignant ultrasound features (“M-type”), while 30 display benign features (“B-type”). “B-type” MTC is characterised as a low-aggressiveness tumor with a favorable prognosis, whereas “M-type” MTC is linked to cervical lymph node involvement and extrathyroidal invasion.

Our findings demonstrated a higher prevalence of ultrasound features indicative of high invasiveness in the M-MTC group, along with increased rates of lymph node and distant metastasis as well as recurrence. Preoperative lymph node metastasis was closely associated with TNM staging and significantly impacts progression-free survival in MTC patients. Therefore, incorporating preoperative ultrasound characteristics alongside other clinical indicators holds substantial value for predicting therapeutic outcomes and prognosis. These data strongly suggested that comprehensive preoperative ultrasound evaluations in MTC patients can facilitate early detection of B-MTC, thereby assisting surgical treatment and improving survival rates. The staging of MTC and the thoroughness of the initial surgery also emerged as critical factors influencing patient outcome.²⁴

The serum calcitonin positivity rate among MTC patients was reported to be 94%, making it a specific tumour marker for MTC.²⁵ In our study, the eff prognosis active serum calcitonin rate was found to be 94%, with four cases of B-MTC and one case of M-MTC exhibiting levels below 10 ng/L. Notably, the M-MTC group demonstrated higher serum calcitonin levels compared to the B-MTC group. Previous research suggests that serum calcitonin levels exceeding 100 ng/L are indicative of MTC and closely correlate with tumour burden and prognosis.²⁶ Therefore, conducting serum calcitonin tests in patients with a high suspicion of MTC is crucial.

Furthermore, our study revealed a moderate level of concordance between preoperative ultrasound-detected lymph node abnormalities and postoperative pathological lymph node metastasis, emphasising the crucial role of comprehensive ultrasound examinations in guiding surgical decision-making.

Conclusion

The prognosis of M-MTC is comparatively worse than that of B-MTC, and the malignant ultrasound characteristics of B-MTC are typically atypical, often presenting as well-defined, hypoechoic solid masses with a round or oval shape and lacking calcification. This makes them susceptible to misdiagnosis as benign nodules. By conducting meticulous ultrasound examinations and accumulating clinical experience, along with assessing calcitonin levels when necessary, we can enhance diagnostic accuracy and ultimately improve treatment options and patient outcomes.

Footnotes

Acknowledgements

Not applicable

ORCID iD

Yuzhe Wang

Ethical considerations

Author contributions

LW and YW: contributions to conception and design, acquisition of data, analysis and interpretation of data and drafting the article.

XW: contributions to acquisition of data and analysis.

XW: contributions to conception and design.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by National Natural Science Foundation of China (82272008) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A).

Declaration of conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Guarantor

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