Comment on 'Second Primary Papillary Thyroid Carcinoma: Insights From Competing Risk Analysis and Post-RAIT'.

The expression profiles of the galectin gene family in primary and metastatic papillary thyroid carcinoma with particular emphasis on galectin-1 and galectin-3 expression

Improved cancer survival rates have highlighted second primary malignancies (SPMs), with the thyroid gland being one of the most common organs developing SPMs in cancer survivors. Second primary papillary thyroid carcinoma (2-PTC) is the predominant type, yet it remains poorly understood. This study aims to delineate the clinicopathological features and survival outcomes of 2-PTC and assess the efficacy of postoperative radioactive iodine therapy (post-RAIT) in reducing mortality risks in intermediate-risk 2-PTC patients. Using the SEER-17 database (2004-2019), we identified 6399 2-PTC patients as Cohort 1 to analyze characteristics and outcomes, and 1743 as Cohort 2 to examine post-RAIT effects. Competing risk regression models were applied to assess mortality risks from prior primary malignancies (PPMs) and other causes. Propensity score matching and stabilized inverse probability treatment weighting with 500 bootstrap samples were used for robust analysis. Predominant demographic characteristics of 2-PTC patients included older age, female sex, and white ethnicity. Breast (25.5%), prostate (9.8%), and skin cancer (6.7%) were the most common PPMs. Unfavorable PPMs were found in 6.3% of patients. Despite lower cumulative mortality from 2-PTC compared to PPMs and other causes, post-RAIT did not significantly reduce mortality risks in Cohort 2, even among patients aged ≥ 55 years, with clinical stage IV disease, or unfavorable PPMs. Sensitivity analyses confirmed these findings. The survival prognosis for 2-PTC patients is generally favorable, and post-RAIT does not significantly affect mortality in intermediate-risk cases, indicating a need for reevaluation of its use.

Sonographic Features Of Multifocal Papillary Thyroid Carcinomas

Following the Chernobyl nuclear power plant explosion in Ukraine in 1986, increased childhood exposure to radioactive iodine (131I), which occurred primarily through contaminated food sources, has been consistently associated with increased risk of developing papillary thyroid carcinoma (PTC). Increased frequency of cervical lymph node metastases (LNM) is well recognized in pediatric PTC, including pediatric cases following the Chernobyl accident. We recently leveraged the collection of fresh-frozen tumor tissues from the Chernobyl Tissue Bank to conduct a genomic landscape analysis of 440 cases of PTC that provided new insights into radiation-related molecular characteristics of PTC occurring after the accident (Morton et al., Science 2021). Here, we extend that study to conduct a genomic landscape analysis of LNMs for a subset of 48 PTC cases to investigate the specific genomic alterations occurring in LNM. The analysis set comprised 144 samples, including fresh-frozen treatment-naïve primary and LNM PTC tumor samples as well as matched normal tissue or blood. Overall, the mutational load was highly concordant between primary and metastatic PTC. On average, 50% of somatic single nucleotide variants and 97% structural variants were shared between primary and metastatic PTCs. In contrast, the burden of somatic copy number alterations (SCNA) between primary tumor and LNM pairs was less concordant, particularly for copy number gains, whereas most of the copy number loss was found to be shared between matched pairs. PTC is usually driven by one driver mutation, most often involving the mitogen-activated protein kinase (MAPK) pathway. All driver mutations were shared between primary and metastatic PTC and were clonal; thus, no additional driver mutations were detected in metastatic PTC. Notably, however, the matched pairs in this study disproportionately had fusion drivers (77%), whereas only 23% of the drivers were BRAF V600E and none were RAS mutations. Transcriptome analysis revealed differentially expressed genes (DEGs) in metastatic PTC compared to primary PTC; three-quarters of the DEGs were overexpressed in metastatic PTC. Half of the LNM overexpressed DEGs were members of the HOXC family, which has been linked with epithelial-mesenchymal transition in cancer progression. There was also reduced expression in LNM for the DLX family, which relates to TGF-beta signaling. Our findings did not reveal a relationship between radiation dose and expression profiles in the LNM, comparable to our findings for the primary PTCs. We still observe that the efficiency of the radiation-induced PTC is paramount and subsequent events are directly related to the drivers in the MAPK pathway. For the cervical LNMs, we observed expression profiles not observed in the primary PTC that could give new insights into PTC local metastases. Citation Format: Olivia W. Lee, Danielle M. Karyadi, Chip Stewart, Tetiana I. Bogdanova, Jieqiong Dai, Stephen W. Hartley, Sara J. Schonfeld, Vidushi Kapoor, Marko Krznaric, Meredith Yeager, Amy Hutchinson, Belynda D. Hicks, Casey L. Dagnall, Julie M. Gastier-Foster, Jay Bowen, Mitchell J. Machiela, Elizabeth K. Cahoon, Kiyohiko Mabuchi, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Y. Zurnadzhy, Amy Berrington de González, Gad Getz, Gerry A. Thomas, Mykola D. Tronko, Lindsay M. Morton, Stephen J. Chanock. Genomic characterization of lymph node metastases in papillary thyroid carcinoma following the Chernobyl accident reveals an expression profile specific to metastatic process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 980.

BackgroundThyroid cancer dedifferentiation is an unusual observation among young patients and is poorly understood, although a recent correlation to DICER1 gene mutations has been proposed.Case presentationA 28-year old patient presented with a sub-centimeter cytology-verified primary papillary thyroid carcinoma (PTC) and a synchronous lateral lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous metastasis of poorly differentiated thyroid carcinoma (PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion.ConclusionsThe question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these tumors.

A primary papillary thyroid carcinoma in the intrathoracic lymph node is very rare. There are two potential explanations of the lesion. The first possibility of the lesion is metastatic disease from an occult primary thyroid papillary microcarcinoma. Other possibility is malignant transformation of the aberrant thyroid tissue within the intrathoracic lymph node, which is the favored etiology in this case. We experienced an extremely rare case of true intrathoracic thyroid cancer in a 78-year-old woman, presenting with an intrathoracic malignancy. We confirmed it as papillary thyroid cancer, but there were no primary sites of thyroid glands. So, we report this rare case of a primary papillary thyroid carcinoma in the intrathoracic lymph node. � Korean J Otorhinolaryngol-Head Neck Surg 2011;54:300-3 Key WordsZZIntrathoracic lymph node ㆍPapillary thyroid carcinoma ㆍAberrant thyroid tissue.

Background Thyroglossal duct cysts (TGDC) are remnants of the thyroglossal duct tract that do not atrophy and disappear, instead undergoing cystic expansion and often presenting as a midline neck mass. Rarely, carcinomas of the thyroglossal duct cyst occur, either arising as a primary carcinoma or as a cystic metastasis from a primary thyroid cancer; the former are particularly rare. These thyroglossal duct cyst carcinomas most commonly present in the adult population. Case Report We present the case of a 32-year-old female without any significant past medical history who presented with a non-tender midline neck mass identified as a thyroglossal duct cyst and completely excised; pathology results were positive for a primary papillary thyroid carcinoma with a tumor measuring 1.3 cm in diameter within the TGDC. Thyroid Ultrasound also showed the presence of two nodules measuring 1.4 cm on the right and 1.2 cm on the left, respectively, with fine needle aspiration (FNA) of both the nodules confirming papillary thyroid carcinoma as well. Lymph node FNA was negative for metastatic carcinoma. The patient underwent a thyroidectomy which definitively confirmed both a classic papillary carcinoma as well as an encapsulated, non-invasive follicular variant. In keeping with the original finding of the patient having a primary thyroglossal duct cyst carcinoma, samples from the thyroidectomy had negative tumor margins, and were also negative for any angioinvasion, lymphatic invasion, or extrathyroidal extension. Conclusion While thyroglossal duct cysts are the most common type of congenital neck cyst, primary carcinomas arising from thyroglossal duct cysts are rare. Masses that occur anywhere along the thyroglossal duct tract should be investigated for malignancy, with additional investigation of the thyroid gland for either a primary or secondary thyroid cancer. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

BRAF mutation, selected miRNAs and genes expression in primary papillary thyroid carcinomas and local lymph node metastases

The aim of the present study was to evaluate total and membranous Na+/I- symporter (NIS) expressions in papillary thyroid carcinoma (PTC) tissue, correlation of NIS expression between primary and metastatic lymph node (LN) PTC tissues, and relationship of NIS expression with I131 whole body scan (WBS) uptake between primary and metastatic LN PTC tissues by analyzing 17 pairs of primary and metastatic LN PTC tissues. Staining positivity was calculated, and staining intensity was graded as negative (0), weak (1+), moderate (2+) and strong (3+). In primary PTC tissues, positivities and intensities of normal cells were higher than those of carcinoma cells but had no correlation with those in matched metastatic LN PTC tissues. In classic type, positivities, intensities and membranous intensities (mIS) were correlated between primary and matched metastatic LN PTC tissues. In patients aged younger than 45 yr, positivities and intensities in primary PTC tissues had correlation with those in matched metastatic LN PTC tissues. Positivities, intensities, mIS and pathological subtype of carcinoma cells in primary PTC tissues were not correlated with age, tumor size, TNM stage, MACIS score and thyroglobulin (Tg) levels at the time of I131 WBS. Sensitivity, specificity, as well as positive and negative predicted values of mIS in patients with I131 WBS uptake were 69.2, 75, 90 and 42.9% in primary PTC tissues, and 92.3, 100, 100 and 80% in metastatic LN PTC tissues. The results of mIS taken either as positive or negative were correlated with those of I131 WBS after controlling for age. Our results demonstrate that PTC tissues have altered total and membranous NIS expressions, suggesting that NIS expression in primary PTC tissues may predict NIS expression and I131 WBS uptake in matched metastatic LN PTC tissues.

Reduced Tumor Size of Untreated Papillary Thyroid Carcinoma After Immune Checkpoint Inhibitor–Induced Thyroiditis

TERT promoter (TERTp) mutations represent a common oncogenic event in sporadic thyroid follicular cell carcinogenesis. Though TERTp mutations have been statistically associated with aggressiveness and metastatic spreading, their involvement in lymph node metastases (LNMs) and / or distant metastases (DMs) development among papillary thyroid carcinoma (PTC) patients remains to be defined. To evaluate the role of TERTp mutations on metastatic tumor expansion, primary tumors (Pt) and matched LNMs and/or DMs were genotyped by means of PCR-direct sequencing in a cohort of 33 patients diagnosed of PTC, which had been previously analyzed for BRAF and RAS mutations. Focal changes in the growth pattern or microscopic grade within the Pt or the metastases were separately genotyped to determine the clonal/subclonal nature of TERTp mutations, their association with particular histological variants of PTC or their presence in intra-tumoral PDC-like foci. Results were correlated with clinico-pathological parameters of pour outcome and survival. The analysis of 99 tumor samples obtained from 33 PTC cases revealed that TERTp mutations were quite common (42.4%).The mutation C228T was much more common than the C250T (78,6% vs 21,4%). TERTp mutations did not correlate with specific PTC subtypes [CL-PTC, FV-PTC or Mixed-PTC] and were subclonal in half of the cases. The mutations segregated to LNMs in 73% of cases [100% CL-PTC and FV-PTC; 57% Mixed PTC]. In 2 Mixed-PTC cases the mutation seemingly originated the novo in the LNM. TERTp mutations were present in all samples of DM. While 71% of the cases mutated at TERTp bore the BRAFV600E mutation, the coexistence of TERTp and RAS mutations was exceptional. TERTp mutations were found to be significantly correlated with age ≥ 45 years old, high grade poorly differentiated PTC foci or nesting-PDC-like foci, stage at diagnosis or at last follow-up and patient status. A trend of correlation with male sex, vascular invasion, tumor recurrence and development of LNM during the follow-up was also seen. Tumor multifocality was inversely correlated with TERTp mutations. The coexistence of TERTp and BRAFV600E mutants did not increase the prognostic power of TERTp mutations alone. All of the patients who died of disease displayed TERTp mutations. Kaplan-Meier analysis revealed that patients with PTC bearing TERTp mutations had a poor prognosis showing a higher tumor recurrence probability [p= 0.0085] and a reduced disease specific survival [p<0.0001]. The coexistence of other mutations did not significantly increase the risk of recurrence or dying of disease. The study indicates that TERTp mutations: 1) are common in metastatic PTC; 2) are subclonal in half of the cases; 3) spread in most cases with metastatic cells to LNM and DM but do not drive the development of LNM; 4) identify PTCs patients with increased risk of recurrence and mortality; 5) represent “per se” a biomarker for poor outcome among PTCs Citation Format: Noa Feás Rodríguez, Miram Corraliza Gómez, Tomás Alvarez Gago, Juan José Mateos Otero, Raquel Muñoz Martínez, Ginesa Maria Garcia-Rostan. TERT promoter mutations in primary papillary thyroid carcinomas and matched local / distant metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5505. doi:10.1158/1538-7445.AM2017-5505

Recently, thermal ablation has been proposed for treating primary papillary thyroid carcinoma (PTC), triggering an extensive debate. This study aimed to analyze surgical outcomes of post-ablation cases to investigate the effectiveness and safety of thermal ablation in primary PTC. Primary PTC patients treated with thermal ablation were retrospectively searched for from the authors' medical record database prior to August 2017. The surgical patients met the following criteria: (i) primary PTC treated with thermal ablation, (ii) findings suspicious for malignancy of the post-ablation lesions on ultrasound or malignancy confirmed by cytology, or with clinical evidence of cervical lymph node metastasis (LNM), (iii) written informed consent for surgery, (iv) preference for definite diagnosis of the post-ablation lesions for the patients without evidence for malignant findings, and (v) tolerance of a thyroidectomy and without severe illness. Moreover, a systematic review of the literature was made to analyze relevant cases. Twelve patients with an average age of 41.0 ± 13.6 years constituted the Fudan University Shanghai Cancer Center cohort in this study. Twenty-two foci with a mean size of 1.3 ± 0.7 cm were ablated percutaneously under ultrasound guidance. Residual PTCs were confirmed in all cases by histopathology, and LNM was present in 66.7% (8/12) of the patients. Intraoperatively, adhesion of the post-ablation lesions with the strap muscles was observed in six cases. Strap muscles were found to be cauterized in five cases, and notably the recurrent laryngeal nerve was involved in one case. Furthermore, seven relevant studies from Korea, Italy, and China were retrospectively reviewed, and incomplete ablation of primary PTC and omission of LNM by thermal ablation were observed frequently. Surgical therapy demonstrated incomplete ablation of primary PTC and omission of LNM by thermal ablation in this cohort of patients. Thermal ablation should be recommended with caution as treatment of operable patients with primary PTC.

We assessed the associations between FDG uptake in primary papillary thyroid carcinomas (PTCs) and clinicopathological features, including the BRAF V600E mutation, using quantitative and qualitative analyses of preoperative PET/CT data. This was a retrospective review of 106 patients with PTC who underwent PET/CT scans between February 2009 and January 2011 before undergoing total thyroidectomy. Data collected from surgical specimens were compared with FDG uptake in the primary tumour using quantitative and qualitative analyses of preoperative PET/CT data. Clinicopathological data included the primary tumour size, subtype, capsular invasion, extrathyroid extension, multifocality, BRAF V600E mutation status, lymph node metastasis and distant metastasis. The SUVmax of the primary tumour was significantly higher in patients with a primary tumour >1cm, extrathyroid extension or the BRAF V600E mutation than in patients without these features (P<.001, .049 and <.001). Univariate analyses showed that primary tumour size, extrathyroid extension and BRAF V600E mutation status were associated with the SUVmax of the PTC. Multivariate analysis indicated that primary tumour size and the BRAF V600E mutation were associated with the SUVmax of the PTC. In a visual assessment, the primary tumour size was larger in FDG-avid than in non-FDG-avid PTCs (P<.001). There was no significant difference in the presence of multifocality, thyroid capsular invasion, extrathyroid extension, BRAF V600E mutation, lymph node metastasis or distant metastasis between FDG-avid and non-FDG-avid PTCs. Primary tumour size and the BRAF V600E mutation are significant factors associated with the SUVmax on preoperative PET/CT in patients with PTC.

BackgroundProphylactic central neck dissection (pCND) in patients with well-differentiated primary papillary thyroid carcinoma (PTC) has become controversial. Several attempts have been made to predict central compartment lymph node metastasis (CLNM) based on clinical and conventional ultrasonic parameters. This study aimed to develop a decision tree (DT) model for predicting the risk of CLNM in patients with PTC based on clinical and preoperative multimodal ultrasound (US) characteristics.MethodsA total of 148 PTC nodules confirmed by surgical pathology at Beijing Tiantan Hospital were retrospectively analyzed. All nodules underwent multimodal US examinations preoperatively from January 2020 to September 2021. Correlation analysis of CLNM with clinical characteristics as well as multimodal US parameters of PTC lesions based on gray-scale US, color Doppler flow imaging (CDFI), superb microvascular imaging (SMI), contrast-enhanced ultrasound (CEUS), and shear wave elastography (SWE) technology was carried out. Finally, the chi-squared automatic interaction detector (CHAID) with a 10-fold cross-validation was used to establish DTs for CLNM prediction. The area under the curve was calculated to compare the predictive performance.ResultsUnivariate analysis indicated that CLNM was positively correlated with thyroglobulin level, maximum size, taller-than-wide, the number of microcalcifications greater than or equal to 5, contact capsule, abnormal cervical lymph node on conventional US, noncentripetal perfusion, delayed clearance, the average shear wave velocity (SWV mean), and the SWV ratio (P<0.05). The multimodal US DT based on taller-than-wide, contact capsule, abnormal cervical lymph node on conventional US, and centripetal enhancement as independent variables showed good discrimination: the sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve were 80.0%, 76.7%, 78.4%, and 0.837 [95% confidence interval (CI): 0.771–0.902]. There was a significant difference between the multimodal and conventional US DTs (P=0.009).ConclusionsOur results indicated that the DT based on the preoperative multimodal US characteristics of PTCs has a reasonable predictive ability for CLNM and can be conveniently used for clinical decision-making of individualized treatment in patients with well-differentiated PTC.

This retrospective study aimed to establish ultrasound radiomics models to predict central lymph node metastasis (CLNM) based on preoperative multimodal ultrasound imaging features fusion of primary papillary thyroid carcinoma (PTC). In total, 498 cases of unifocal PTC were randomly divided into two sets which comprised 348 cases (training set) and 150 cases (validition set). In addition, the testing set contained 120 cases of PTC at different times. Post-operative histopathology was the gold standard for CLNM. The following steps were used to build models: the regions of interest were segmented in PTC ultrasound images, multimodal ultrasound image features were then extracted by the deep learning residual neural network with 50-layer network, followed by feature selection and fusion; subsequently, classification was performed using three classical classifiers-adaptive boosting (AB), linear discriminant analysis (LDA), and support vector machine (SVM). The performances of the unimodal models (Unimodal-AB, Unimodal-LDA, and Unimodal-SVM) and the multimodal models (Multimodal-AB, Multimodal-LDA, and Multimodal-SVM) were evaluated and compared. The Multimodal-SVM model achieved the best predictive performance than the other models (P < 0.05). For the Multimodal-SVM model validation and testing sets, the areas under the receiver operating characteristic curves (AUCs) were 0.910 (95% CI, 0.894-0.926) and 0.851 (95% CI, 0.833-0.869), respectively. The AUCs of the Multimodal-SVM model were 0.920 (95% CI, 0.881-0.959) in the cN0 subgroup-1 cases and 0.828 (95% CI, 0.769-0.887) in the cN0 subgroup-2 cases. The ultrasound radiomics model only based on the PTC multimodal ultrasound image have high clinical value in predicting CLNM and can provide a reference for treatment decisions.