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An Ultrasound-based Prediction Model for Occult Contralateral Papillary Thyroid Carcinoma in Adolescents and Young Adults

  • Author Footnotes
    # These authors contributed equally to this work.
    Yi Wei
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
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  • Author Footnotes
    # These authors contributed equally to this work.
    Danli Sheng
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
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  • Cai Chang
    Affiliations
    Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
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  • Yuyang Tong
    Correspondence
    Address correspondence to: Y.T.
    Affiliations
    Department of Ultrasound, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China
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  • Author Footnotes
    # These authors contributed equally to this work.
Open AccessPublished:September 06, 2022DOI:https://doi.org/10.1016/j.acra.2022.07.022

      Rationale and Objectives

      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.

      Key Words

      Abbreviations:

      PTC (papillary thyroid carcinoma), US (ultrasound), AYAs (adolescents and young adults), TT (total thyroidectomy), TL (thyroid lobectomy), AUC (area under the receiver operating characteristic curve), LNM (lymph node metastasis), ATA (American Thyroid Association), FNA (fine-needle aspiration), AJCC (American Joint Committee on Cancer), ETE (extrathyroidal extension), TI-RADS (Thyroid Imaging Report and Data System), CLNM (central lymph node metastasis), LLNM (lateral lymph node metastasis), ROC (Receiver operating characteristic)

      INTRODUCTION

      In recent years, the incidence of thyroid carcinoma in patients under 30 years has been increasing rapidly (
      • Moon EK
      • Park HJ
      • Oh CM
      • et al.
      Cancer incidence and survival among adolescents and young adults in Korea.
      ,
      • de Souza Reis R
      • Gatta G
      • de Camargo B.
      Thyroid carcinoma in children, adolescents, and young adults in Brazil: a report from 11 population-based cancer registries.
      ), accounting for nearly 10% of all malignancies in this age group (
      • Rapkin L
      • Pashankar FD.
      Management of thyroid carcinoma in children and young adults.
      ). Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (
      • Lim H
      • Devesa SS
      • Sosa JA
      • et al.
      Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013.
      ). 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 (
      • Agac Ay A
      • Kutun S
      • Cetin A
      Are the characteristics of thyroid cancer different in young patients?.
      ,
      • Guo K
      • Qian K
      • Shi Y
      • et al.
      Clinical and molecular characterizations of papillary thyroid cancer in children and young adults: a multicenter retrospective study.
      ,
      • Ito Y
      • Miyauchi A
      • Kihara M
      • et al.
      Prognostic significance of young age in papillary thyroid carcinoma: analysis of 5,733 patients with 150 months' median follow-up.
      ), which place a higher demand on clinical management.
      Total thyroidectomy (TT) is the optimal extent of surgery for patients with bilateral thyroid carcinoma (
      • Feroci F
      • Rettori M
      • Borrelli A
      • et al.
      A systematic review and meta-analysis of total thyroidectomy versus bilateral subtotal thyroidectomy for Graves' disease.
      ), 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 (
      • Frank ED
      • Park JS
      • Watson W
      • et al.
      Total thyroidectomy: Safe and curative treatment option for hyperthyroidism.
      ), 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 (
      • Haugen BR
      • Alexander EK
      • Bible KC
      • 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.
      ). Nevertheless, PTC often presents as multiple foci (
      • Kuhn E
      • Teller L
      • Piana S
      • et al.
      Different clonal origin of bilateral papillary thyroid carcinoma, with a review of the literature.
      ,
      • Park SY
      • Jung YS
      • Ryu CH
      • et al.
      Identification of occult tumors by whole-specimen mapping in solitary papillary thyroid carcinoma.
      ), and the prevalence of occult contralateral carcinoma ranges from 13% to 56% (
      • Koo BS
      • Lim HS
      • Lim YC
      • et al.
      Occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma.
      ).
      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 (
      • Yang Z
      • Heng Y
      • Lin J
      • et al.
      Nomogram for predicting central lymph node metastasis in papillary thyroid cancer: a retrospective cohort study of two clinical centers.
      ). Thus, accurate identification of occult contralateral PTC in AYAs is valuable for treatment selection.
      Ultrasound (US) is the first-line imaging modality for PTC (
      • Chen HY
      • Liu WY
      • Zhu H
      • et al.
      Diagnostic value of contrast-enhanced ultrasound in papillary thyroid microcarcinoma.
      ,
      • Tong Y
      • Li J
      • Huang Y
      • et al.
      Ultrasound-based radiomic nomogram for predicting lateral cervical lymph node metastasis in papillary thyroid carcinoma.
      ), 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 (
      • Oliveira CM
      • Costa RA
      • Patricio M
      • et al.
      Sonographic criteria predictive of malignant thyroid nodules: which lesions should be biopsied?.
      ), but it can be performed only on US-visible nodules, and, as an invasive procedure, it carries the risks of bleeding and infection (
      • Abbasian Ardakani A
      • Reiazi R
      • Mohammadi A
      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.
      ). Therefore, identifying the risk factors for occult contralateral PTC, and developing a convenient prediction model might be helpful.
      Although several studies have explored the predictive factors related to occult contralateral PTC (
      • Zhang F
      • Zheng B
      • Yu X
      • et al.
      Risk factors for contralateral occult carcinoma in patients with unilateral papillary thyroid carcinoma: a retrospective study and meta-analysis.
      ,
      • Lv T
      • Zhu C
      • Di Z.
      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 (
      • Chen X
      • Zhong Z
      • Song M
      • et al.
      Predictive factors of contralateral occult carcinoma in patients with papillary thyroid carcinoma: a retrospective study.
      ) 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 1
      Figure 1Flowchart of patient selection. PTC, papillary thyroid carcinoma; TT, total thyroidectomy; TL, thyroid lobectomy; US, ultrasound. (Color version of figure is available online.)

      Clinicopathological Data Collection

      Surgical procedures of patients were performed according to the 8th American Joint Committee on Cancer (AJCC) staging systems and ATA guidelines (
      • Haugen BR
      • Alexander EK
      • Bible KC
      • 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.
      ,
      • Lamartina L
      • Grani G
      • Arvat E
      • et al.
      8th edition of the AJCC/TNM staging system of thyroid cancer: what to expect (ITCO#2).
      ). 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 (
      • Caturegli P
      • De Remigis A
      • Rose NR.
      Hashimoto thyroiditis: clinical and diagnostic criteria.
      ). 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 (
      • Tessler FN
      • Middleton WD
      • Grant EG
      • et al.
      ACR Thyroid Imaging, Reporting and Data System (TI-RADS): white paper of the ACR TI-RADS Committee.
      ), 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 2
      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 3
      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. (Color version of figure is available online.)
      Table 1Baseline Characteristics of 365 PTC Patients
      CharacteristicsNo. (%)
      Age at diagnosis (years)
      Median26.0
      (Interquartile range)24.0–29.0
      Gender (%)
      Female251(68.8)
      Male114(31.2)
      Multifocality on US (%)
      Yes311(85.2)
      No54(14.8)
      Maximum diameter on US (mm)
      Median12.0
      (Interquartile range)7.0–20.0
      TI-RADS (%)
      4A36(9.9)
      4B80(21.9)
      4C139(38.1)
      595(26.0)
      615(4.1)
      US-reported lymph nodes status (%)
      Normal181(49.6)
      CLNM32(8.8)
      LLNM30(8.2)
      CLNM+LLNM122(33.4)
      Pathological maximum diameter (mm)
      Median14.0
      (Interquartile range)9.0–24.0
      Intraglandular dissemination (%)
      Yes16(4.4)
      No349(95.6)
      Extrathyroidal extension (%)
      Yes51(13.9)
      No314(86.1)
      Pathological lymph nodes status (%)
      No metastasis97(26.6)
      CLNM111(30.4)
      LLNM9(2.5)
      CLNM+LLNM148(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
      CharacteristicsOccult Contralateral PTCp
      NegativePositive
      No. of patients274(75.1)91(24.9)
      Multifocality (%).387
      Yes38(70.4)16(29.6)
      No236(75.9)75(24.1)
      Contralateral benign nodule (%)< .001
      Yes86(63.7)49(36.3)
      No188(81.7)42(18.3)
      Maximum diameter on US (mm).331
      Median13.016.0
      (Interquartile range)9.0-23.59.0-25.0
      US background of Thyroid (%).632
      Normal191(75.8)61(24.2)
      Abnormal83(73.5)30(26.5)
      TI-RADS (%).382
      4A26(72.2)10(27.8)
      4B61(76.3)19(23.7)
      4C111(79.9)28(20.1)
      565(68.4)30(31.6)
      611(73.3)4(26.7)
      US-reported lymph nodes status (%).308
      Normal142(78.5)39(21.5)
      CLNM23(71.9)9(28.1)
      LLNM19(63.3)11(36.7)
      CLNM+LLNM90(73.8)32(26.2)
      Orientation (%).068
      Parallel221(73.2)81(26.8)
      Vertical53(84.1)10(15.9)
      Margin (%).278
      Circumscribed22(88.0)3(12.0)
      Poorly defined97(74.0)34(26.0)
      Irregular or extrathyroidal extension151(73.7)54(26.3)
      No discrete mass4(100.0)0(0)
      Echogenicity (%).565
      Hyperechoic1(100.0)0(0)
      Isoechoic45(80.4)11(19.6)
      Hypoechoic207(73.4)75(26.6)
      Markedly hypoechoic21(80.8)5(19.2)
      Intra-tumoral calcification (%).006
      Yes223(72.4)85(27.6)
      No51(89.5)6(10.5)
      Types of Intratumoral Calcifications (%)0.599
      Microcalcification133(70.7)55(29.3)
      Macrocalcification11(68.7)5(31.3)
      Mixed calcification79(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
      CharacteristicsOccult Contralateral PTCp
      NegativePositive
      No. of patients274(75.1)91(24.9)
      Age at diagnosis (years).938
      Median26.027.0
      (Interquartile range)24.0-29.024.0-29.0
      Gender (%).350
      Female192(76.5)59(23.5)
      Male82(71.9)32(28.1)
      Initial symptoms (%).766
      PE or unintentional discovery244(75.3)80(24.7)
      Palpable mass, hoarse or pain30(73.2)11(26.8)
      Family history (%).766
      No241(73.9)85(26.1)
      Yes33(73.2)6(26.8)
      Hashimoto's thyroiditis (%).346
      Yes114(72.6)43(27.4)
      No160(76.9)48(23.1)
      BRAF mutation (%).449
      No8(72.7)3(27.3)
      Yes10(55.6)8(44.4)
      Pathological maximum diameter (mm).688
      Median12.012.0
      (Interquartile range)7.0-20.06.0-20.0
      Intraglandular dissemination (%).033
      Yes8(50.0)8(50.0)
      No266(76.2)83(23.8)
      Extrathyroidal extension (%).135
      Yes34(66.7)17(33.3)
      No240(76.4)74(23.6)
      Pathological lymph nodes status (%).936
      No metastasis74(76.3)23(23.7)
      CLNM83(74.8)28(25.2)
      LLNM6(66.7)3(33.3)
      CLNM+LLNM111(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
      ParametersMultivariate Analysis
      βOR (95%CI)p Value
      Intercept-2.538
      Contralateral benign nodule
      Yes0.9472.578(1.576, 4.243)< .001
      No
      Intra-tumoral calcification
      Yes1.1063.021(1.324, 5.263).016
      No
      Intraglandular dissemination1.0812.948(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 4
      Figure 4Receiver operating characteristic curves of the US-based model for predicting occult contralateral papillary thyroid carcinoma in adolescents and young adults. (Color version of figure is available online.)

      DISCUSSION

      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 (
      • Zhang F
      • Zheng B
      • Yu X
      • et al.
      Risk factors for contralateral occult carcinoma in patients with unilateral papillary thyroid carcinoma: a retrospective study and meta-analysis.
      ,
      • Chen X
      • Zhong Z
      • Song M
      • et al.
      Predictive factors of contralateral occult carcinoma in patients with papillary thyroid carcinoma: a retrospective study.
      ,
      • Wan H
      • Zhang B
      • Yan D
      • et al.
      Prediction of occult carcinoma in contralateral nodules for unilateral papillary thyroid carcinoma.
      ). 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 (
      • Gregory A
      • Bayat M
      • Kumar V
      • et al.
      Differentiation of benign and malignant thyroid nodules by using comb-push ultrasound shear elastography: a preliminary two-plane view study.
      ), 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 (
      • Wang Y
      • Deng C
      • Shu X
      • et al.
      Risk Factors and a prediction model of lateral lymph node metastasis in CN0 papillary thyroid carcinoma patients with 1-2 central lymph node metastases.
      ,
      • Xu JM
      • Xu XH
      • Xu HX
      • et al.
      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 (
      • Yin L
      • Zhang W
      • Bai W
      • et al.
      Relationship between morphologic characteristics of ultrasonic calcification in thyroid nodules and thyroid carcinoma.
      ). 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 (
      • Li C
      • Zhou L
      • Dionigi G
      • et al.
      The association between tumor tissue calcification, obesity, and thyroid cancer invasiveness in a cohort study.
      ). Occult contralateral PTC is a form of multifocality, and multifocality is also a manifestation of aggressiveness (
      • Harries V
      • Wang LY
      • McGill M
      • et al.
      Should multifocality be an indication for completion thyroidectomy in papillary thyroid carcinoma?.
      ). 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 (
      • Dzepina D
      • Zurak K
      • Petric V
      • et al.
      Pathological characteristics and clinical perspectives of papillary thyroid cancer: study of 714 patients.
      ,
      • Hirokawa M
      • Kudo T
      • Ota H
      • et al.
      Pathological characteristics of low-risk papillary thyroid microcarcinoma with progression during active surveillance.
      ,
      • Jung YY
      • Lee CH
      • Park SY
      • et al.
      Characteristic tumor growth patterns as novel histomorphologic predictors for lymph node metastasis in papillary thyroid carcinoma.
      ). 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 (
      • Qian B
      • Guo S
      • Zhou J
      • et al.
      Intraglandular dissemination is a risk factor for lymph node metastasis in papillary thyroid carcinoma: a propensity score matching analysis.
      ), 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 (
      • Koo BS
      • Lim HS
      • Lim YC
      • et al.
      Occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma.
      ,
      • Zhang F
      • Zheng B
      • Yu X
      • et al.
      Risk factors for contralateral occult carcinoma in patients with unilateral papillary thyroid carcinoma: a retrospective study and meta-analysis.
      ,
      • Feng JW
      • Ye J
      • Wu WX
      • et al.
      Management of clinically solitary papillary thyroid carcinoma patients according to risk-scoring model for contralateral occult carcinoma.
      ,
      • Wang N
      • Qian LX.
      Predictive factors for occult bilateral papillary thyroid carcinoma.
      ). However, in a sizeable children-targeted study, tumor size and lymph node status were also found irrelevant to the occult contralateral PTC (
      • Cherella CE
      • Richman DM
      • Liu E
      • et al.
      Predictors of bilateral disease in pediatric differentiated thyroid cancer.
      ). 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 (
      • Koo BS
      • Lim HS
      • Lim YC
      • et al.
      Occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma.
      ,
      • Zhang F
      • Zheng B
      • Yu X
      • et al.
      Risk factors for contralateral occult carcinoma in patients with unilateral papillary thyroid carcinoma: a retrospective study and meta-analysis.
      ,
      • Feng JW
      • Ye J
      • Wu WX
      • et al.
      Management of clinically solitary papillary thyroid carcinoma patients according to risk-scoring model for contralateral occult carcinoma.
      ). 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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