A nomogram based on ultrasound characteristics to predict large-number cervical lymph node metastasis in papillary thyroid carcinoma

Abstract

To establish a nomogram for predicting large-number cervical lymph node metastases (LNMs) of primary papillary thyroid carcinoma (PTC) based on ultrasound characteristics. This retrospective study included patients with PTC diagnosed by pathological examination and who underwent surgery between August 2015 and May 2021 at Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo, China). Large-number LNM was defined as >5 lymph nodes with metastases. The patients were propensity score-matched (PSM) for age and sex. A multivariable analysis was used to determine the risk factors for massive LNM. After PSM, the 78 patients with large-number LNM were matched with 312 patients with small-number LNM. Compared with the patients with small-number LNM, those with large-number LNM had larger tumors (13.0 ± 7.7 vs. 6.8 ± 3.8 mm, p < 0.001), and higher frequencies of multifocal nodules (42.3% vs. 22.4%, p < 0.001), taller-than-wide shape (82.1% vs. 56.7%, p < 0.001), calcifications (76.9% vs. 47.4%, p < 0.001), microcalcifications (68.0% vs. 36.5%, p < 0.001), capsule invasion (32.1% vs. 17.6%, p = 0.005), and ultrasound diagnosis of LNM (44.9% vs. 9.3%, p < 0.001). The multivariable analysis showed that nodule size (OR = 1.19, 95%CI: 1.11–1.27, p < 0.001), multifocal disease (OR = 2.50, 95%CI: 1.30–4.80, p = 0.006), taller-than-wide shape (OR = 0.45, 95%CI: 0.22–0.93, p = 0.032), and ultrasound diagnosis of LNM (OR = 5.57, 95%CI: 2.73–11.37, p < 0.001) were independently associated with large-number LNM. A nomogram was built, and the area under the receiver operating characteristics curve was 0.86 (95%CI: 0.81–0.90). A nomogram was successfully built to predict large-number LNM in patients with PTC, based on nodule size, multifocality, taller-than-wide shape, and ultrasound diagnosis of LNM.

THYROID CANCER had an estimated 586,202 new cases in 2020, with 43,646 deaths [1]. Papillary thyroid carcinoma (PTC) is the most common malignant thyroid tumor and accounts for about 70%–80% of all thyroid carcinomas [2]. PTC has extremely diverse biology, from indolent and nonprogressive nodules within the thyroid gland (most common) to aggressive metastatic cancers [3, 4]. Despite this diversity, papillary thyroid cancer is usually associated with an excellent prognosis in adults and children, especially for patients with papillary microcarcinomas (diameter <1 cm) [5-8]. The 15-year overall survival (OS) and cancer-specific survival (CSS) rates after PTC surgery are 91% and 99%, respectively [9, 10]. With advancements in diagnostic techniques such as sonography, the detection rate of thyroid nodules has increased significantly, especially the small PTCs with a good prognosis [11]. Nevertheless, prognostic assessment has become a key research subject since the major issue in PTC is the risk of a second surgery due to disease recurrence.

The patient and cancer features associated with a poor prognosis of PTC include age >45 years, very young age, male sex, African American race, large tumor, multifocality, lymph node metastases (LNM), lymphovascular invasion, extrathyroidal invasion, distant metastases, aggressive variants (e.g., tall cell, solid, columnar, diffuse-sclerosing, and hobnail), mutations (e.g., BRAF, RAS, RET, and TERT), and elevated or raising blood thyroglobulin [8, 12, 13]. Cervical LNMs are associated with decreased survival in adults <45 years old with PTC [14]. A nomogram is available for the 5-year CSS in patients with thyroid cancer and includes LNM as one of the most important factors [15].

Hence, LNM is one of the most important prognostic factors in PTC. About 40%–46% of the patients have LNM at PTC diagnosis [16, 17]; most patients have a good prognosis, but cervical LNM is still associated with a poorer prognosis [18-20]. Recurrence occurs in approximately 5% of patients with a small number of LNMs but occurs in approximately 20% when there are multiple LNMs [21-23]. Therefore, the American Thyroid Association (ATA) updated the recurrence risk stratifications in 2015, which classified multiple LNM (>5 metastatic lymph nodes) as a moderate-risk factor for recurrence [8]. Nevertheless, the risk factors for the presence of massive LNM are poorly known.

Therefore, this study aimed to explore the association between the sonographic features of primary PTC and large-number cervical LNMs and establish a nomogram. A nomogram is a graphical representation of a risk model that allows a clinician to intuitively and rapidly calculate a risk score based on a few clinical variables [24, 25]. The results could provide additional references for clinical practices and a better selection of patients for the appropriate therapeutic strategies.

Materials and Methods

Study design and patients

This retrospective study included patients with PTC diagnosed by pathological examination and who underwent surgery between August 2015 and May 2021 at the Department of Interventional Therapy of Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo, China). The study was approved by the Research Ethics Committee of Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo, China) (PJ-NBEY-KY-2019-150-01). This study used the data extracted from the medical records, i.e., data regarding previous clinical diagnoses and treatments. No additional tests, procedures, or interventions were performed for the purpose of this study. The relevant data were collected and analyzed retrospectively, and all data were anonymized prior to analysis. Hence, the Ethics Committee waived the requirement for individual informed consent, as per the research ethics regulations in China.

The inclusion criteria were 1) thyroid ultrasound data available and 2) BRAF gene mutation data available. The exclusion criteria were 1) the location of the thyroid lesion on preoperative ultrasound was inconsistent with the location on postoperative pathological examination, 2) ultrasound images were poor, or 3) clinical data were incomplete.

Data collection and definition

Age, sex, body mass index (BMI, kg/m²), and the presence or absence of Hashimoto’s thyroiditis were extracted from the medical charts. The ultrasound features and BRAF mutation were also extracted from the medical charts. During the study period, a MyLab90 color Doppler ultrasound diagnosis system with a 4–13 MHz LA523 probe (Esaote S.p.A., Genova, Italy) was used to perform a routine ultrasound for the suspect thyroid lesions, as per published guidelines [7, 8].

The size of the thyroid nodule was assessed as to its maximum diameter. The location of the nodule was classified as three levels: up/down [including the superior pole of the thyroid (1/3 of the upper gland), the middle of the thyroid (1/3 of the middle gland), the inferior pole of the thyroid (1/3 of the lower gland), and isthmus]. Morphology, boundary, echo intensity, homogeneity of the internal echo, taller-than-wide shape (≥1 vs. <1), calcifications [macrocalcification (>1 mm), microcalcification (≤1 mm), and absent], presence or absence of cervical lymph nodes by preoperative ultrasound (according to the ATA guidelines, ultrasound signs of cervical LNM of PTC: micro-calcification, cystic changes, morphological rounding, hyperechoic, peripheral blood flow signals), and other ultrasonic features were determined based on the ultrasound reports. Capsule invasion meant that the thyroid gland capsule was invaded by thyroid carcinoma. Large-number LNM was defined as >5 lymph nodes with metastases. Small-number was defined as ≤5 lymph nodes with metastases.

Statistical analysis

SPSS 26.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The nonrandom package of R 4.1.2 was used for propensity score matching (PSM) using age and sex for 1:4 matching. Continuous data with a normal distribution were presented as means ± standard deviations (SD) and analyzed using the independent-samples t-test. The categorical data were presented as n (%) and analyzed using the chi-square test or Fisher’s exact test, and the ordinal data were compared using the Mann-Whitney U-test. In the multivariable logistic analysis, large-number LNM was used as the dependent variable. The factors with statistical differences in the univariable analysis were used as independent variables. The diagnostic model nomogram and calibration curve were prepared using the RMS package of R 4.1.2. The predictive value was analyzed by receiver operating curve (ROC) analysis. Decision curve analysis (DCA) was used to evaluate the clinical usefulness of the model by quantifying the net benefits at different threshold probabilities using the RMDA package of R 4.1.2. p-values <0.05 were considered statistically significant.

Results

Characteristics of the patients

Table 1 presents the characteristics of the patients. Before matching, there were 967 patients with small-number LNM and 78 with large-number LNM. After PSM, the 78 patients with large-number LNM were matched with 312 patients with small-number LNM. Compared with the patients with small-number LNM, those with large-number LNM had larger tumors (13.0 ± 7.7 vs. 6.8 ± 3.8 mm, p < 0.001), and higher frequencies of multifocal nodules (42.3% vs. 22.4%, p < 0.001), taller-than-wide shape (82.1% vs. 56.7%, p < 0.001), calcifications (76.9% vs. 47.4%, p < 0.001), microcalcifications (68.0% vs. 36.5%, p < 0.001), capsule invasion (32.1% vs. 17.6%, p = 0.005), and ultrasound diagnosis of LNM (44.9% vs. 9.3%, p < 0.001). There were no significant differences between the two groups regarding the BRAF V600E mutation (p = 0.562).

Table 1 Comparison between patients with large-number vs. small-number lymph node metastases of papillary thyroid carcinoma

Factor	Before matching			After matching
	Small-number metastases (n = 967)	Large-number metastases (n = 78)	p	Small-number metastases (n = 312)	Large-number metastases (n = 78)	p
Age, years	44.6 ± 12.4	38.6 ± 11.7	<0.001	38.0 ± 11.3	38.6 ± 11.7	0.692
Body mass index (kg/m2)	23.2 ± 3.3	23.1 ± 3.7	0.848	23.2 ± 3.6	23.1 ± 3.7	0.898
Nodule size (mm)	6.6 ± 3.7	13.0 ± 7.7	<0.001	6.82 ± 3.80	13.01 ± 7.69	<0.001
Sex, n (%)			0.013			0.473
Male	205 (21.2)	26 (33.3)		91 (29.2)	26 (33.3)
Female	762 (78.8)	52 (66.7)		221 (70.8)	52 (66.7)
Complicated with Hashimoto’s thyroiditis, n (%)	191 (19.8)	19 (24.4)	0.329	69 (22.1)	19 (24.4)	0.672
Number of nodules, n (%)			0.001			<0.001
Single	728 (75.3)	45 (57.7)		242 (77.6)	45 (57.7)
Multifocal	239 (24.7)	33 (42.3)		70 (22.4)	33 (42.3)
Location of the nodule, n (%)			0.277			0.159
Upper	222 (23.0)	25 (32.1)		66 (21.2)	25 (32.1)
Middle	365 (37.7)	23 (29.5)		125 (40.1)	23 (29.5)
Lower	279 (28.9)	22 (28.2)		93 (29.8)	22 (28.2)
Isthmus	101 (10.4)	8 (10.3)		28 (9.0)	8 (10.3)
Nodular morphology, n (%)			0.605			0.117
Regular	259 (26.8)	23 (29.5)		66 (21.2)	23 (29.5)
Irregular	708 (73.2)	55 (70.5)		246 (78.9)	55 (70.5)
Boundary, n (%)			0.271			0.454
Clear	345 (35.7)	23 (29.5)		79 (25.32)	23 (29.5)
Unclear	622 (64.3)	55 (70.5)		233 (74.7)	55 (70.5)
Hypoechoic echo intensity, n (%)	896 (92.7)	70 (89.7)	0.349	284 (91.0)	70 (89.7)	0.726
Internal echo, n (%)			0.011			0.876
Homogeneous	504 (52.1)	29 (37.2)		119 (38.1)	29 (37.2)
Heterogeneous	463 (47.9)	49 (62.8)		193 (61.9)	49 (62.8)
Taller than wide shape, n (%)			<0.001			<0.001
≥1	511 (52.8)	64 (82.1)		177 (56.7)	64 (82.1)
<1	456 (47.2)	14 (17.9)		135 (43.3)	14 (18.0)
Calcification, n (%)	407 (42.1)	60 (76.9)	<0.001	148 (47.4)	60 (76.9)	<0.001
Microcalcification, n (%)	300 (31.0)	53 (67.9)	<0.001	114 (36.5)	53 (68.0)	<0.001
Capsule invasion, n (%)	183 (18.9)	25 (32.1)	0.005	55 (17.6)	25 (32.1)	0.005
Ultrasound diagnosis of lymph nodes, n (%)	57 (5.9)	35 (44.9)	<0.001	29 (9.3)	35 (44.9)	<0.001
BRAF V600E mutation, n (%)	735 (76.0)	56 (71.8)	0.404	234 (75.0)	56 (71.8)	0.562

Multivariable analysis

The multivariable analysis showed that nodule size (OR = 1.19, 95%CI: 1.11–1.27, p < 0.001), multifocal disease (OR = 2.50, 95%CI: 1.30–4.80, p = 0.006), taller-than-wide shape (OR = 0.45, 95%CI: 0.22–0.93, p = 0.032), and ultrasound diagnosis of LNM (OR = 5.57, 95%CI: 2.73–11.37, p < 0.001) were independently associated with large-number LNM (Table 2).

Table 2 Multivariable logistic regression of risk factors of large-number lymph node metastases of papillary thyroid carcinoma (after matching)

Factor	OR	95% CI	p
Size of nodules	1.186	1.111–1.267	<0.001
Number of nodules (multiple vs. single)	2.498	1.299–4.804	0.006
Taller-than-wide shape (≥1 vs. <1)	0.449	0.216–0.934	0.032
Calcification (yes vs. no)	1.409	0.460–4.314	0.549
Morphology of calcification (microcalcification vs. non-microcalcification)	1.588	0.555–4.541	0.388
Capsule invasion (yes vs. no)	1.521	0.735–3.145	0.258
US-LNM (metastasis vs. non-metastasis)	5.566	2.726–11.366	<0.001

OR: odds ratio; CI: confidence interval; US-LNM: ultrasound diagnosis of lymph nodes.

Nomogram

The results of the multivariable analysis were used to build the nomogram (Fig. 1). The ROC analysis showed that the AUC of the model was 0.86 (95%CI: 0.81–0.90) (Fig. 2A). The calibration curve showed that the predicted and actual curves were basically superposed (Fig. 2B). Fig. 3 shows the decision curve of the model. The DCA curve showed that within the entire range of prediction thresholds, using the new model to predict the large-number LNM risk achieved net benefits.

Fig. 1

Nomogram of the diagnostic model.

Fig. 2

(A) Receiver operating curve of the diagnostic model (area under the curve = 0.856; 95% confidence interval: 0.811–0.902). (B) Calibration curve of the diagnostic model.

Fig. 3

Decision curve of the diagnostic model. The black line and light grey line represent the hypothesis that no patients and all patients had large-number LNM, respectively.

This study suggests a nomogram to predict large-number LNM in patients with PTC, based on nodule size, multifocality, taller-than-wide shape, and ultrasound diagnosis of LNM.

Discussion

The present study examined the risk factors for large-number LNM, i.e., >5 LNMs, not only the presence of LNMs. Nodule size is a well-known risk factor for LNM [8, 12, 13]. It is consistent with the fact that large tumors tend to be more aggressive [26]. Still, there is no consensus on the best cutoff tumor size for predicting LNMs. Indeed, Aljohani et al. [27] showed that 75% of the patients with PTCs >30 mm had ≥5 LNMs. Jin et al. [28] showed that tumors >20 mm were independently associated with ≥5 LNMs, as supported by Ito et al. [29] and Sun et al. [30], while other studies used a cutoff of 10 mm [31-33].

Multifocal PTC is a risk factor for LNM [30]. The BRAF V600E is a risk factor for LNM [34, 35], but there were no differences in the present study between the two groups before or after matching. Recent studies also showed that multifocal PTC is a risk factor for large-number LNMs [36, 37]. On the other hand, other studies suggest no association between multifocality and large-number LNMs [28, 38]. The sonographer’s experience could influence those results since small foci <2 mm could be missed.

In the present study, a taller-than-wide shape was indicative of a higher risk of large-number LNMs, which was not observed in previous studies [39, 40]. In the study by Ye et al. [41], a taller-than-wide shape was associated with LNM in the univariable analysis but not in the multivariable one. The discrepancies could be due to the factors used for adjustment. On the other hand, a preoperative diagnosis of LNM by ultrasound carries a risk of finding LNMs during the surgery. Ultrasound cannot detect micrometastases, but detecting macrometastases by ultrasound might suggest that other lymph nodes contain microscopic lesions. Ultrasound is a good option for detecting LNMs from PTC [42, 43].

A nomogram was developed by Zhao et al. [44] to determine the risk of central LNM in patients with PTC and Hashimoto’s thyroiditis based on younger age, normal body mass index, BRAF V600E mutation, larger size, left lobe, taller-than-wide shape, capsular invasion, and calcification. A nomogram by Shen et al. [45] included multifocality, tumor size, and TI-RADS score in determining the risk of LNM in patients suspected of PTC. Still, the present study is the first to build a nomogram specifically for predicting large-number LNMs in PTC. Nodule size, multifocality, taller-than-wide shape, and ultrasound diagnosis of LNM could be combined to predict large-number LNMs before surgery for PTC.

This study has limitations. The sample size was relatively small since only one center was included. The sample size was too small to perform a formal validation of the nomogram using training and validation cohorts. The data were limited to those available in the medical charts since data collection was performed retrospectively. Future studies should confirm and validate this nomogram.

In conclusion, this study allowed the building of a nomogram to predict large-number cervical LNM in patients with PTC. This nomogram was based on nodule size, multifocality, taller-than-shape, and ultrasound diagnosis of LNM, which are all data that are routinely obtained in the preoperative workup of patients suspected of PTC.

Statements

Acknowledgments

Zhanbo Yi, chief physician of Thyroid Surgery, and Yan Zhang, associate chief physician of Interventional Therapy, in the authors’ hospital.

Conflicts of interest

The authors have no financial relationships or conflicts of interest to disclose.

Ethics approval

This study was approved by the Ethics Committee of the Department of Interventional Therapy, Hwa Mei Hospital, University of Chinese Academy of Sciences (PJ-NBEY-KY-2019-150-01). The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Funding

This study was funded by the Value of Ultrasound Radiomics Combined with BRAF Gene Detection in Predicting Papillary Thyroid Microcarcinoma with Cervical Lymph Node Metastasis, Zhejiang Medical, and Health Science and Technology Project (#2020KY834).

Author Contributions

All authors contributed to the conceptualization, writing, and editing of this work.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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