Nonmedullary Thyroid Carcinoma Research Articles

Coexisting parathyroid adenoma, thyroid carcinoma, and tuberculosis of thyroid: a case report

BackgroundCoexisting parathyroid adenoma, thyroid carcinoma, and tuberculosis of thyroid is a very rare phenomenon. Primary thyroid tuberculosis is itself very rare despite high global prevalence of tuberculosis in developing countries. Majority of thyroid tuberculosis identified in postoperative histopathology or cytopathology. The coexistence of thyroid cancer with tuberculosis or parathyroid adenoma has been reported in the literature but not a single case of the three pathologies coexisting together has been found in the literature published. We are presenting a rare case of a constellation of synchronous parathyroid adenoma, thyroid carcinoma, and thyroid tuberculosis. This case report will provoke researchers to work on understanding the association of hypercalcemia or chronic inflammation leading to development of malignancy or parathyroid adenoma in the presence of hypothyroidism will give future perspective in managing such patients.Case presentationA Islam lady aged 45 years old, diagnosed with hypothyroidism, was evaluated for pregnancy loss and rapid weight gain from 13 years back and started on tablets of levothyroxine 25 µg once daily. She was doing well until the past 2 years; there after she noticed insidious onset of a swelling over anterior aspect of right side of the neck and bone pain in back and lower limbs. Patient underwent routine investigations and was found to have raised serum calcium (11.4 mg/dl) and parathyroid hormone (253 pg/ml). Anti-thyroid peroxidase (TPO) and anti-thyroglobulin (Tg) level were normal. Ultrasounds showed multiple nodules in both lobe of thyroid and left inferior parathyroid adenoma. The patient underwent total thyroidectomy with left inferior parathyroidectomy, and final histopathology showed features of subacute granulomatous thyroiditis along with hurthle cell change in right lobe of thyroid. The left lobe additionally showed necrotizing epitheloid cell granulomas, which on Zeihl–Neelson staining revealed presence of acid-fast bacilli. Sections from the isthmus show a focus of papillary thyroid microcarcinoma. The left inferior parathyroid gland sent as a frozen sample was found to be parathyroid adenoma. On 6-month follow-up, the patient was feeling much relief in bone pain and tolerating antitubercular drugs uneventfully.ConclusionCoexistence of parathyroid adenoma, nonmedullary thyroid carcinoma, and thyroid tuberculosis is extremely rare. Surgery is curative for hyper parathyroidism and thyroid carcinoma. Thyroid tuberculosis responds well to current antitubercular drugs. Its etiology needs to be explored more; the probable hypothesis is chronic inflammation due to latent tuberculosis might leads to development of thyroid carcinoma and parathyroid adenoma. Further studies need to be done for better understanding of underlying mechanism and better management options for such patients. To the best of our knowledge, similar cases have not been reported.

Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.

The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair-related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next-generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients' clinical management, and reinforces the relevance of DICER1 in disease etiology.

Digoxin treatment does not reinduce uptake of radioiodine in metastatic radioiodine refractory non-medullary thyroid carcinoma

Digoxin treatment does not reinduce uptake of radioiodine in metastatic radioiodine refractory non-medullary thyroid carcinoma

Exploring the genetic links between voltage-gated potassium channels and familial non-medullary thyroid carcinoma: a family study

Exploring the genetic links between voltage-gated potassium channels and familial non-medullary thyroid carcinoma: a family study

Digoxin treatment does not reinduce radioiodine uptake in radioiodine refractory non-medullary thyroid carcinoma.

Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC. Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies. Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial. Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.

Epidemiological, clinicopathological, and evolutionary profile of familial non-medullary thyroid carcinoma (FNMTC) in 3 families

Epidemiological, clinicopathological, and evolutionary profile of familial non-medullary thyroid carcinoma (FNMTC) in 3 families

Identification of P21 (CDKN1A) Activated Kinase 4 as a Susceptibility Gene for Familial Non-Medullary Thyroid Carcinoma.

Background: Familial non-medullary thyroid carcinoma (FNMTC) is a genetically predisposed disease with unclear genetic mechanisms. This makes research on susceptibility genes important for the diagnosis and treatment options. Methods: This study included a five-member family affected by papillary thyroid carcinoma. The candidate genes were identified through whole-exome sequencing and Sanger sequencing in family members, other FNMTC patients, and sporadic non-medullary thyroid carcinoma patients. The pathogenicity of the mutation was predicted using in silico tools. Cell phenotype experiments in vitro and models of lung distant metastasis in vivo were conducted to confirm the characteristics of the mutation. Transcriptome sequencing and mechanistic validation were employed to compare the disparities between PAK4 wild-type (WT) and PAK4 mutant (MUT) cell lines. Results: This mutation alters the protein structure, potentially increasing instability by affecting hydrophobicity, intra-molecular hydrogen bonding, and phosphorylation sites. It specifically promotes phosphorylated PAK4 nuclear translocation and expression in thyroid tissue and cell lines. Compared with the WT cells line, PAK4 I417T demonstrates enhanced proliferation, invasiveness, accelerated cell division, and inhibition of cell apoptosis in vitro. In addition, it exhibits a significant propensity for metastasis in vivo. It activates tumor necrosis factor signaling through increased phosphorylation of PAK4, JNK, NFκB, and c-Jun, unlike the WT that activates it via the PAK4-NFκ-MMP9 axis. In addition, PAK4 MUT protein interacts with matrix metalloproteinase (MMP)3 and regulates MMP3 promoter activity, which is not observed in the WT. Conclusions: Our study identified PAK4: c.T1250C: p.I417T as a potential susceptibility gene for FNMTC. The study concludes that the mutant form of PAK4 exhibits oncogenic function, suggesting its potential as a novel diagnostic molecular marker for FNMTC.

Chromosomal localization of mutated genes in non-syndromic familial thyroid cancer.

Familial non-medullary thyroid carcinoma (FNMTC) is a type of thyroid cancer characterized by genetic susceptibility, representing approximately 5% of all non-medullary thyroid carcinomas. While some cases of FNMTC are associated with familial multi-organ tumor predisposition syndromes, the majority occur independently. The genetic mechanisms underlying non-syndromic FNMTC remain unclear. Initial studies utilized SNP linkage analysis to identify susceptibility loci, including the 1q21 locus, 2q21 locus, and 4q32 locus, among others. Subsequent research employed more advanced techniques such as Genome-wide Association Study and Whole Exome Sequencing, leading to the discovery of genes such as IMMP2L, GALNTL4, WDR11-AS1, DUOX2, NOP53, MAP2K5, and others. But FNMTC exhibits strong genetic heterogeneity, with each family having its own pathogenic genes. This is the first article to provide a chromosomal landscape map of susceptibility genes associated with non-syndromic FNMTC and analyze their potential associations. It also presents a detailed summary of variant loci, characteristics, research methodologies, and validation results from different countries.

Investigating USP42 Mutation as Underlying Cause of Familial Non-Medullary Thyroid Carcinoma.

In a family with Familial Non-Medullary Thyroid Carcinoma (FNMTC), our investigation using Whole-Exome Sequencing (WES) uncovered a novel germline USP42 mutation [p.(Gly486Arg)]. USP42 is known for regulating p53, cell cycle arrest, and apoptosis, and for being reported as overexpressed in breast and gastric cancer patients. Recently, a USP13 missense mutation was described in FNMTC, suggesting a potential involvement in thyroid cancer. Aiming to explore the USP42 mutation as an underlying cause of FNMTC, our team validated the mutation in blood and tissue samples from the family. Using immunohistochemistry, the expression of USP42, Caspase-3, and p53 was assessed. The USP42 gene was silenced in human thyroid Nthy-Ori 3-1 cells using siRNAs. Subsequently, expression, viability, and morphological assays were conducted. p53, Cyclin D1, p21, and p27 proteins were evaluated by Western blot. USP42 protein was confirmed in all family members and was found to be overexpressed in tumor samples, along with an increased expression of p53 and cleaved Caspase-3. siRNA-mediated USP42 downregulation in Nthy-Ori 3-1 cells resulted in reduced cell viability, morphological changes, and modifications in cell cycle-related proteins. Our results suggest a pivotal role of USP42 mutation in thyroid cell biology, and this finding indicates that USP42 may serve as a new putative target in FNMTC.

Identification of a Novel Germline PPP4R3A Missense Mutation Asp409Asn on Familial Non-Medullary Thyroid Carcinoma.

Familial non-medullary thyroid carcinoma (FNMTC) accounts for 3% to 9% of all thyroid cancer cases, yet its genetic mechanisms remain unknown. Our study aimed to screen and identify novel susceptibility genes for FNMTC. Whole-exome sequencing (WES) was conducted on a confirmed FNMTC pedigree, comprising four affected individuals across two generations. Variants were filtered and analyzed using ExAC and 1000 Genomes Project, with candidate gene pathogenicity predicted using SIFT, PolyPhen, and MutationTaster. Validation was performed through Sanger sequencing in affected pedigree members and sporadic patients (TCGA database) as well as general population data (gnomAD database). Ultimately, we identified the mutant PPP4R3A (NC_000014.8:g.91942196C>T, or NM_001366432.2(NP_001353361.1):p.(Asp409Asn), based on GRCH37) as an FNMTC susceptibility gene. Subsequently, a series of functional experiments were conducted to investigate the impact of PPP4R3A and its Asp409Asn missense variant in thyroid cancer. Our findings demonstrated that wild-type PPP4R3A exerted tumor-suppressive effects via the Akt-mTOR-P70 S6K/4E-BP1 axis. However, overexpression of the PPP4R3A Asp409Asn mutant resulted in loss of tumor-suppressive function, ineffective inhibition of cell invasion, and even promotion of cell proliferation and migration by activating the Akt/mTOR signaling pathway. These results indicated that the missense variant PPP4R3A Asp409Asn is a candidate susceptibility gene for FNMTC, providing new insights into the diagnosis and intervention of FNMTC.

Genetics of familial non-medullary thyroid carcinoma - investigation of two families'

Genetics of familial non-medullary thyroid carcinoma - investigation of two families'

Strategies for Treatment of Thyroid Cancer.

More people are diagnosed with thyroid cancer than any other endocrine tumor. Differentiated thyroid cancer is often treated by removing the thyroid gland (thyroidectomy), iodizing radiation, or inhibiting thyroid stimulating hormone (TSH). Advanced thyroid carcinomas are notoriously resistant to chemotherapy, thus the pursuit of alternative treatments is vital. The best methods for treating individuals with advanced nonmedullary and medullary thyroid carcinomas are discussed in this post. Numerous tyrosine kinase inhibitors and antiangiogenic inhibitors, two types of novel target therapy, have shown promise in studies for individuals with thyroid cancer. Both the positive and unfavourable outcomes of clinical studies of these drugs were addressed. The findings presented here are encouraging, but more study is required to establish whether or not this method is effective in the treatment of thyroid cancer.

An unusual presentation of coexisting parathyroid carcinoma and papillary carcinoma thyroid: a case report and literature review

Parathyroid carcinoma is the rarest endocrine cancer with aggressive behaviour. It may be presented as a feature of severe hypercalcemia, musculoskeletal involvement and a neck mass. There should be a high clinical suspicion if there is marked hypercalcemia, very high parathyroid hormone levels, palpable neck mass, recurrent laryngeal nerve palsy due to invasion and severe bone and renal symptoms. Thyroid pathology has been seen in 15-70% of patients with primary hyperparathyroidism (PHPT) especially with parathyroid adenoma. Medullary thyroid carcinoma is common with PHPT as in MEN 2 syndrome and rarely co-existed with non-medullary thyroid carcinoma. Parathyroid carcinoma and papillary thyroid carcinoma is extremely rare. Only 16 cases are reported in the literature.

Influence of Lenvatinib on the Functional Reprogramming of Peripheral Myeloid Cells in the Context of Non-Medullary Thyroid Carcinoma

Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of several types of cancers, including metastatic differentiated thyroid cancer (DTC). The intended targets include VEGFR 1-3, FGFR 1-4, PDGFRα, RET, and KIT signaling pathways, but drug resistance inevitably develops and a complete cure is very rare. Recent data has revealed that most of the TKIs have additional 'off-target' immunological effects, which might contribute to a protective antitumor immune response; however, human cellular data are lacking regarding Lenvatinib-mediated immunomodulation in DTC. Here, we investigated in ex vivo models the impact of Lenvatinib on the function of immune cells in healthy volunteers. We found that monocytes and macrophages were particularly susceptible to Lenvatinib, while neutrophiles and lymphocytes were less affected. In tumor-immune cell co-culture experiments, Lenvatinib exerted a broad inhibitory effect on the proinflammatory response in TC-induced macrophages. Interestingly, Lenvatinib-treated cells had decreased cellular M2 membrane markers, whereas they secreted a significantly higher level of the anti-inflammatory cytokine IL-10 upon LPS stimulation. In addition, prolonged exposure to Lenvatinib impaired macrophages survival and phenotypical differentiation, which was accompanied by remarkable morphological changes and suppressed cellular metabolic activity. These effects were mediated by myeloid cell-intrinsic mechanisms which are independent of Lenvatinib's on-target activity. Finally, using specific inhibitors, we argue that dual effects on p38 MAPK and Syk pathways are likely the underlying mechanism of the off-target immunological effects we observed in this study. Collectively, our data show the immunomodulatory properties of Lenvatinib on human monocytes. These insights could be harnessed for the future design of novel treatment strategies involving a combination of Lenvatinib with other immunotherapeutic agents.

FAMILIAL NON-MEDULLARY THYROID CARCINOMA.

Familial non-medullary thyroid carcinoma (FNMTC) is defined as cancer developing in two or more first-degree relatives if predisposing factors, for example, radiation, are absent. The disease can be either syndromic, when it is a component of complex genetic syndromes, or non-syndromic (95% cases). The genetic basis of non-syndromic FNMTC is unknown; the clinical behavior of tumorsis unclear and, at times, contradictory. To analyze clinical manifestations of FNMTC and compare them with the data for sporadic papillary thyroid carcinomas in patients of the same age groups. We examined 22 patients (a "parents" group and a "children" group) suffering from the non-syndromic FNMTC. For comparison, two groups of sporadic papillary carcinomas patients of the same age were drawn up("adult" and "young"). We analyzed tumor size and frequency of the distributionby the categoryof TNM system, invasiveness, multifocality, metastases to lymph nodes, type and extent of surgical and radioiodine treatment, and prognosis according to the MACIS criterion. Whether sporadic or familial, the tumor size, metastatic potential, and invasive potential are higher in young people, asalready known. There was no significant difference between the "parents" and "adult" groups of patients in terms of tumor parameters. One exception was the higher frequency of multifocal tumors in the FNMTC patients. Meanwhile, compared to the "young" sporadic papillary carcinomas patients, the FNMTC "children" had a higher frequency of T2 tumors, metastasizing (N1a-N1ab), and multifocal tumors, but a lower frequency of carcinomas with intrathyroidal invasions.In the FNMTC "children" compared to FNMTC "parents" was a higher frequency of T2 tumors, metastasizing carcinomas, and tumors with capsular invasion. FNMTC carcinomas are more aggressive than sporadic ones, especially in patients who are first-degree relatives in a family with parents already diagnosed with the disease.

PSAT373 Metformin Decreases Serum Thyroglobulin Concentration in Non-Medullary Thyroid Carcinoma

Abstract Background The conventional treatment of non-medullary thyroid carcinoma (NMTC) includes surgical resection, TSH suppression and 131-iodine. Although highly successful, some patients develop persistent/recurrent NMTC requiring alternative therapies, including external radiation and multikinase inhibitors, which may have clinically significant adverse side effects. In vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional metformin trials have been performed in humans. Hypothesis We performed a proof-of-concept intervention trial to test the hypothesis that metformin will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC, in humans with persistent/recurrent NMTC burden. Methods In this IRB approved study, we administered metformin to patients with persistent/recurrent NMTC and analyzed the change in Tg. When available and possible, tumor burden was evaluated by CT imaging. Ten patients with persistent/recurrent well-differentiated NMTC (6 classic papillary thyroid cancer, 1 tall cell variant of papillary thyroid cancer, 2 follicular thyroid cancer, and 1 hurthle cell thyroid cancer) were included. All had exhausted conventional therapies including total thyroidectomy and 131-iodine. All had biochemical evidence of NMTC with Tg > 2 ng/mL, and with non-detectable serum thyroglobulin antibody concentrations. Six had microscopic NMTC not detectable by conventional imaging, and four had NMTC detectable on CT imaging. Five patients elected to be treated with metformin (500 to 2000 mg/d) for two to five months. The remaining five served as untreated controls. Since the Tg variances in the two groups were not equal, the nonparametric Mann-Whitney test was used to determine if the change in Tg was different in the metformin treated and untreated groups. Results Tg decreased in all five patients receiving metformin and increased in all five controls. The mean Tg decrease with metformin therapy was 21.7 ± 8.4%, and the mean Tg increase in the control group was 16.6 ± 12.1%; p < 0.02. TSH was suppressed to < 0.1 mIU/L in both groups at baseline and did not change significantly during the study. Two of the five patients receiving metformin elected to continue the metformin for longer, and the CT imaging studies were evaluable by RECIST criteria. There was no decrease in tumor size in either patient. The progression-free survival was 6 months in one patient and 10 months in the other, which may be longer than that reported for similar historical controls that range from 3.6 to 5.8 months. Summary In summary, metformin caused a TSH-independent decrease of Tg in patients with persistent/recurrent NMTC, but no decrease in tumor size in two evaluable patients. More extensive studies are necessary to determine if metformin slows NMTC progression. Conclusion Metformin decreases Tg in NMTC. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Reprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma

Myeloid cells, crucial players in antitumoral defense, are affected by tumor-derived factors and treatment. The role of myeloid cells and their progenitors prior to tumor infiltration is poorly understood. Here we show single-cell transcriptomics and functional analyses of the myeloid cell lineage in patients with non-medullary thyroid carcinoma (TC) and multinodular goiter, before and after treatment with radioactive iodine compared to healthy controls. Integrative data analysis indicates that monocytes of TC patients have transcriptional upregulation of antigen presentation, reduced cytokine production capacity, and overproduction of reactive oxygen species. Interestingly, these cancer-related pathological changes are partially removed upon treatment. In bone marrow, TC patients tend to shift from myelopoiesis towards lymphopoiesis, reflected in transcriptional differences. Taken together, distinct transcriptional and functional changes in myeloid cells arise before their infiltration of the tumor and are already initiated in bone marrow, which suggests an active role in forming the tumor immune microenvironment.

Ultrasonography screening in children and adolescents who have one parent with familial non-medullary thyroid carcinoma.

To evaluate ultrasonography (US) screening for thyroid cancer in children and adolescents who have one parent with familial non-medullary thyroid carcinoma (FNMTC) unrelated to known genetic syndromes. In this prospective study, we selected 72 children and adolescents (age ≤18 years) without a palpable thyroid nodule or history of radiation exposure, but who have one parent diagnosed with FNMTC (i.e. at least one other affected first-degree relative). The children and adolescents were evaluated by US during initial assessment and after 5 years. Initial US revealed pure cysts in five participants and nodules in seven, which were ≥5 mm in five. These patients were submitted to fine needle aspiration, which revealed benign cytology in four and a follicular lesion of undetermined significance in one. Fine needle aspiration was repeated in the last case and in one case with benign cytology but suspicious US. The second cytology was benign in both cases. After 5 years, another two participants with initially normal US had nodules <5 mm in the absence of suspicious findings. The frequency of lesions detected by US was not associated with participant sex or age, number of relatives with thyroid cancer (2 or 3), maternal or paternal origin of tumour, or age of the relatives at diagnosis. The present results suggest that US screening is not necessary in children or adolescents when one parent has a diagnosis of FNMTC (≥2 affected relatives).

Metformin Decreases Serum Thyroglobulin Concentration in Nonmedullary Thyroid Carcinoma.

ContextThe conventional treatment of nonmedullary thyroid carcinoma (NMTC) includes surgical resection, thyrotropin (TSH) suppression, and 131-iodine. Some patients develop persistent/recurrent metastatic disease requiring expensive alternative therapies, such as external radiation and multikinase inhibitors, which may have clinically significant side effects. Recent in vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional trials analyzing the effect of metformin have been performed in humans.ObjectiveWe hypothesize that metformin administration will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC burden.MethodsThis retrospective institutional review board–approved study included 10 patients with persistent/recurrent NMTC who had exhausted conventional therapies including total thyroidectomy and 131-iodine. Five had detectable disease on computed tomography imaging. All had biochemical evidence of NMTC with Tg > 2.0 ng/mL with nondetectable serum thyroglobulin antibody concentrations. Five elected to have metformin treatment at doses varying from 500 to 2000 mg/day for 2 to 5 months. The remaining 5 served as untreated controls. Statistical significance was determined by the Mann–Whitney test.ResultsTg decreased (mean decrease = 21.7 ± 8.4%) in all 5 patients receiving metformin and increased (mean increase = 16.6 ± 12.1%) in all 5 controls (P < .01). TSH did not change significantly in either group.ConclusionIn summary, metformin caused a TSH-independent Tg decrease in patients with persistent/recurrent NMTC. More extensive studies are required to determine if metformin slows NMTC progression

Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma.

Objective Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).Methods We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.Results Twenty-nine patients (median age: 60; range: 6–80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51–87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64–97) for PTC/FTC and 29% (95% CI 4–71) for ATC. Median time to response was 1.87 months (range 1.64–3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1–2.Conclusion In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.Significance statementNTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.