Abstract
Objective
Recently, several scientific societies designed ultrasound (US) risk stratification systems (RSS) to guide the workup of thyroid nodules and decide which nodules should undergo fine-needle aspiration cytology (FNAC). However, these systems have been developed against papillary thyroid carcinoma, and scanty data on their role in identifying medullary thyroid carcinoma (MTC) are available. The aims of this study are to describe the US features of MTC and evaluate the performance of RSS in identifying MTC.
Methods
Data of 152 consecutive patients with MTC was evaluated. The results of the pre-operative neck US of all patients were collected. Ultrasound features of each MTC were evaluated and classified according to the five main RSS available.
Results
Median MTC dimension was 1.3 cm. Most of the nodules showed solid composition, hypoechoic pattern, and regular margins. About half of them showed the presence of calcifications, but only a subgroup had microcalcifications. A minority of the nodules showed a 'taller than wide' shape. Only 7.9% of all MTC showed the simultaneous presence of at least four US features suggestive of malignancy. Ultrasonographic high-risk of malignancy of the MTC included in the five RSS, varied from 45.4 to 47.4%, and performing FNAC was suggested in only 48.7 to 63.8% of all MTC.
Conclusions
In this series, neither single nor the association of US features are specific for MTC. The five main RSS correctly identify less than 50% of MTC and do not suggest performing FNAC in about half of them with potentially missed or delayed diagnosis.
Introduction
Medullary thyroid carcinoma (MTC) is rare cancer (1), occurring in sporadic or hereditary form. At variance with differentiated thyroid carcinomas, particularly papillary (PTC), the early diagnosis is crucial because at the time of diagnosis, cervical lymph nodes metastasis is very frequent, distant metastasis is present in about 10% of patients (2), and mortality during the follow-up is not negligible (3). Nevertheless, the pre-operative workup for the diagnosis of MTC is still controversial; the routine use of serum calcitonin (CT) in the evaluation of thyroid nodules is debated (4), the ability of neck ultrasonography (US) in identifying MTC is not well-defined (5, 6) and fine-needle aspiration cytology (FNAC) showed low sensitivity (7, 8, 9).
Since the increasing incidence of thyroid cancer and wide diffusion of neck US, in the last years, various scientific societies have designed several US risk stratification systems (RSS) to help clinicians in defining the US risk of malignancy (ROM) of the thyroid nodules. The five main RSS were designed by the European Thyroid Association (European Thyroid Imaging and Reporting Data System – EU-TIRADS) (10), the American Thyroid Association (2015 ATA) (11), the American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi (AACE/ACE-AME) (12), the American College of Radiology (ACR-TIRADS) (13) and the Korean Society of Thyroid Radiology (K-TIRADS) (14). However, all these RSS are developed against PTC, and although their predictive value is rather good for PTC, it is not yet validated for MTC, whose US features are less specific (15, 16) and widely variable (17).
The aims of this study were to characterize the US features of MTC and compare the performance of the five main US RSS in the diagnostic ability to identify MTC. Moreover, we evaluated the suggestions to perform or not FNAC, according to US ROM and nodule dimension.
Patients and methods
Patients
One-hundred and fifty-two consecutive patients with a histologically confirmed diagnosis of MTC were retrospectively analyzed. All of them performed clinical, biochemical and US evaluation before surgery at the Endocrine Unit of the Pisa University Hospital and were subsequently submitted to surgery at the Endocrine Surgery Unit of the same hospital, from January 2014 to September 2020. We excluded those patients without a pre-operative US evaluation and patients in whom the MTC was incidentally discovered after surgery and then not identified at neck US before.
For each patient, we collected epidemiologic, clinical, and pathologic data. The presence of RET (rearranged during Transfection) germline mutation was investigated and reported for each patient.
The study was approved by the local Ethical Committee (CEAVNO – Comitato Etico Area Vasta Nord-Ovest) and, for the policy of the University Hospital, all patients signed a written informed consent to use their data for scientific purposes.
Neck US
A color Doppler apparatus (MyLab 50, Esaote Biomedica, Firenze, Italy) with a 7.5–12 MHz linear transducer was used to perform neck US. Pre-operative neck US was performed by the same team of endocrinologists over time, with more than 5 years of experience in thyroid ultrasonography. US imaging and report, available in all patients, were used to define thyroid features (estimated thyroid volume, echostructure, echogenicity, presence of single or multiple nodules). Moreover, the nodule that resulted in MTC at histology was identified and its US features were collected. When more than one focus of MTC was discovered in the same patient, for the purpose of the study, we only considered the nodule with a larger dimension. We evaluated maximum diameter of the nodule, composition (solid, mixed, or cystic), echogenicity (anechoic, hypoechoic, isoechoic and hyperechoic), margins (well defined or irregular), presence and types of calcifications (macro, peripheral, micro and hyperechoic spots), shape ('taller than wide') and the presence of a peripheral halo. We decided to not include the vascularization of the nodule in the analyzed US features, both because it was not available in all patients and this parameter was not included in the RSS. Then, we classified each nodule according to the five RSS (10, 11, 12, 13, 14). Moreover, we evaluated the indications derived from the five RSS to perform FNAC according to US risk features and nodule dimension. We used these indications in our cohort of patients to evaluate how many patients FNAC was or was not suggested.
Statistical analysis
Categorical variables are expressed as counts and percentages, and continuous variables as median and interquartile ranges (IQR) because of their skewed distribution. Chi-square test was used to evaluate the association between categorical variables. The Mann–Whitney U-test was used for continuous numerical variables. A P-value less than 0.05 was considered statistically significant. Analysis was performed with SPSS (version 20.0, Armonk, NY: IBM Corp).
Results
Epidemiologic, clinical and US features of both thyroid and nodule, which was histologically proven MTC, are reported in Table 1. The median age at diagnosis was 53 years and females were 53.3% of the study group. All patients performed RET germline mutation investigation, 126/152 (82.9%) patients were negative for the mutation and then defined as sporadic cases.
Epidemiologic, clinical, pathologic and ultrasonographic features of the study group (n = 152). Values are presented as n (%) or median (IQR).
| Characteristics | Values |
|---|---|
| Sex | |
| Male | 71 (46.7%) |
| Female | 81 (53.3%) |
| Age (years) | 53 (43–63.8) |
| RET germline mutation | |
| Yes | 26 (17.1%) |
| No | 126 (82.9%) |
| Thyroid features at US | |
| Estimated thyroid volume (mL) | 16.4 (10.5–25.2) |
| Echostructure | |
| Homogenoeus | 35 (23%) |
| Inhomogeneous | 83 (54.6%) |
| Markedly inhomogeneous | 34 (22.4%) |
| Echogenicity | |
| Isoechoic | 89 (58.6%) |
| Slightly hypoechoic | 27 (17.8%) |
| Markedly hypoechoic | 36 (23.7%) |
| Mulitinodularity | |
| Yes | 88 (57.9%) |
| No | 64 (42.1%) |
| †MTC features at US (maximum diameter (cm)) | |
| ≤1 | 52 (34.2%) |
| 1.1–2 | 54 (35.5%) |
| 2.1–4 | 40 (26.3%) |
| > 4 | 6 (4%) |
| Composition | |
| Solid | 141 (92.8%) |
| Mixed | 10 (6.6%) |
| Cystic | 1 (0.7%) |
| Echogenicity | |
| Anechoic | 1 (0.7%) |
| Slightly hypoechoic | 82 (53.9%) |
| Markedly hypoechoic | 44 (29%) |
| Isoechoic | 25 (16.4%) |
| Hyperechoic | – |
| Margins | |
| Well defined | 102 (67.1%) |
| Irregular | 50 (32.9%) |
| Halo | |
| Yes | 42 (27.6%) |
| No | 110 (72.4%) |
| Calcifications | |
| Yes | 84 (55.3%) |
| No | 68 (44.7%) |
| Types of calcification | |
| Macro | 11 (13.1%) |
| Peripheral | 2 (2.4%) |
| Micro | 27 (32.1%) |
| Hyperechoic spots | 44 (52.4%) |
| Taller than wide | |
| Yes | 16 (10.5%) |
| No | 136 (89.5%) |
| ‡Histology (maximum MTC diameter (cm)) | |
| ≤1 | 56 (36.8%) |
| 1.1–2 | 45 (29.6%) |
| 2.1–4 | 42 (27.6%) |
| > 4 | 9 (5.9%) |
| Multifocality | |
| Yes | 49 (32.2%) |
| No | 103 (67.8%) |
†Median (IQR):1.3 (0.9–2.2); ‡Median (IQR): 1.3 (0.9–2.5).
US features
Median thyroid estimated volume was 16.4 mL. In most of the cases, the thyroid gland showed a non homogeneous structure (77%), isoechoic pattern (58.6%) and more than one nodule (57.9%).
At neck US, the nodule histologically proven MTC showed a median diameter of 1.3 cm in its larger dimension. In 61.8% of the cases, the nodule was between 1.1 and 4 cm, microcarcinoma (<1 cm) was present in 34.2%, conversely MTC larger than 4 cm was less common (4%).
Almost all MTC showed solid composition (92.8%) and most of them had a hypoechoic pattern (82.9%). In 16.4% of cases, the nodules were isoechoic, and one single case showed a cystic appearance (0.7%). Only 32.9% of the nodules appeared with irregular margins, conversely in most of the cases (67.1%), margins were regular. About half of them (55.3%) showed the presence of calcifications, the most common of which were hyperechoic spots (52.4%), followed by microcalcifications (32.1%). Only a minority of nodules had peripheral halo (27.6%) and a 'taller than wide' shape (10.5%).
In Table 2, we divided the MTC according to the presence of the four main US features associated with malignancy in thyroid nodules. If the presence of solid composition was very frequent in our series (92.8%), the simultaneous occurrence of three (30.3%) or four (7.9%) US features suggestive for malignancy in the same nodule was less frequent.
Combination of US features suggestive for malignancy in 152 MTC study group.
| Yes | No | |
|---|---|---|
| Solid | 141 (92.8%) | 11 (7.2%) |
| Solid + hypoechoic | 123 (80.9%) | 29 (19.1%) |
| Solid + hypoechoic + irregular margins | 46 (30.3%) | 106 (69.7%) |
| Solid + hypoechoic + irregular margins + microcalcifications | 12 (7.9%) | 140 (92.1%) |
MTC and US RSS
According to the US features of the MTC, we applied the five US RSS to our study group (Fig. 1).
Distribution of 152 MTC in the five different RSS.
Citation: European Journal of Endocrinology 185, 2; 10.1530/EJE-21-0313
Distribution of 152 MTC in the five different RSS.
Citation: European Journal of Endocrinology 185, 2; 10.1530/EJE-21-0313
Distribution of 152 MTC in the five different RSS.
Citation: European Journal of Endocrinology 185, 2; 10.1530/EJE-21-0313
In all RSS, less than 50% of MTC were correctly classified as a high-risk suspicious category with some differences among the different classifications. Relevant percentages of the remaining cases were classified as intermediate-suspicious category.
The calculation of the ROM of our nodules according to each category of RSS (10, 11, 12, 13, 14) is reported in Table 3. We found that in our MTC group, ROM was similar in both intermediate- and high-risk suspicious category, with few differences in the 2015 ATA and EU-TIRADS in which the ROM of intermediate-risk suspicious was slightly lower than high-suspicious category.
ROM reported in RSS compared with ROM identified in our MTC study group.
| RSS/US risk categories | ROM reported in RSS (%) | ROM in our MTC study group (%) |
|---|---|---|
| EU-TIRADS | ||
| EU-TIRADS 1:normal | None | – |
| EU-TIRADS 2: benign | ≈ 0 | 3.9 |
| EU-TIRADS 3: low risk | 2–4 | 7.9 |
| EU-TIRADS 4: intermediate risk | 6–17 | 40.8 |
| EU-TIRADS 5: high risk | 26–87 | 47.4 |
| 2015 ATA | ||
| Benign | <1 | 0.7 |
| Very low suspicion | <3 | 3.3 |
| Low suspicion | 5–10 | 7.9 |
| Intermediate suspicion | 10–20 | 40.8 |
| High suspicion | >70–90 | 47.4 |
| AACE/ACE -AME | ||
| Low risk | ≈1 | 4.6 |
| Intermediate risk | 5–15 | 49.3 |
| High risk | 50–90 | 46.1 |
| ACR-TIRADS | ||
| TR1 benign | 0.3 | 0.7 |
| TR2 not suspicious | 1.5 | 2 |
| TR3 mildly suspicious | 4.8 | 5.9 |
| TR4 moderately suspicious | 9.1 | 46.1 |
| TR5 highly suspicious | 35 | 45.4 |
| K-TIRADS | ||
| Benign | 1–3 | 0.7 |
| Low suspicion | 3–15 | 7.9 |
| Intermediate suspicion | 15–50 | 48 |
| High suspicion | >60 | 46.4 |
Indication to FNAC according to different RSS
According to the suggestions of the five RSS that also take care of nodule size, FNAC was not indicated in a relatively high percentage of cases, varying from 36.2 to 51.3% of all MTC patients of our study group, depending on RSS considered (Table 4). Particularly, if we focused on the intermediate-risk suspicion alone, FNAC was not suggested in a large percentage of the cases varying from 43.8 (K-TIRADS) to 78.7% (AACE/ACE-AME). Moreover, also in the high-risk suspicious category, according to the indications of the five RSS, FNAC was not suggested in about 25% of MTC.
Distribution of 152 MTC in the risk category, according to the five RSS and nodule dimension with and without indication to FNAC. Data are presented as n (%).
| Nodule dimension | Indication to FNAC | ||||||
|---|---|---|---|---|---|---|---|
| ≤1 cm | 1.1–1.5* cm | 1.6–2 cm | >2 cm | Total | No | Yes | |
| EU-TIRADS | |||||||
| EU-TIRADS 2 | 1 (16.7%) | – | – | 5 (83.3%) | 6 (3.9%) | 6 (100%) | – |
| EU-TIRADS 3 | 3 (25%) | 5 (41.7%) | 1 (8.3%) | 3 (25%) | 12 (7.9%) | 9 (75%) | 3 (25%) |
| EU-TIRADS 4 | 30 (48.4%) | 13 (21%) | 6 (9.7%) | 13 (21%) | 62 (40.8%) | 43 (69.4%) | 19 (30.6%) |
| EU-TIRADS 5 | 18 (25%) | 22 (30.6%) | 7 (9.7%) | 25 (34.7%) | 72 (47.4%) | 18 (25%) | 54 (75%) |
| Total | 52 (34.2%) | 40 (26.3%) | 14 (9.2%) | 46 (30.3%) | 152 | 76 (50%) | 76 (50%) |
| 2015 ATA | |||||||
| Benign | – | – | – | 1 (100%) | 1 (0.7%) | 1 (100%) | – |
| Very low suspicion | 1 (20%) | – | – | 4 (80%) | 5 (3.3%) | 1 (20%) | 4 (80%) |
| Low suspicion | 3 (25%) | 5 (41.7%) | 1 (8.3%) | 3 (25%) | 12 (7.9%) | 8 (66.7%) | 4 (33.3%) |
| Intermediate suspicion | 30 (48.4%) | 13 (21%) | 6 (9.7%) | 13 (21%) | 62 (40.8%) | 30 (48.4%) | 32 (51.6%) |
| High suspicion | 18 (25%) | 22 (30.6%) | 7 (9.7%) | 25 (34.7%) | 72 (47.4%) | 18 (25%) | 54 (75%) |
| Total | 52 (34.2%) | 40 (26.3%) | 14 (9.2%) | 46 (30.3%) | 152 | 58 (38.2%) | 94 (61.8%) |
| AACE/ACE-AME | |||||||
| Low risk | 2 (28.6%) | – | 5 (71.4%) | 7 (4.6%) | 2 (28.6%) | 5 (71.4%) | |
| Intermediate risk | 33 (44%) | 26 (34.7%) | 16 (21.3%) | 75 (49.3%) | 59 (78.7%) | 16 (21.3%) | |
| High risk | 17 (24.3%) | 28 (40%) | 25 (35.7%) | 70 (46%) | 17 (24.3%) | 53 (75.7%) | |
| Total | 52 (34.2%) | 54 (35.5%) | 46 (30.3%) | 152 | 78 (51.3%) | 74 (48.7%) | |
| ACR-TIRADS | |||||||
| TR1 benign | – | – | – | 1 (100%) | 1 (0.7%) | 1 (100%) | – |
| TR2 not suspicious | – | – | – | 3 (100%) | 3 (2%) | 3 (100%) | – |
| TR3 mildly suspicious | 2 (22.2%) | 3 (33.3%) | 1 (11.1%) | 3 (33.3%) | 9 (5.9%) | 6 (66.7%) | 3 (33.3%) |
| TR4 moderately suspicious | 32 (45.7%) | 18 (25.7%) | 10 (14.3%) | 10 (14.3%) | 70 (46%) | 50 (71.4%) | 20 (28.6%) |
| TR5 highly suspicious | 18 (26.1%) | 19 (27.5%) | 22 (31.9%) | 10 (14.5%) | 69 (45.4%) | 18 (26.1%) | 51 (73.9%) |
| Total | 52 (34.2%) | 40 (26.3%) | 33 (21.7%) | 27 (17.8%) | 152 | 78 (51.3%) | 74 (48.7%) |
| K-TIRADS | |||||||
| Benign | – | – | – | 1 (100%) | 1 (0.7%) | – | 1 (100%) |
| Low suspicion | 3 (25%) | 3 (25%) | 1 (8.3%) | 5 (41.7%) | 12 (7.9%) | 6 (50%) | 6 (50%) |
| Intermediate suspicion | 32 (43.8%) | 20 (27.4%) | 5 (6.8%) | 16 (21.9%) | 73 (48%) | 32 (43.8%) | 41 (56.2%) |
| High suspicion | 17 (25.8%) | 17 (25.8%) | 8 (12.1%) | 24 (36.4%) | 66 (43.4%) | 17 (25.8%) | 49 (74.2%) |
| Total | 52 (34.2%) | 40 (26.3%) | 14 (9.2%) | 46 (30.3%) | 152 | 55 (36.2%) | 97 (63.8%) |
Bold numbers show the cases without indication to FNAC.
*1.1–2 cm for AACE/ACE_AME.
Discussion
Medullary thyroid carcinoma is an uncommon malignancy, that can occur in sporadic or hereditary form (1). At variance with differentiated thyroid cancer, and particularly PTC, neck US and cytology performance in identifying MTC are debated (6, 7). Because of the increased incidence of thyroid cancer (18), and widespread use of neck US, the scientific community developed several ultrasonographic RSS indicating the ROM of thyroid nodules, to suggest the right approach to perform FNAC to avoid overdiagnosis and overtreatment. However, the RSS has been standardized against PTC, the most frequent thyroid cancer, and not MTC. Furthermore, due to its rarity, few studies with a quite small number of patients were performed to evaluate the role of neck US in identifying MTC.
In our study cohort of 152 consecutive patients, MTC appeared at neck US prevalently as a solid (92.8%) and hypoechoic (82.9%) nodule. These results are similar to those reported in other studies. In a meta-analysis of Valderrabano et al. (5), who tested the performance of 2015 ATA RSS in identifying MTC, 92.5% of 249 MTC analyzed showed a solid composition and 96.1% a hypoechoic appearance. Also, Zhu et al. (19), who evaluated a large series of thyroid nodules, highlighted that in 118 MTC, 96.6% showed a solid composition and 94.1% a hypoechoic or markedly hypoechoic appearance.
At variance with PTC (20, 21), in MTC the prevalence of irregular margins showed a higher variability according to different studies. Kim et al. (22) reported a prevalence of spiculated or irregular margins at US in 17/21 (81%) MTC, similar prevalence was reported by Zhu et al. (75/118 – 63.6%) (19). In our series, the prevalence of irregular margins was lower (32.9%), more similar to those reported in the meta-analysis of Wolinski et al. (38%), who analyzed 4 studies and 114 patients with MTC (6).
We detected the presence of calcifications in about half of the patients (55.3%). Particularly, microcalcifications and hyperechoic spots accounted for 84.5% of all types of calcifications found in US. Overall prevalence of microcalcifications in our series was 17.8%, similar to that found by Trimboli et al. (23) who reported 16% of microcalcifications at neck US in 12 MTC patients analyzed. In other series, a higher prevalence of microcalcifications was reported. Choi et al. (24) and Zhu et al. (19) found this US sign in 47% and 45% of cases, respectively. However, in our clinical practice, by following the AACE/ACE-AME guidelines (12), we usually distinguish the microcalcifications, defined as tiny hyperechoic punctuate spots <1 mm, without posterior shadow, which are suggestive of malignancy, from the more frequent, and innocuous 'comet tail' sign characterized by bright hyperechoic spots that can be also associated to not malignant nodules (12, 25). Therefore, if we included in this evaluation also the presence of hyperechoic spots in addition to the microcalcifications, the prevalence increased up to 46.7% more similar to that reported by Choi et al. and Zhu et al. (19, 24).
Taller than wide shape, another US sign associated to the malignancy in thyroid nodules (26, 27), was present in only 10.5% of our study group. Available data on the prevalence of taller than wide sign are very discordant and in MTC series it varies from 13 to 67% (16, 28) and the real predictive value of this specific feature is not well defined (29). Certainly, in our series, it was even lower in respect to other series and thus, at least in our hands, it cannot be used as a predictive sign of MTC.
Previous studies showed that, even in PTC cases, one single US feature cannot be suggestive for malignancy and some of them should be combined to increase the predictive value (30). We looked at this specific issue but in our series of MTC, the simultaneous presence of more than two US features suspicious for malignancy in the same nodule was a quite unusual occurrence. Particularly, the association of solid composition, hypoechogenicity, irregular margins and microcalcifications was detected in only 7.9% of all MTC nodules, thus questioning the real predictive value of malignancy also when combining more features together.
In the last years, the scientific societies developed the RSS, in which thyroid nodules were classified according to several US features, with the aim to characterize the US ROM. However, these RSS were developed against PTC, with less or no indications about the US ROM of MTC.
When applying the five main RSS (1, 10, 12, 13, 14) to our study group, the MTC identified in the highest suspicious categories varied from 45.4% to 47.4%. Therefore, in all the main RSS, more than half of MTC were identified at neck US as nodules at intermediate or low ROM. At variance with our results, few other studies analyzing US MTC features showed a higher prevalence of high-suspicious categories. Particularly, Valderrabano et al. (5) applying the 2015 ATA RSS in 30 MTC showed that 80% of the cases were classified as 'high suspicion', however, these results could be influenced by the quite small study group. Similar prevalence was reported by Zhao et al. (31) who defined 160/189 (84.7%) cases as 'malignant MTC' according to the ACR-TIRADS (score ≥ 7). In another study, Yun et al. (32) reported that 68% of 57 MTC patients evaluated before surgery could be classified in K-TIRADS 5 category. A possible explanation of the difference between our results and those of other studies may be that while in our series MTC showed irregular margins in only 32.9% of cases, in previous studies (5, 6, 19, 22, 31, 32) this feature, that upgrades the nodule to the highest risk category, was present in a 38–81% of the MTC. Similarly, the presence of microcalcifications was more frequent in other series varying from 28.6 to 44.9% (5, 6, 19, 22, 32). We cannot explain the difference in the prevalence of these features in our series compared to others, but it is likely due to a different description of some of them. For example, we commonly distinguish microcalcifications from tiny intranodular hyperechoic spots, and only true microcalcifications are associated with malignancy (12). It is more difficult to explain the difference in the prevalence of irregular margins but if we consider that in our series the median tumor dimension was smaller compared to those of other series (1.3 vs 2 to 2.4 cm) (5, 32), it is conceivable that a smaller tumor could have not yet developed irregular margins (33).
As far as the indication of FNAC is regarded, if we correctly applied the indication of the five RSS in suggesting FNAC, we should not perform the FNAC in about half of our study group (36.2–51.3%). Particularly, in the intermediate-risk suspicious category, the prevalence of cases that should not undergo FNAC was even higher (43.8–78.7%). This is also correlated to the small dimension of our MTC, since according to the last ATA guidelines, nodules smaller than 1 cm should not undergo FNAC (11). FNAC is also not recommended in hereditary MTC cases where the decision making to operate the patient is based on the serum CT levels and the type of RET mutation (1).
Whether these patients could be followed over time, particularly those with small nodules, is still a matter of discussion. To date, the wait and see strategy is highly recommended for thyroid nodules <1 cm, even if the diagnosis refers to microPTC since it has been well documented that this strategy has not to impact on the outcome of the disease (34, 35). However, it is worth to note that MTC could be able to early metastasize to loco-regional lymph-nodes and to distant sites (3, 36), even if diagnosed when small in size (37) and, delaying surgery could severely affect the possibility to definitively cure the patient (38, 39).
In our experience, the routine evaluation of CT measurement in the workup of thyroid nodules is crucial both to early identify MTC and to improve the disease-specific survival (36, 40, 41). However, this assumption is still debated, also in the referral guidelines (11, 12) and neck US continues to be suggested as an ancillary tool in identifying MTC.
This paper has some limitations due to its retrospective nature and the absence of a control group of benign or malignant non-MTC patients. However, to our knowledge, this is the first study which compares the five main RSS in the diagnostic ability to detect MTC, with a rather large number of patients, all of them evaluated before and after surgery in the same tertiary care center. Moreover, all the diagnostic procedures, including neck US, were performed with the same equipment, by the same team of endocrinologists, for the duration of the study. Nevertheless, a prospective and comparative study have been already started although, because of the low incidence of MTC, it will take several years to be completed.
In conclusion, our study showed that there are no specific US features of MTC. By applying any one of the RSS available, only less than 50% of cases are identified as highly suspicious for malignancy and FNAC would be suggested only in a relatively small percentage of cases. According to our data, the diagnosis of almost 50% of MTC would be missed or postponed and, at variance with PTC, there is no evidence that this delay in diagnosis, even in smaller tumors, cannot severely compromise the final outcome of the disease.
Declaration of interest
Rossella Elisei is on the editorial board of EJE. Rossella Elisei was not involved in the review or editorial process for this paper, on which she is listed as an author. All the other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This study has been supported by grants to R E from Associazione Italiana per la Ricerca sul Cancro (AIRC, Investigator grant 2018, project code 21790), Agenzia Italiana del Farmaco (AIFA, project code AIFA-2016- 02365049)
References
- 1↑
Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF & Pacini F et al.Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015 25 567–610. (https://doi.org/10.1089/thy.2014.0335)
- 2↑
Moley JF Medullary thyroid carcinoma: management of lymph node metastases. Journal of the National Comprehensive Cancer Network 2010 8 549–556. (https://doi.org/10.6004/jnccn.2010.0042)
- 3↑
Matrone A, Gambale C, Prete A, Piaggi P, Cappagli V, Bottici V, Romei C, Ciampi R, Torregrossa L & De Napoli L et al.Impact of advanced age on the clinical presentation and outcome of sporadic medullary thyroid carcinoma. Cancers 2020 13 94. (https://doi.org/10.3390/cancers13010094)
- 4↑
Tuttle RM, Ball DW, Byrd D, Daniels GH, Dilawari RA, Doherty GM, Duh QY, Ehya H, Farrar WB & Haddad RI et al.Medullary carcinoma. Journal of the National Comprehensive Cancer Network 2010 8 512–530. (https://doi.org/10.6004/jnccn.2010.0040)
- 5↑
Valderrabano P, Klippenstein DL, Tourtelot JB, Ma Z, Thompson ZJ, Lilienfeld HS & McIver B New American Thyroid Association sonographic patterns for thyroid nodules perform well in medullary thyroid carcinoma: institutional experience, systematic review, and meta-analysis. Thyroid 2016 26 1093–1100. (https://doi.org/10.1089/thy.2016.0196)
- 6↑
Wolinski K, Rewaj-Losyk M & Ruchala M Sonographic features of medullary thyroid carcinomas--a systematic review and meta-analysis. Endokrynologia Polska 2014 65 314–318. (https://doi.org/10.5603/EP.2014.0043)
- 7↑
Essig GF, Porter K, Schneider D, Debora A, Lindsey SC, Busonero G, Fineberg D, Fruci B, Boelaert K & Smit JW et al.Fine needle aspiration and medullary thyroid carcinoma: the risk of inadequate preoperative evaluation and initial surgery when relying upon FNAB cytology alone. Endocrine Practice 2013 19 920–927. (https://doi.org/10.4158/EP13143.OR)
- 8↑
Trimboli P, Treglia G, Guidobaldi L, Romanelli F, Nigri G, Valabrega S, Sadeghi R, Crescenzi A, Faquin WC & Bongiovanni M et al.Detection rate of FNA cytology in medullary thyroid carcinoma: a meta-analysis. Clinical Endocrinology 2015 82 280–285. (https://doi.org/10.1111/cen.12563)
- 9↑
Workman AD, Soylu S, Kamani D, Nourmahnad A, Kyriazidis N, Saade R, Ren Y, Wirth L, Faquin WC & Onenerk AM et al.Limitations of preoperative cytology for medullary thyroid cancer: proposal for improved preoperative diagnosis for optimal initial medullary thyroid carcinoma specific surgery. Head and Neck 2021 43 920–927. (https://doi.org/10.1002/hed.26550)
- 10↑
Russ G, Bonnema SJ, Erdogan MF, Durante C, Ngu R & Leenhardt L European Thyroid Association guidelines for ultrasound malignancy risk stratification of thyroid nodules in adults: the EU-TIRADS. European Thyroid Journal 2017 6 225–237. (https://doi.org/10.1159/000478927)
- 11↑
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM & Schlumberger M et al.2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016 26 1–133. (https://doi.org/10.1089/thy.2015.0020)
- 12↑
Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, Paschke R, Valcavi R, Vitti P & AACE/ACE/AME Task Force on Thyroid Nodules. American association of clinical endocrinologists, American college of endocrinology, and associazione medici endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules--2016 update. Endocrine Practice 2016 22 622–639. (https://doi.org/10.4158/EP161208.GL)
- 13↑
Tessler FN, Middleton WD, Grant EG, Hoang JK, Berland LL, Teefey SA, Cronan JJ, Beland MD, Desser TS & Frates MC et al.ACR thyroid imaging, reporting and data system (TI-RADS): white paper of the ACR TI-RADS committee. Journal of the American College of Radiology 2017 14 587–595. (https://doi.org/10.1016/j.jacr.2017.01.046)
- 14↑
Shin JH, Baek JH, Chung J, Ha EJ, Kim JH, Lee YH, Lim HK, Moon WJ, Na DG & Park JS et al.Ultrasonography diagnosis and imaging-based management of thyroid nodules: revised Korean Society of Thyroid Radiology Consensus statement and recommendations. Korean Journal of Radiology 2016 17 370–395. (https://doi.org/10.3348/kjr.2016.17.3.370)
- 15↑
Gorman B, Charboneau JW, James EM, Reading CC, Wold LE, Grant CS, Gharib H & Hay ID Medullary thyroid carcinoma: role of high-resolution US. Radiology 1987 162 147–150. (https://doi.org/10.1148/radiology.162.1.3538147)
- 16↑
Lee S, Shin JH, Han BK & Ko EY Medullary thyroid carcinoma: comparison with papillary thyroid carcinoma and application of current sonographic criteria. AJR: American Journal of Roentgenology 2010 194 1090–1094. (https://doi.org/10.2214/AJR.09.3276)
- 17↑
Trimboli P, Giovanella L, Crescenzi A, Romanelli F, Valabrega S, Spriano G, Cremonini N, Guglielmi R & Papini E Medullary thyroid cancer diagnosis: an appraisal. Head and Neck 2014 36 1216–1223. (https://doi.org/10.1002/hed.23449)
- 18↑
Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. Journal of the American Medical Association 2006 295 2164–2167. (https://doi.org/10.1001/jama.295.18.2164)
- 19↑
Zhu J, Li X, Wei X, Yang X, Zhao J, Zhang S & Guo Z The application value of modified thyroid imaging report and data system in diagnosing medullary thyroid carcinoma. Cancer Medicine 2019 8 3389–3400. (https://doi.org/10.1002/cam4.2217)
- 20↑
Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna S, Nardi F, Panunzi C, Rinaldi R, Toscano V & Pacella CM Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. Journal of Clinical Endocrinology and Metabolism 2002 87 1941–1946. (https://doi.org/10.1210/jcem.87.5.8504)
- 21↑
Kwak JY, Han KH, Yoon JH, Moon HJ, Son EJ, Park SH, Jung HK, Choi JS, Kim BM & Kim EK Thyroid imaging reporting and data system for US features of nodules: a step in establishing better stratification of cancer risk. Radiology 2011 260 892–899. (https://doi.org/10.1148/radiol.11110206)
- 22↑
Kim SH, Kim BS, Jung SL, Lee JW, Yang PS, Kang BJ, Lim HW, Kim JY, Whang IY & Kwon HS et al.Ultrasonographic findings of medullary thyroid carcinoma: a comparison with papillary thyroid carcinoma. Korean Journal of Radiology 2009 10 101–105. (https://doi.org/10.3348/kjr.2009.10.2.101)
- 23↑
Trimboli P, Nasrollah N, Amendola S, Rossi F, Ramacciato G, Romanelli F, Aurello P, Crescenzi A, Laurenti O & Condorelli E et al.Should we use ultrasound features associated with papillary thyroid cancer in diagnosing medullary thyroid cancer? Endocrine Journal 2012 59 503–508. (https://doi.org/10.1507/endocrj.ej12-0050)
- 24↑
Choi N, Moon WJ, Lee JH, Baek JH, Kim DW & Park SW Ultrasonographic findings of medullary thyroid cancer: differences according to tumor size and correlation with fine needle aspiration results. Acta Radiologica 2011 52 312–316. (https://doi.org/10.1258/ar.2010.100247)
- 25↑
Hong YJ, Son EJ, Kim EK, Kwak JY, Hong SW & Chang HS Positive predictive values of sonographic features of solid thyroid nodule. Clinical Imaging 2010 34 127–133. (https://doi.org/10.1016/j.clinimag.2008.10.034)
- 26↑
Cappelli C, Pirola I, Cumetti D, Micheletti L, Tironi A, Gandossi E, Martino E, Cherubini L, Agosti B & Castellano M et al.Is the anteroposterior and transverse diameter ratio of nonpalpable thyroid nodules a sonographic criteria for recommending fine-needle aspiration cytology? Clinical Endocrinology 2005 63 689–693. (https://doi.org/10.1111/j.1365-2265.2005.02406.x)
- 27↑
Ren J, Liu B, Zhang LL, Li HY, Zhang F, Li S & Zhao LR A taller-than-wide shape is a good predictor of papillary thyroid carcinoma in small solid nodules. Journal of Ultrasound in Medicine 2015 34 19–26. (https://doi.org/10.7863/ultra.34.1.19)
- 28↑
Dobruch-Sobczak K, Guminska A, Bakula-Zalewska E, Mlosek K, Slapa RZ, Wareluk P, Krauze A, Ziemiecka A, Migda B & Jakubowski W et al.Shear wave elastography in medullary thyroid carcinoma diagnostics. Journal of Ultrasonography 2015 15 358–367. (https://doi.org/10.15557/JoU.2015.0033)
- 29↑
Remonti LR, Kramer CK, Leitao CB, Pinto LC & Gross JL Thyroid ultrasound features and risk of carcinoma: a systematic review and meta-analysis of observational studies. Thyroid 2015 25 538–550. (https://doi.org/10.1089/thy.2014.0353)
- 30↑
Rago T, Vitti P, Chiovato L, Mazzeo S, De Liperi A, Miccoli P, Viacava P, Bogazzi F, Martino E & Pinchera A Role of conventional ultrasonography and color flow-Doppler sonography in predicting malignancy in ‘cold’ thyroid nodules. European Journal of Endocrinology 1998 138 41–46. (https://doi.org/10.1530/eje.0.1380041)
- 31↑
Zhao J, Yang F, Wei X, Mao Y, Mu J, Zhao L, Wu J, Xin X, Zhang S & Tan J Ultrasound features value in the diagnosis and prognosis of medullary thyroid carcinoma. Endocrine 2020 72 725– 734. (https://doi.org/10.1007/s12020-020-02510-2)
- 32↑
Yun G, Kim YK, Choi SI & Kim JH Medullary thyroid carcinoma: application of Thyroid Imaging Reporting and Data System (TI-RADS) Classification. Endocrine 2018 61 285–292. (https://doi.org/10.1007/s12020-018-1594-4)
- 33↑
Wang Y, Li L, Wang YX, Feng XL, Zhao F, Zou SM, Hao YZ, Ying JM & Zhou CW Ultrasound findings of papillary thyroid microcarcinoma: a review of 113 consecutive cases with histopathologic correlation. Ultrasound in Medicine and Biology 2012 38 1681–1688. (https://doi.org/10.1016/j.ultrasmedbio.2012.05.019)
- 34↑
Ito Y, Miyauchi A. Active surveillance of low-risk papillary thyroid microcarcinomas. Gland Surgery 2020 9 1663–1673. (https://doi.org/10.21037/gs-2019-catp-03)
- 35↑
Molinaro E, Campopiano MC, Pieruzzi L, Matrone A, Agate L, Bottici V, Viola D, Cappagli V, Valerio L & Giani C et al.Active surveillance in papillary thyroid microcarcinomas is feasible and safe: experience at a single Italian center. Journal of Clinical Endocrinology and Metabolism 2020 105 e172–e180. (https://doi.org/10.1210/clinem/dgz113)
- 36↑
Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, Iacconi P, Basolo F & Pinchera A et al.Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. Journal of Clinical Endocrinology and Metabolism 2004 89 163–168. (https://doi.org/10.1210/jc.2003-030550)
- 37↑
Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2010 95 2655–2663. (https://doi.org/10.1210/jc.2009-2368)
- 38↑
Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S & Schlumberger M Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2003 88 2070–2075. (https://doi.org/10.1210/jc.2002-021713)
- 39↑
Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, Schlumberger M, Bigorgne JC, Dumontier P & Leclerc L et al.Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'etude des tumeurs a calcitonine. Clinical Endocrinology 1998 48 265–273. (https://doi.org/10.1046/j.1365-2265.1998.00392.x)
- 40↑
Elisei R Routine serum calcitonin measurement in the evaluation of thyroid nodules. Best Practice and Research. Clinical Endocrinology and Metabolism 2008 22 941–953. (https://doi.org/10.1016/j.beem.2008.09.008)
- 41↑
Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, Miccoli P & Pinchera A Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 1994 78 826–829. (https://doi.org/10.1210/jcem.78.4.8157706)
