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Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
To investigate the occult contralateral papillary thyroid carcinoma (PTC)-associated ultrasound (US) and clinical characteristics and establish a US-based model for the prediction of occult contralateral carcinoma in adolescents and young adults (AYAs) who were diagnosed with unilateral thyroid carcinoma preoperatively.
Materials and Methods
From January 2015 to December 2020, patients who were diagnosed with unilateral thyroid carcinoma by preoperative US examination and underwent total thyroidectomy or thyroid lobectomy with more than 60 months of US follow-up at our hospital were retrospectively collected. Univariate and multivariate analyses were applied to identify the independent risk factors associated with occult contralateral PTC in AYAs, on which a prediction model was developed. The performance of the model was evaluated with accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve.
Results
Occult contralateral PTC was found in 91 of 365 (24.9%) PTC patients with a median age at diagnosis of 26 years (interquartile range, 24–29 years). The multivariate analysis indicated that the presence of contralateral benign nodule, intra-tumoral calcification, and intraglandular dissemination were significantly associated with occult contralateral PTC in AYAs. The prediction model, which incorporated all independent predictors, yielded an area under the receiver operating characteristic curve of .661 (95% CI: .602–.719). The accuracy, sensitivity and specificity were 67.9%, 54.9%, and 72.3%, respectively.
Conclusion
The US-based prediction model proposed here exhibited a favorable performance for predicting occult contralateral PTC, which might be used to determine the appropriate extent of surgery for AYAs who had a preoperative diagnosis of unilateral thyroid carcinoma.
). In adolescents and young adults (AYAs), PTC tends to exhibit some invasive biological behaviors, including higher rates of lymph node metastasis (LNM) extrathyroidal locoregional and distant occurrence (
), while for patients with a preoperative diagnosis of unilateral malignancy, the adequate extent of surgery is a matter of debate. Considering the high rate of complications, such as hematoma, recurrent laryngeal nerve injury and hypoparathyroidism (
), TT might not be an appropriate surgical approach for all patients with unilateral carcinoma. According to the latest American Thyroid Association (ATA) guidelines, thyroid lobectomy (TL) alone is sufficient for small, unifocal, intrathyroidal carcinomas without radiation therapy, familial thyroid carcinoma, or LNM (
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.
Occult carcinoma is defined as a pathologically confirmed tumor that could not be recognized preoperatively. For patients who have undergone TL, occult contralateral PTC may lead to tumor recurrence, LNM and even reoperation, which will bring more surgical risks than the primary surgery. Considering the aggressive behavior of PTC in AYAs, the adequate extent of resection is of more significance (
), nevertheless, it can detect only lesions larger than 2mm. Moreover, US is operator-dependent and limited by the experience of the physician. Fine-needle aspiration (FNA) is the most accurate method to confirm PTC preoperatively (
A Clinical decision support system using ultrasound textures and radiologic features to distinguish metastasis from tumor-free cervical lymph nodes in patients with papillary thyroid carcinoma.
Risk factors stratifying malignancy of nodules in contralateral thyroid lobe in patients with pre-operative ultrasound indicated unilateral papillary thyroid carcinoma: a retrospective analysis from single centre.
), the primary population included was middle-aged and elderly, and the occult contralateral PTC-associated characteristics in AYAs are still unknown. In addition, only patients who received TT were included in the previous studies (
) and the characteristic of patients with occult contralateral PTC who initially underwent TL have not been previously reported. This study aimed to investigate the occult contralateral PTC-associated US and clinical characteristics, and to develop a US-based prediction model for AYAs with a preoperative diagnosis of unilateral thyroid tumor.
METHODS
Patients Selection
This study was approved by the Institutional Review Board at our center and the requirement for informed consent was waived for its retrospective nature. From January 2015 to December 2020, 3546 consecutive patients with the age at diagnosis younger than 30 years of age were recruited for the study. All patients underwent preoperative US examination and thyroid surgery, and had a pathological diagnosis of PTC at our institution. The inclusion criteria were as follows: (i) patients with high suspicion of unilateral thyroid carcinoma by preoperative imaging; (ii) patients who underwent TT or received TL initially with an adequate US follow-up period of more than 60 months. The exclusion criteria were as follows: (i) suspicious lesions detected during follow-up without pathological confirmation; (ii) history of neck surgery or radiation therapy; (iii) incomplete pathology or US data. The presence of occult contralateral PTC was confirmed by postoperative pathological examination in patients who received TT initially. In patients who received TL as the initial approach of surgery, occult contralateral PTC was considered present if suspicious lesions were detected in the residual thyroid lobe during follow-up and eventually confirmed by pathology. Otherwise, no occult contralateral PTC was considered. The endpoint of follow-up was February 2022. Finally, a total of 365 patients were enrolled in this study, 215 of whom underwent TT, and 150 of whom underwent TL. The flowchart of patient selection was shown in Figure 1.
Figure 1Flowchart of patient selection. PTC, papillary thyroid carcinoma; TT, total thyroidectomy; TL, thyroid lobectomy; US, ultrasound.
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.
). Baseline clinical data, including age at diagnosis, gender, initial symptoms and family history of thyroid cancer, were obtained from medical records. Hashimoto's thyroiditis was diagnosed according to the titers of thyroglobulin and thyroid peroxidase antibodies (
). Experienced pathologists at our institution reviewed the slides and validated the results on the pathological reports, including the pathological maximum diameter, presence of intraglandular dissemination and extrathyroidal extension (ETE), as well as the lymph nodes status.
US Examination and Image Evaluation
All patients routinely underwent preoperative thyroid and neck US examinations by radiologists with more than 5 years of experience. Images of suspicious thyroid lesions and cervical lymph nodes were stored in the digital workstation for a secondary assessment. The evaluation of US images was performed independently by two radiologists with 5+ years of experience in thyroid US, when it came to a dispute, the final diagnosis was made by another radiologist with more than 10 years of expertise.
The assessment of US images included multifocality (yes or no), contralateral benign nodules (yes or no), maximum diameter on US, the background of the thyroid (normal or abnormal), Thyroid Imaging Report and Data System (TI-RADS) grade of the suspected lesion (
), US-reported lymph node status (normal, central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM) or CLNM+LLNM), orientation (parallel or vertical), margin (circumscribed, poorly defined, irregular or extrathyroidal extension, or discrete mass), echogenicity (hyperechoic, isoechoic, hypoechoic, markedly hypoechoic), intra-tumoral calcification (yes or no), and types of intra-tumoral calcifications (microcalcification, macrocalcification, and mixed-calcification). When multiple foci were present ipsilaterally, we only assessed the lesion with the highest TI-RADS grade. When more than one lesion with the same highest TI-RADS grade, the US features of the largest lesion were assessed.
Statistical Analysis
All statistical analyses were performed by using the SPSS v 26.0 software (IBM, Armonk, NY, USA) and R software (version 4.1.1, www.Rproject.org). Patients were categorized into two groups based on the presence of occult contralateral PTC. Continuous variables were presented as the median (interquartile range) and compared by Mann–Whitney U test. Categorical variables were compared to chi-square test or Fisher's exact test. Binary univariate and multivariate logistic regression analyses were used to determine the independent risk factors that were correlated with occult contralateral PTC. Odds ratios with 95% confidence intervals were recorded to quantify the correlations between covariates and outcomes. The prediction model was established based on the multivariate analysis. Receiver operating characteristic (ROC) curve analysis was plotted to evaluate the performance of the model. The optimal threshold of the model was set according to the maximum Youden index, and the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity of the model were calculated. Statistical significance was set at a p-value < .05.
RESULTS
Patients and Tumor Characteristics
A total of 365 patients were included in this study, occult contralateral PTC was present in 91 patients, 74 (81.3%) of whom underwent TT, and 17 (18.7%) who underwent TL initially were found to have contralateral PTC during follow-up (Fig. 2). Of the 274 patients with unilateral PTC, 141 (51.5%) underwent TT, and 133 (48.5%) underwent TL initially showed no suspicious lesions in the residual lobe during follow-up (Fig. 3). The median follow-up period of patients who underwent TL was 67 months (interquartile range, 62–72 months). The baseline characteristics of patients were summarized in Table 1.
Figure 2A 29-year-old female with a 28-mm papillary thyroid carcinoma in the left lobe and a 4-mm occult papillary thyroid carcinoma in the right lobe confirmed by surgical pathology. (A), (B) Grayscale images of calcification within the nodule in the left lobe. (C) A benign-looking nodule is shown in the right lobe. (Color version of figure is available online.)
Figure 3A 23-year-old female with a 11-mm papillary thyroid carcinoma in the left lobe was confirmed to have no occult carcinoma in the right lobe after total thyroidectomy. (A), (B) Grayscale images of no calcification within the nodule in the left lobe. (C) No benign-looking nodules were found in the right thyroid.
Table 1Baseline Characteristics of 365 PTC Patients
Characteristics
No. (%)
Age at diagnosis (years)
Median
26.0
(Interquartile range)
24.0–29.0
Gender (%)
Female
251(68.8)
Male
114(31.2)
Multifocality on US (%)
Yes
311(85.2)
No
54(14.8)
Maximum diameter on US (mm)
Median
12.0
(Interquartile range)
7.0–20.0
TI-RADS (%)
4A
36(9.9)
4B
80(21.9)
4C
139(38.1)
5
95(26.0)
6
15(4.1)
US-reported lymph nodes status (%)
Normal
181(49.6)
CLNM
32(8.8)
LLNM
30(8.2)
CLNM+LLNM
122(33.4)
Pathological maximum diameter (mm)
Median
14.0
(Interquartile range)
9.0–24.0
Intraglandular dissemination (%)
Yes
16(4.4)
No
349(95.6)
Extrathyroidal extension (%)
Yes
51(13.9)
No
314(86.1)
Pathological lymph nodes status (%)
No metastasis
97(26.6)
CLNM
111(30.4)
LLNM
9(2.5)
CLNM+LLNM
148(40.5)
Data are the number of patients and percentage if not specified. CLNM, central lymph node metastasis; LLNM, lateral lymph node metastasis; PTC, papillary thyroid carcinoma; TI-RADS, Thyroid Imaging Report and Data System; US, ultrasound. Significant differences are highlighted in boldface.
US and Clinicopathological Characteristics Associated With Occult Contralateral PTC
In the univariate analysis, US features such as contralateral benign nodule (p < .001) and intra-tumoral calcification (p =.006) were significantly associated with the presence of occult contralateral PTC. However, multifocality, tumor size, US background of thyroid, TI-RADS grade, US-reported lymph nodes status and other sonographic features of the thyroid lesion were not significantly correlated with occult contralateral PTC (all p > .05). Details were shown in Table 2.
Table 2Univariate Analysis of US Characteristics Between Negative and Positive Occult Contralateral PTC Patients
Characteristics
Occult Contralateral PTC
p
Negative
Positive
No. of patients
274(75.1)
91(24.9)
Multifocality (%)
.387
Yes
38(70.4)
16(29.6)
No
236(75.9)
75(24.1)
Contralateral benign nodule (%)
< .001
Yes
86(63.7)
49(36.3)
No
188(81.7)
42(18.3)
Maximum diameter on US (mm)
.331
Median
13.0
16.0
(Interquartile range)
9.0-23.5
9.0-25.0
US background of Thyroid (%)
.632
Normal
191(75.8)
61(24.2)
Abnormal
83(73.5)
30(26.5)
TI-RADS (%)
.382
4A
26(72.2)
10(27.8)
4B
61(76.3)
19(23.7)
4C
111(79.9)
28(20.1)
5
65(68.4)
30(31.6)
6
11(73.3)
4(26.7)
US-reported lymph nodes status (%)
.308
Normal
142(78.5)
39(21.5)
CLNM
23(71.9)
9(28.1)
LLNM
19(63.3)
11(36.7)
CLNM+LLNM
90(73.8)
32(26.2)
Orientation (%)
.068
Parallel
221(73.2)
81(26.8)
Vertical
53(84.1)
10(15.9)
Margin (%)
.278
Circumscribed
22(88.0)
3(12.0)
Poorly defined
97(74.0)
34(26.0)
Irregular or extrathyroidal extension
151(73.7)
54(26.3)
No discrete mass
4(100.0)
0(0)
Echogenicity (%)
.565
Hyperechoic
1(100.0)
0(0)
Isoechoic
45(80.4)
11(19.6)
Hypoechoic
207(73.4)
75(26.6)
Markedly hypoechoic
21(80.8)
5(19.2)
Intra-tumoral calcification (%)
.006
Yes
223(72.4)
85(27.6)
No
51(89.5)
6(10.5)
Types of Intratumoral Calcifications (%)
0.599
Microcalcification
133(70.7)
55(29.3)
Macrocalcification
11(68.7)
5(31.3)
Mixed calcification
79(76.0)
25(24.0)
Data are the number of patients and percentage if not specified. Significant differences are highlighted in boldface. CLNM, central lymph node metastasis; LLNM, lateral lymph node metastasis; PTC, papillary thyroid carcinoma; TI-RADS, Thyroid Imaging Report and Data System; US, ultrasound. Significant differences are highlighted in boldface.
Among all clinicopathological variables, intraglandular dissemination was identified to be a significant predictor for occult contralateral PTC (p = .033). No significant differences were found between negative and positive occult contralateral PTC in terms of other clinicopathological characteristics, including the age at diagnosis, gender, initial symptoms, family history, Hashimoto's Thyroiditis, BRAF mutation, tumor size, extrathyroidal extension, and pathological lymph node status (all p > .05, Table 3).
Table 3Univariate Analysis of Clinicopathological Characteristics Between Negative and Positive Occult Contralateral PTC Patients
Characteristics
Occult Contralateral PTC
p
Negative
Positive
No. of patients
274(75.1)
91(24.9)
Age at diagnosis (years)
.938
Median
26.0
27.0
(Interquartile range)
24.0-29.0
24.0-29.0
Gender (%)
.350
Female
192(76.5)
59(23.5)
Male
82(71.9)
32(28.1)
Initial symptoms (%)
.766
PE or unintentional discovery
244(75.3)
80(24.7)
Palpable mass, hoarse or pain
30(73.2)
11(26.8)
Family history (%)
.766
No
241(73.9)
85(26.1)
Yes
33(73.2)
6(26.8)
Hashimoto's thyroiditis (%)
.346
Yes
114(72.6)
43(27.4)
No
160(76.9)
48(23.1)
BRAF mutation (%)
.449
No
8(72.7)
3(27.3)
Yes
10(55.6)
8(44.4)
Pathological maximum diameter (mm)
.688
Median
12.0
12.0
(Interquartile range)
7.0-20.0
6.0-20.0
Intraglandular dissemination (%)
.033
Yes
8(50.0)
8(50.0)
No
266(76.2)
83(23.8)
Extrathyroidal extension (%)
.135
Yes
34(66.7)
17(33.3)
No
240(76.4)
74(23.6)
Pathological lymph nodes status (%)
.936
No metastasis
74(76.3)
23(23.7)
CLNM
83(74.8)
28(25.2)
LLNM
6(66.7)
3(33.3)
CLNM+LLNM
111(75.0)
37(25.0)
Data are the number of patients and percentage if not specified. CLNM, central lymph node metastasis; LLNM, lateral lymph node metastasis; PE, physical examination; PTC, papillary thyroid carcinoma. Significant differences are highlighted in boldface.
Subsequently, contralateral benign nodule (p < .001), intratumoral calcification (p = .016) and intraglandular dissemination (p = .042) were identified to be independent risk factors for occult contralateral PTC in AYAs by multivariate logistic regression analysis (Table 4). Then a predictive model was thereby established, which yielded an AUC of .661 (95% CI: .601–.719) for predicting occult contralateral PTC (Fig. 4) with the cutoff value of -.959. The accuracy, sensitivity, and specificity of the prediction model were 67.9%, 54.9%, and 72.3%, respectively.
Table 4Multivariate Analysis for Predictive Factors of Occult Contralateral PTC in Adolescent and Young Adults
Parameters
Multivariate Analysis
β
OR (95%CI)
p Value
Intercept
-2.538
Contralateral benign nodule
Yes
0.947
2.578(1.576, 4.243)
< .001
No
Intra-tumoral calcification
Yes
1.106
3.021(1.324, 5.263)
.016
No
Intraglandular dissemination
1.081
2.948(1.024, 8.504)
.042
Yes
No
CI, confidence interval; OR, odds ratio; PTC, papillary thyroid carcinoma. β is the regression coefficient. Significant differences are highlighted in boldface.
Figure 4Receiver operating characteristic curves of the US-based model for predicting occult contralateral papillary thyroid carcinoma in adolescents and young adults.
In this study, we investigated the incidence of occult contralateral PTC in patients under 30 years of age, and established a prediction model by incorporating US and clinical characteristics for an individualized prediction of occult contralateral PTC in AYAs. This prediction model may serve as an easy-to-use tool for determining the extent of surgery and optimizing the clinical decision-making.
Our results showed that the presence of contralateral benign nodule, intra-tumoral calcification and intraglandular dissemination were independent predictors of occult contralateral PTC. The positive association between contralateral benign nodule and the presence of occult contralateral PTC has been well documented in several studies (
). Our study indicated that the presence of contralateral benign nodule was related to an increased likelihood of malignancy in the contralateral lobe. The obscuration of tumor foci by benign nodules, or lesions without apparent malignant sonographic features (
), might contribute to this finding. Notably, the presence of intra-tumoral calcification was also a significant predictor for occult contralateral PTC. Although calcification, particularly microcalcification, has been found to be associated with the aggressiveness of PTC in many studies (
Risk Factors and a prediction model of lateral lymph node metastasis in CN0 papillary thyroid carcinoma patients with 1-2 central lymph node metastases.
Prediction of cervical lymph node metastasis in patients with papillary thyroid cancer using combined conventional ultrasound, strain elastography, and acoustic radiation force impulse (ARFI) elastography.
), the correlation between calcification and occult contralateral PTC in this study was the first to be reported. Calcifications usually develop from the proliferation of blood vessels and dense fibrous tissue and the deposition of calcium salts (
). Li et al. retrospectively analyzed the relationship between intra-tumoral calcification and biological behavior of PTCs in 13,995 patients and found that intra-tumoral calcification was positively correlated with tumor multifocality and invasiveness of PTC (
). Therefore, the positive correlation between intra-tumoral calcification and occult contralateral PTC is justified. Furthermore, our results showed that the morphology of calcification was not significantly related to occult contralateral tumors. Therefore, the presence of calcification, as a whole, was included as an independent factor in the prediction model. Consistent with our study, previous studies have reported that intraglandular dissemination was an indicator of progressive and multifocal PTC (
). Intraglandular dissemination is thought to be a form of metastasis for thyroid carcinoma, by which the disseminated lesions may spread bilaterally through the intralobular lymphatics network (
), which may contribute to the increased risk of occult contralateral PTC in patients with intraglandular disseminated tumors.
Inconsistent with our observations, some US and clinicopathological characteristics such as ipsilateral multifocality, tumor size and pathological and US-reported lymph node status have been frequently selected as risk factors for occult contralateral PTC in previous whole-population-based studies (
). We speculate that different participant selection strategies may result in this inconsistency, which implies differences in the characteristics of AYAs patients with PTC compared to that of the entire population.
Previous studies on occult contralateral PTC included only patients who underwent TT (
). However, successful prediction of occult contralateral PTC brings more clinical significance to patients who underwent TL initially. In our study, the overall incidence of occult contralateral cancer was as high as 24.9%, and 17 (11.3%) of 150 patients who underwent TL initially presented with pathologically confirmed contralateral PTC nodules during follow-up. Due to the aggressive nature of PTC in young patients, in this study, we focused on the occult contralateral PTC in patients under 30 years old. Occult carcinoma in the residual thyroid gland may lead to tumor recurrence, LNM, and reoperation, of which the difficulty is much greater than the primary surgery. Reoperation might aggravate the clinical and patient burden, and have an adverse effect on the long-term life quality of patients. Therefore, for PTC patients with a high risk of occult contralateral carcinoma, adopting more aggressive treatment protocols, such as TT as the primary surgery and receiving more frequent follow-up is reasonable. In this context, we developed a convenient prediction model to predict occult contralateral PTC in AYAs, which made it possible for clinicians to select the individualized treatment for patients. With easily accessible US and clinicopathological characteristics, young patients with a high risk predicted by the prediction model can be selected to perform TT, and unnecessary TT may be avoided for those with a low risk of occult contralateral PTC.
The study had several limitations which we hope to address in subsequent studies. First, as a retrospective study conducted in a single medical center, the inherent selection bias was inevitable. Second, the findings of this study lacked external validation. Thus, a prospective multi-center study with larger sample size is required. Furthermore, since the US data was extracted only from two-dimensional US images, the diagnostic capability of the prediction model was not as satisfactory as expected. In future studies, latest technological parameters from shear wave elastography, contrast-enhanced US, radiomics, and deep learning will be incorporated to improve the performance of the prediction model.
CONCLUSION
Contralateral benign nodule, intra-tumoral calcification and intraglandular dissemination were identified as the independent predictors for occult contralateral PTC in AYAs, and the consequent prediction model may be important in guiding the clinical management.
AUTHOR CONTRIBUTION
YT designed the study. YW and DS collected and analyzed the data. YT and YW wrote the paper. CC provided administrative support. All authors contributed to the article and approved the submitted version. We thank Changming Zhou for his kind help with the statistical analysis.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China [grant number 82102069].
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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.
A Clinical decision support system using ultrasound textures and radiologic features to distinguish metastasis from tumor-free cervical lymph nodes in patients with papillary thyroid carcinoma.
Risk factors stratifying malignancy of nodules in contralateral thyroid lobe in patients with pre-operative ultrasound indicated unilateral papillary thyroid carcinoma: a retrospective analysis from single centre.
Risk Factors and a prediction model of lateral lymph node metastasis in CN0 papillary thyroid carcinoma patients with 1-2 central lymph node metastases.
Prediction of cervical lymph node metastasis in patients with papillary thyroid cancer using combined conventional ultrasound, strain elastography, and acoustic radiation force impulse (ARFI) elastography.
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