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Background Sarcoid lesions may mimic metastatic disease or recurrence in thyroid cancer (TC) patients as both diseases may affect the lungs and lymph nodes. We present the first study to systematically evaluate the clinical course of patients with (TC) after adjuvant radioactive iodine therapy (RIT) and concomitant sarcoidosis of the lung or the lymph nodes. Methods We screened 3285 patients and retrospectively identified 16 patients with TC (11 papillary thyroid cancer (PTC), 3 follicular thyroid cancer (FTC), 1 oncocytic PTC, 1 oncocytic FTC) and coexisting sarcoidosis of the lung and/or the lymph nodes treated at our institute. All patients had undergone thyroidectomy and initial adjuvant RIT. Challenges in diagnosing and the management of these patients were evaluated during long term follow-up (median 4.9 years (0.8–15.0 years)). Results Median age at first diagnosis of TC was 50.1 years (33.0–71.5 years) and of sarcoidosis 39.4 years (18.0–63.9 years). During follow-up, physicians were able to differentiate between SA and persistent or recurrent TC in 10 of 16 patients (63%). Diagnosis was complicated by initial negative thyroglobulin (Tg), positive Tg antibodies and non-specific imaging findings. Histopathology can reliably distinguish between SA and TC in patients with one suspicious lesion. Conclusion Physicians should be aware of the rare coexistence of sarcoidosis and TC. Lymphadenopathy and pulmonary lesions could be metastases, sarcoidosis or even a mix of both. Therefore, this rare patient group should receive a thorough work up including histopathological clarification and, if necessary, separately for each lesion.

The thyroid is a vital endocrine organ that regulates metabolism, heart rate, respiration, digestion, body temperature, brain development, skin and bone maintenance, and reproduction and fertility. Thyroid cancer (TC) is the most common endocrine malignancy, with an estimate of 44,020 new cases in 2025. Incidence has been increasing, most notably at 4–5% per year in young adults. Papillary thyroid cancer (PTC), the most common TC subtype, accounts for approximately 80% of newly diagnosed TC cases. Furthermore, 2290 deaths are expected from the disease in 2025, with survival at over 98% with treatment. However, as PTC occurs most frequently in young women, recurrences are frequent and the 10-year disease-specific survival rate for advanced PTC is less than 50%. This narrative review aims to describe the current understanding of the thyroid gland, the incidence and subtypes of thyroid cancer, and specifically the diagnosis, prognosis, treatment, and recurrence of PTC. This is supplemented by the role of molecular pathways and biomarkers in PTC.

The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.

Abstract Context BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). Objectives To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). Design This was a pilot trial that enrolled from June 2014 to January 2016. Setting Academic cancer center. Patients Patients with RAIR, BRAF mutant thyroid cancer. Intervention Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. Main Outcome Measure The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. Results Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). Conclusions Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit. The BRAF inhibitor vemurafenib increased radioiodine uptake in a subset of patients with BRAF mutant, radioiodine-refractory thyroid cancer.

Abstract Context Active surveillance for papillary thyroid cancer (PTC) meeting criteria for surgical resection is uncommon. Which patients may prove reasonable candidates for this approach is not well defined. Objective This work aimed to examine the feasibility and safety of active surveillance for patients with known or suspected intrathyroidal PTC up to 4 cm in diameter. Methods A retrospective review was conducted of all consecutive patients who underwent nonoperative active surveillance of suspicious or malignant thyroid nodules over a 20-year period from 2001 to 2021. We included patients with an initial ultrasound–fine-needle aspiration confirming either (a) Bethesda 5 or 6 cytology or (b) a “suspicious” Afirma molecular test. The primary outcomes and measures included the rate of adverse oncologic outcomes (mortality and recurrence), as well as the cumulative incidence of size/volume growth. Results Sixty-nine patients were followed with active surveillance for 1 year or longer (average 55 months), with 26 patients (38%) having nodules 2 cm or larger. No patients were found to develop new-incident occurrence of lymph node or distant metastasis. One patient, however, demonstrated concern for progression to a dedifferentiated cancer on repeat core biopsy 17 years after initial start of nonoperative selection. A total of 21% of patients had an increase in maximum diameter more than 3 mm, while volume increase of 50% or greater was noted in 25% of patients. Thirteen patients ultimately underwent delayed (rescue) surgery, and no disease recurrence was noted after such treatment. Age and initial nodule size were not predictors of nodule growth. Conclusion These data expand consideration of active surveillance of PTC in select patients with intrathyroidal suspected malignancy greater than 1 cm in diameter. Rescue surgery, if required at a later time point, appears effective.

BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Emerging evidence has indicated that m5C modification plays a vital role in cancer development. However, the function of m5C-lncRNAs in PTC has never been reported. This study aims to explore the regulation mechanism of m5C RNA methylation-related long noncoding RNAs (m5C-lncRNAs) in papillary thyroid cancer (PTC). Bioinformatics analysis was used to investigate the role of m5C-lncRNAs in the prognosis and tumor immune microenvironment of PTC. Subsequently, we preliminarily verified the regulation mechanisms of m5C-lncRNAs in vivo and in vitro experiments. A total of six m5C-lncRNAs and five immune cell types were selected to construct the risk score and immune risk score (IRS) model, respectively. Patients with a high-risk score had a worse prognosis and the ROC indicated a reliable prediction performance (AUC = 0.796). As expected, the ESTIMATE and immune scores were higher ( P  < 0.001) and the tumor purity ( P  < 0.05) was significantly lower in the low-risk subgroup. CIBERSORT analysis showed Tregs, M0 macrophages, dendritic cells resting, and eosinophils were positively correlated to the risk score. Moreover, the expression levels of PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, and KLRB1 were lower in the high-risk subgroup. Importantly, patients in high-risk subgroup tended to have a better response to immunotherapy than those in low-risk subgroup ( P  = 0.022). Similar to the above risk score, the IRS model also showed favorable prognosis predictive performance (AUC = 0.764). An integrated nomogram combining risk score, IRS, and age exhibited good prognostic predictive performance. Additionally, we validate the downregulation of PPP1R12A-AS1 promotes proliferation and metastasis by activating the MAPK signaling pathway. Our research confirms that m5C-lncRNAs not only contribute to evaluating the prognosis of patients with PTC but also help predict immune cell infiltration and immunotherapy response.

Background Thyroid cancer is ranked as the most common malignancy within the endocrine system and the seventh most prevalent cancer in women globally. Thyroid malignancies require evaluating biomarkers capable of distinguishing between them for accurate diagnosis. We examined both mRNA and protein levels of TSPAN1 in plasma and tissue samples from individuals with thyroid nodules to aid this endeavour. Methods In this case-control study, TSPAN1 was assessed at both protein and mRNA levels in 90 subjects, including papillary thyroid cancer (PTC; N  = 60), benign ( N  = 30), and healthy subjects ( N  = 26) using enzyme-linked immunosorbent assay (ELISA) and SYBR-Green Real-Time PCR, respectively. Results TSPAN1 plasma levels were decreased in PTC and benign compared to healthy subjects ( P  = 0.002). TSPAN1 mRNA levels were also decremented in the tumoral compared to the paired normal tissues ( P  = 0.012); this drop was also observed in PTC patients compared to benign patients ( P  = 0.001). Further, TSPAN1 had an appropriate diagnostic value for detecting PTC patients from healthy plasma samples with a sensitivity of 76.7% and specificity of 65.4% at the cutoff value < 2.7 (ng/ml). Conclusion TSPAN1 levels are significantly reduced in patients with benign and PTC, demonstrating its potential value as a diagnostic biomarker. Additionally, the significant reduction in TSPAN1 mRNA expression within PTC tumor tissues may suggest its involvement in tumor progression and development. Further studies, including larger-scale validation studies and mechanistic investigations, are imperative to clarify the molecular mechanisms behind TSPAN1 and, ultimately, its clinical utility for treating thyroid disorders.

Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP’s function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target. Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from thyroid parafollicular cells, generally associated with a poor prognosis. By comparing MTC with less aggressive papillary thyroid cancer, here the authors find that the neurotransmitter calcitonin gene-related peptide (CGRP) promotes an immunosuppressive microenvironment in MTC.

Graves’ disease has been associated with increased tumor aggressiveness in differentiated thyroid carcinoma, however, its correlation with thyroid stimulating immunoglobulin (TSI) remains unclear. A tri-institutional retrospective review of 96 thyroidectomy patients with Graves’ disease and papillary thyroid carcinoma (PTC) was performed (2002–2020). Clinicopathologic features and recurrence were compared based on TSI level. ATA risk stratification distribution was low (72.9 ​%), intermediate (14.6 ​%), and high (12.5 ​%). Recurrence rate was 11.5 ​% with median follow-up of 3.2 years. TSI was not associated with high-risk clinicopathologic features at its 50 ​% and 75 ​% quartiles. There was no difference in median TSI between patients with recurrence versus no recurrence [212 (IQR 98–361) vs. 327 (IQR 152–461), p ​= ​0.148]. TSI was not associated with recurrence on univariable Cox regression, even when excluding microcarcinomas. In this majority low-risk PTC cohort with concomitant Graves’ disease, TSI level is not associated with aggressive clinicopathologic features or recurrence. [Display omitted] •Graves' disease has been associated with tumor aggressiveness in thyroid cancer.•Thyroid stimulating immunoglobulin (TSI) can stimulate thyroid cell growth.•TSI level is not associated with aggressive tumor pathologic features.•Patients with high TSI are not at higher risk for thyroid cancer recurrence.