DOI: https://doi.org/10.21203/rs.3.rs-1819511/v1
Background: To investigate sonographic features of cervical lymph node metastases from medullary thyroid cancer (LNM-MTC), as compared with lymph node metastases from papillary thyroid cancer (LNM-PTC).
Methods: A total of 42 MTC patients with 52 metastatic LNs and 188 PTC patients with 208 metastatic LNs who were confirmed by fine needle aspiration and post-operative pathology, were enrolled in this study. The clinical characteristics and sonographic features of LNs were compared between the two groups. Univariate analysis and multivariate logistic regression analysis were performed on the sonographic features of LNs, including short and long-axis diameter, long-axis diameter/short-axis, shape, border, hilum, echogenicity, calcifications, cystic change and vascularity pattern.
Results: The mean age of patients with LNM-MTC was 46.81±13.05, which was older than that of LNM-PTC group (P=0.000). No differences were observed in gender, location, long-axis diameter/short-axis, shape, border, echogenicity, cystic change and vascularity pattern between LNM-MTC and LNM-PTC groups (P >0.05, for all). However, long-axis and short-axis diameter, hilum and calcifications were statistically different between these two groups (P<0.05, for all).
Conclusion: Compared with LNM-PTC, LNM-MTC tended to have the sonographic characteristics of larger size, absence of hilum, and less calcifications, and awareness of these features might be helpful to in the diagnosis of LNM-MTC.
As a neuroendocrine tumor, medullary thyroid carcinoma (MTC) is originated from parafollicular cells (C cells), which could secrete calcitonin[1]. MTC accounts for 5–8% of all thyroid malignant nodules[2], and it is prone to present lymph node metastasis (LNM), with a high recurrence rate and poor prognosis. Even after the initial surgery, the recurrence rate is still up to 40–66%[3]. Therefore, early diagnosis of regional lymph nodes is important for determining surgical strategy, which may be helpful to improve quality of life and reduce the mortality rate.
Ultrasound(US) is an effective method to distinguish benign from metastatic lymph nodes(LN), with a high specificity, however, the sensitivity is low for LNMs, especially for central LNs.[4, 5] Previous studies showed that specific sonographic features of metastatic LNs from thyroid carcinoma included microcalcifications, hyperechogenicity, partially cystic change, peripheral or diffusely increased vascularization.[6, 7] However, the results of these studies were mainly based on lymph node metastases from papillary thyroid cancer(LNM-PTC), which might not be applicable to lymph node metastases from medullary thyroid cancer(LNM-MTC). To the best of our knowledge, only a few studies with limited cases had focused on the sonographic features of LNM-MTC[8]. Therefore, this study aimed to investigate the clinical and sonographic characteristics of LNM-MTC compared with LNM-PTC.
This retrospective study was approved by Ethics Committee of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, with waiver of informed consent. Consecutive patients with suspicious LNs who underwent US and fine needle aspiration (FNA) at our hospital from January 2014 to December 2020 were reviewed. Finally, 42 patients with 52 LNM-MTC and 188 patients with 208 LNM-PTC, who were confirmed by preoperative FNA and postoperative pathology, were enrolled in our study.
The inclusion criteria were as follows: (1) patients with cervical LNs which were evaluated by US examination and FNA; (2) patients with suspicious thyroid nodules; (3) US was performed by senior physicians. (4) LN dissection was performed, and LN was confirmed with post-operative pathology. Exclusion criteria were as follows: (1) patients without complete medical and US image information. (2) patients with history of neck irradiation; (3) undiagnosable or unsatisfactory cytological results; (4) patients associated with other LN diseases, such as LN tuberculosis, lymphoma, Kikuchi-Fujimoto disease and metastasis from other diseases.
During the sonographic examination, the patient was in the supine position, and the anterior area of the neck was fully exposed. All gray scale and Doppler sonographic examinations were performed with a 4- to 13-MHz linear probe (MyLab 90; EsaoteSpA, Genoa, Italy & iU22 system, Philips, Seattle,WA, USA) by 1 of 2 radiologists with 5 to 10 years of experience in thyroid and LN sonography. The gray scale and Doppler US were carefully adjusted to obtain the best image. Images of each suspicious LN were obtained in both transverse and longitudinal orientations, and images were recorded and uploaded for later retrospective analysis.
The sonographic appearances of LNs were assessed carefully, including location, long-axis diameter(L), short-axis diameter(S), Long-axis diameter/short-axis (L/S), shape, border, cortex echogenicity, hilum, calcifications, cystic change and vascularity pattern. Location was divided lateral region (level I-V) and central region (level VI or VII). If multiple LNMs were found in the same region, only the largest one was selected. Long-axis and short-axis diameters were obtained at the maximum of the longitudinal section of LN. L/S was classified into ≤ 2 and > 2. Shape was assessed as irregular/regular. Border was divided into sharp and unsharp. The cortex echogenicity was determined as hyperechoic, isoechoic, and hypoechoic, as compared with the surrounding muscles. Hilum, calcifications and cystic change were categorized into absent or present. Vascularity pattern was classified as abnormal flow, hilar flow or absent flow. If peripheral or diffusely increased flow was observed, it was regarded as abnormal flow.[6, 9]
FNA was performed by 2 of 3 radiologists with more than 5 years of experience in thyroid FNA, and the procedure was performed by freehand technique with 23G or 25G gauge needle and 5 ml syringe. Each LN was punctured for at least 3 times. Cytological smears were assessed by professional cytopathologists. LNs were included only if the FNA results were consistent with postoperative pathology.
Mann-Whitney U test, χ2 and Fisher exact tests by univariate analysis were used to analyze clinical information, sonographic features on grey scale and color Doppler. In order to obtain the best cut-off points, receiver operating characteristic (ROC) curve analysis was used for long and short-axis diameter. A multiple logistic regression analysis was applied to evaluate the malignancy risk for the independent features of sonographic features. The B value, Wals χ, ratio (OR) and 95% CI were recorded. A p value < 0.05 was considered to indicate statistical significance. The statistical analysis was performed using SPSS version 25 (IBM Corporation, Armonk, NY, USA).
Clinicopathological characteristics of LNM-MTC and LNM-PTC groups
The clinical characteristics of the patients with LNM-MTC and LNM-PTC were listed in Table 1. There were no significant differences in gender and location between LNM-MTC and LNM-PTC groups (P>0.05). The mean age of patients with LNM-MTC was older than that of patients with LNM-PTC (46.81±13.05 vs 39.07±12.02, P=0.000).
Univariate analysis of US features in LNM-MTC and LNM-PTC groups
Table 1 showed the US features in LNM-MTC and LNM-PTC groups.. LNM-MTCs were more likely to have the following US features (Table 1): L/S≤2, regular shape, sharp border, isoechoic or hypoechoic, however, there were no significant differences in these features between LNM-MTC and LNM-PTC groups (P>0.05). The ROC curve was used for the long and short-axis diameters. The cutoff points of long-axis diameter and short diameter were 8.95 and 6.95, and the areas under the curve were 0.640 and 0.661, respectively. Then, long and short-axis diameters were converted into binary variables. The mean sizes of LNM-MTC (Fig 1) were larger than those of LNM-PTC (Fig 2) in both long-axis diameter and short-axis diameter (P<0.05). There were statistically significant differences in the features of hilum, calcifications and vascularity pattern between LNM-MTC and LNM-PTC (P<0.05). By comparing the US characteristics of LNM-MTC in the lateral and central groups, it showed that the long axis diameter was significantly different between the two groups(P<0.05), while the other characteristics had no differences (Table 2).
Multivariate logistic regression analysis of US features in LNM-MTC and LNM-PTC groups
The results of multivariate logistic regression analysis were listed in table 3. The ultrasonic indicators with statistical significance in the univariate analysis were included in the multivariate logistic regression analysis, and the malignancy risk was further evaluated for the independent features. Compared with LNM-PTC, long-axis diameter>8.95 (OR=3.355), short-axis diameter>6.95 (OR=2.210), absence of hilum (OR=2.896) and absence of calcification (OR=0.147) were more common in LNM-MTC (P<0.05), while there was no statistical significance in vascularity pattern (P>0.05).
As previously reported, MTC is a rare thyroid malignant tumor with an incidence of 0.11/100,000 in the population, which can be divided into sporadic and genetic types[10]. The C cells of MTC can secrete many kinds of substances, among which serum calcitonin is a valuable tumor marker of MTC. MTC is more aggressive than PTC, and it is prone to distant metastases including lung, liver, bone, and adrenal glands. Weber et al. reported that LNM-MTCs could be found in 75% patients who underwent total thyroidectomy and modified radical neck dissections[11]. Cervical lymph node dissection had certain complications, such as thoracic duct leak, injury to the recurrent laryngeal nerve, and hypoparathyroidism, and repeated operations were very traumatic to patients. Therefore, accurate preoperative diagnosis of LNM is of great significance for surgical plans.
In our study, there was no difference in gender between the two groups, however, patients with LNM-MTC were older than those with LNM-PTC. Similar results have also been reported in primary thyroid cancer. A previous study showed that patients with MTC were older than those with PTC[12]. No difference was observed in the location between LNM-MTC and LNM-PTC groups. However, more LNMs were located at the lateral region in both groups. LNMs of thyroid cancer usually spread to the central region first, followed by the lateral region[13], and central LNs dissection are routinely performed. Moreover, due to the poor US window and small size of LNs in the central region, the sensitivity of US in the detection of central LNMs was low[4]. Thus, many LNs in the central region might not be recognized, and FNA was not performed.
US is important for distinguishing benign and malignant LNs. The related ultrasonographic indicators of LN include size, L/S, shape, border, hilum, echogenicity, calcifications, cystic change and vascularization. LNMs of thyroid carcinoma are mainly manifested as microcalcifications, hyperechogenicity, cystic change and abnormal vascularization.[6] However, these features were commonly seen in LNM-PTC[14, 15], and they were rarely reported in LNM-MTC. To the best of our knowledge, the ultrasonic features of LNM-MTC have not been well documented in the literatures. In our study, no differences were observed in L/S, shape, border, echogenicity, cystic change and vascularity pattern between LNM-MTC and LNM-PTC groups. However, long-axis and short-axis diameter, hilum and calcifications were statistically different between these two groups.
In our study, the mean long-axis and short-axis diameter in LNM-MTC were 16.43 ± 10.36mm and 8.53 ± 5.79mm, both larger than those of LNM-PTC. Compared with PTC, MTC had a higher degree of malignancy and invasion[12, 16], which might be the reason for larger sizes of LNs. Normal LNs usually have an echogenic hilum, while metastatic LNs usually present with absence of hilum.[7, 14, 17] The metastases of the tumor initially appear in the peripheral area of LN, but as the size of metastases become larger, the normal nodal tissue destroyed. When LNs were filled with tumor cells, hilum could not be recognized[18]. However, absence of hilum may be without significance in distinguishing LNM-PTC from normal LNs[6]. Due to its indolent nature, PTC usually develops slowly. When the medullary lymphatic sinuses have not been completely destroyed by tumor cells, hilum also exists in early LNMs[19]. The results in our study showed that absence of hilum was more commonly detected in LNM-MTC than in LNM-PTC. MTC is a moderate malignancy, and the tumor cells commonly grow with invasion. The difference might be due to the more aggressive biological behavior.
Nodal calcification plays an important role in differentiating benign and malignant LNs. It is also an important indicator of primary thyroid carcinoma[20]. Li et al revealed that macrocalcification was more frequent in MTC, while microcalcification was more common in PTC[1]. Microcalcifications are usually round or concentric under the light microscope, with a tiny diameter of 10 to 100 µm, which correspond to the psammoma bodies on pathology. In MTC, macrocalcifications are associated with amyloid deposits [21]. Calcification in LNMs is generally rare, but it is common in LNM from thyroid cancer. Kim et al. found that there was no significant difference in calcifications between PTCs and MTCs[22]. To the best of our knowledge, calcification in metastatic LNs has not been compared between the two tumors. Our results showed that the incidence of calcifications in LNM-MTC group was significantly lower than that in LNM-PTC group (P < 0.05). In the LNM-PTC group, calcification was found in 58.6% (139/237) LNs, with a relatively high incidence. However, in LNM-MTC group, the incidence of calcifications was not high in LNM-MTC group, and it was detected in only 21.2% (11/52) cases. Due to the low prevalence, calcifications were not further subdivided into coarse and fine calcifications. The difference between the two groups indicated that although calcification was regarded as an ultrasonic feature of LNM-PTC, this sign may not be applied to LNM-MTC.
Hyperechogenicity and cystic change are also the characteristic manifestations of PTC-LNMs, and there were no differences between LNM-MTC and LNM-PTC in our study. The typical echogenicity of LNM from thyroid cancer is hyperechoic in the cortex compared to skeletal muscle[9]. This may be due to the deposition of thyroglobulin and clustering of the tumor cells in the LNs [9, 23]. LNM should also be suspected in patients with suspicious thyroid nodules when cystic change existed. The mechanism of cystic change in LNM may be related to necrosis[24]. Our results suggested that hyperechogenicity and cystic change can also be applied to LNM-MTC. Normal LNs usually had hilar flow, while metastatic LNs often showed peripheral flow or mixed flow, which was usually considered as abnormal flow[9]. Peripheral flow was a meaningful feature of LNM from thyroid cancer[25], which was caused by tumor angiogenesis or recruitment of capsular vessels[23]. In our study, abnormal flow was more frequent in LNM-MTC than in LNM-PTC, but the difference was not significant(P༞0.05).
It was reported that the ultrasonographic characteristics of LNM-PTC in the central and cervical groups were different[26]. The high frequency of malignant US characteristics in the lateral LNMs included partial cystic component, microcalcifications and diffusely increased echogenicity, however, these ultrasound findings may not apply to the central group. It was suggested that the taller-than-wide type was only malignant US feature in the central LNMs[26]. Previous studies also suggested that the sensitivity of US in central LNMs was lower than that of lateral cervical LNM in PTC, because the lymph nodes in the central region lacked characteristic sonographic appearances[4, 26]. The comparison of ultrasound images between the central and lateral LNs in LNM-MTC group was performed in our study, however, there were no differences in other indicators except the long-axis diameter. According to the results of our study, we suggested that the US features of LNM-MTC could also be applicable to the central LNMs.
There were several limitations in this study: First, due to the retrospective nature of this study, it is likely to have selection bias and restricted quality of images and data. Second, the sample size of LNM-MTC group was small, and a further study with a larger sample size should be performed.
Although some ultrasonic features were overlapped in LNM-MTC and LNM-PTC, LNM-MTC tended to have the sonographic characteristics of large size, absence of hilum, and less calcifications, and awareness of these features might be helpful to in the diagnosis of LNM-MTC.
MTC: medullary thyroid carcinoma;
LNM: lymph node metastasis;
US: Ultrasound;
LN: lymph node;
LNM-PTC: lymph node metastases from papillary thyroid cancer;
LNM-MTC: lymph node metastases from medullary thyroid cancer;
L: long-axis diameter;
S: short-axis diameter;
ROC: receiver operating characteristic
OR: odd ratio
Authors’ contributions
XN, SX made substantial contributions to conception and design; XN, SX, WZ1, WZ2 have been involved in drafting the manuscript or revised it critically for important intellectual content; all the authors gave final approval of the version to be published.
Founding:
National Natural Science Foundation of China(NO:82071923). The funder(s) conceived of the present idea of the study, but had no role in study design, data analysis, data interpretation or in the decision to submit the manuscript for publication.
Compliance with ethical standards
Conflict of interest: The authors declare that they have no conflict of interest.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The requirements for consent to participate and written informed consent were waived by Ethics Committee of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, for it is a retrospective study. All methods were performed in accordance with the relevant guidelines and regulations.
Consent for publication
Not applicable.
Availability of data and materials
Due to patient privacy protection, materials and data are not publicly available, but are available from the corresponding author for reasonable request.
Competing interests
The authors declare that they have no competing interests
Funding
This work was supported by “National Natural Science Foundation of China”(NO:82071923). The funder(s) conceived of the present idea of the study, but had no role in study design, data analysis, data interpretation or in the decision to submit the manuscript for publication.
Authors’ contributions
XN, SX made substantial contributions to conception and design; XN, WZ1, WZ2 have been involved in drafting the manuscript or revised it critically for important intellectual content; all the authors gave final approval of the version to be published.
Acknowledgements
The authors are grateful to all participants of this study.
Authors' information
1. Department of Ultrasound, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2. Department of Ultrasound, RuiJin Hospital / Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Table 1: Univariate Analysis of Clinical Characteristics and Ultrasound Features of Lymph Nodes in the MTC and PTC Groups
|
|
MTC (n, %) |
PTC (n, %) |
P value |
No. of LNs |
|
52 |
237 |
|
No. of patients |
|
42 |
224 |
|
|
Clinical Characteristics |
|||
Gender |
Male |
17 (40.48) |
60 (26.79) |
0.073 |
|
Female |
25 (59.52) |
164 (73.21) |
|
Age |
|
46.81±13.05 |
39.07±12.02 |
0.000(Z=-3,873) |
Location |
Lateral |
34 (65.38) |
180 () |
0.116 |
|
Central |
18 (34.62) |
57 () |
|
|
Ultrasound Features |
|||
Long-axis diameter |
|
16.43±10.36 |
12.45±7.35 |
0.002 |
|
>8.95 |
45 (86.54) |
151 (63.71) |
0.001# |
|
<8.95 |
7 (13.46) |
86 (36.29) |
|
Short-axis diameter |
|
8.53±5.79 |
5.92±2.75 |
0.000 |
|
>6.95 |
28 (53.85) |
64 (27.00) |
0.000# |
|
<6.95 |
24 (46.15) |
173 (73.00) |
|
L/S |
≤2 |
30 (57.69) |
135 (56.96) |
0.923 |
|
>2 |
22 (42.31) |
102 (43.04) |
|
Shape |
Irregular |
3 (5.77) |
5 (2.11) |
0.147* |
|
Regular |
47 (94.23) |
232 (97.89) |
|
Border |
Unsharp |
2 (3.85) |
4 (1.69) |
0.295* |
|
Sharp |
50 (96.15) |
233 (98.31) |
|
Hilum |
Absent |
47 (90.38) |
170 (71.73) |
0.004# |
|
Present |
5 (9.62) |
67 (28.27) |
|
Echogenicity |
Hyperechoic |
19 (36.54) |
67 (28.27) |
0.238 |
|
Isoechoic or hypoechoic |
33 (63.46) |
170 (71.73) |
|
Calcifications |
Present |
11 (21.15) |
139 (58.65) |
0.000# |
|
Absent |
41 (78.85) |
98 (41.35) |
|
Cystic change |
Present |
2 (3.85) |
29 (12.24) |
0.086* |
|
Absent |
50 (96.15) |
208 (87.76) |
|
Vascularity pattern |
Abnormal flow |
31 (59.61) |
102 (43.04) |
0.030# |
|
Hilar flow or absent flow |
21 (40.38) |
135 (56.96) |
|
Table 2: Univariate Analysis of Ultrasound Features of LNM-MTC in the lateral and central groups
|
|
Lateral (n, %) (n=34) |
Central (n, %) (n=18) |
P value |
Long-axis diameter |
>8.95 |
32 (94.12) |
13 (72.22) |
0.041* |
|
<8.95 |
2 (5.88) |
5 (27.78) |
|
Short-axis diameter |
>6.95 |
19 (55.88) |
9 (50) |
0.686 |
|
<6.95 |
15 (44.12) |
9 (50) |
|
L/S |
≤2 |
17 (50) |
13 (72.22) |
0.123 |
|
>2 |
17 (50) |
5 (27.78) |
|
Shape |
Irregular |
2 (5.88) |
1 () |
1.000* |
|
Regular |
32 (94.12) |
17 () |
|
Border |
Unsharp |
2 (5.88) |
0 (0) |
0.538* |
|
Sharp |
32 (94.12) |
18 (100) |
|
Hilum |
Absent |
31 (91.18) |
16 (88.89) |
1.000* |
|
Present |
3 (8.82) |
2 (11.11) |
|
Echogenicity |
Hyperechoic |
13 (38.24) |
6 (33.33) |
0.727 |
|
Isoechoic or hypoechoic |
21 (61.76) |
12 (66.67) |
|
Calcifications |
Present |
7 (20.58) |
4 (22.22) |
1.000* |
|
Absent |
27 (79.41) |
14 (77.78) |
|
Cystic change |
Present |
2 (5.88) |
0 (0) |
0.538* |
|
Absent |
32 (55.88) |
18 (100) |
|
Vascularity pattern |
Abnormal flow |
22 (64.71) |
9 (50) |
0.304 |
|
Hilar flow or absent flow |
12 (35.29) |
9 (50) |
|
Table 3: Odds Ratios for the Selected Sonographic Features by Multivariate Logistic Regression Analysis
|
Multivariate Analysis |
||||
|
B |
Wals χ2 |
Odds Ratio |
95% CI |
P value |
Long-axis diameter |
1.211 |
.480 |
3.355 |
1.309-8.603 |
.012 |
Short-axis diameter |
.793 |
.372 |
2.210 |
1.065-4.585 |
.033 |
Hilum |
1.063 |
.526 |
2.896 |
1.033-8.113 |
.043 |
Calcifications |
-1.918 |
.388 |
.147 |
.069-0.314 |
.000 |
Vascularity pattern |
.540 |
.348 |
1.716 |
.867-3.394 |
.121 |