Search Results (107)

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as predictors of therapeutic response. Papillary, follicular, oncocytic, medullary, and anaplastic thyroid carcinomas harbor distinct early driver mutations, such as BRAFV600E, RAS, and fusion events (RET, NTRK, and ALK), that cooperate with secondary alterations (TERT promoter, TP53, PIK3CA, and CDKN2A/B loss) to drive dedifferentiation, metastasis, and therapeutic resistance. Insights from The Cancer Genome Atlas (TCGA) and transcriptomic scoring systems (e.g., BRAF–RAS score) now link genotype to tumor morphology, metastatic tropism, and radioactive iodine refractoriness. These molecular insights have been incorporated into updated risk stratification frameworks, preoperative surgical planning, and treatment algorithms, informing the selection of kinase inhibitors, redifferentiation strategies, and enrollment in genotype-directed clinical trials for radioiodine-refractory disease. This review synthesizes recent evidence connecting genomic alterations to clinical behavior and highlights their translation into evolving approaches for thyroid cancer management. Full article

Follicular-cell-derived thyroid carcinoma, while typically associated with a favorable prognosis, can undergo dedifferentiation into poorly differentiated (PDTC) or anaplastic thyroid carcinoma (ATC), leading to enhanced aggressiveness and radioiodine resistance. This review systematically examines the genetic and molecular mechanisms driving this pathological progression, highlighting the roles of key mutations—such as BRAF, RAS, TERT, and TP53—and the disregulation of signaling pathways, including MAPK and PI3K/AKT. These alterations promote the loss of thyroid-specific functions, including iodide metabolism, and correlate with poor clinical outcomes. In recent years, therapeutic strategies aimed at tumor redifferentiation have emerged as a promising approach for radioiodine-refractory disease. We summarize recent advances in the use of targeted agents, particularly BRAF and MEK inhibitors, to restore radioiodine avidity and improve treatment response. While early clinical studies show encouraging results, including tumor shrinkage and restored RAI uptake in selected patients, challenges such as treatment resistance and patient selection remain. Future efforts should focus on refining molecular stratification, developing rational combination therapies, and integrating novel modalities such as immunotherapy to overcome resistance. A deeper understanding of redifferentiation mechanisms not only provides insights into thyroid cancer progression but also supports the development of personalized treatment strategies for high-risk patients. Full article

Background/Objectives: The tumor microenvironment (TME) plays a crucial role in the progression of the malignant phenotype through several mechanisms, such as hypoxia and nutrient deprivation, among others. These insults activate several intracellular pathways, and among them are ER stress and the unfolded protein response (UPR). Our aim was to assess if a specific ER stress inducer causes an exacerbation of the malignant phenotype of anaplastic thyroid carcinoma (ATC) cells. Methods: We used an ATC cell line, FRO cells, that had not undergone a full Epithelial–Mesenchymal Transition (EMT) and an ER stress-adapted cell line derived from FRO cells, A400 cells. Western blot, immunofluorescence, scratch, and invasion assays were used to evaluate the response of the FRO and A400 cells to ER stress. Results: The FRO cells were subjected to high-level ER stress caused by 400 ng/mL of tunicamycin (Tn). This caused the death of a large fraction of cells, but eventually a population emerged that we called A400 cells. Following an over challenge with Tn, the adapted population showed suppression of the UPR, apoptosis, and stress kinase activation. Moreover, the adapted population showed an exacerbation of mesenchymal features with a more invasive phenotype. At the level of a single cell, the adapted cells, caught in the act of moving, showed high-level expressions of vimentin (VIM), fibronectin (FN), and N-cadherin. Conclusions: High-level ER stress acts as a selection factor favoring the emergence of a cell population showing “mesenchymal drift” with a more malignant phenotype. Full article

Background/Objectives: Thyroid cancer (TC) is the most common type of endocrine neoplasm and is increasing in incidence, particularly papillary thyroid carcinoma (PTC). Early-stage disease has a favorable prognosis; however, advanced forms, such as anaplastic thyroid carcinoma, complicate treatment. Long non-coding RNAs (lncRNAs), longer than 200 nucleotides and non-coding, together with microRNAs, have emerged as major regulators of TC pathogenesis. This review summarizes data on how dysregulated lncRNAs influence the hallmarks of cancer in thyroid malignancies. Methods: We reviewed the literature on the role of lncRNAs and microRNAs in TC, focusing on their functions as competing endogenous RNAs (ceRNAs), regulators of PI3K/AKT and Wnt/β-catenin pathways, and controllers of epigenetic alterations. Results: Dysregulated lncRNAs contribute to hallmarks including sustained growth, evading suppressors, resisting death, replicative immortality, angiogenesis, invasion, metabolic reprogramming, immune evasion, genomic instability, and tumor-promoting inflammation. ceRNA mechanisms amplify immune evasion by regulating checkpoint proteins and cytokines, altering immune cell activity. Altered lncRNA profiles correlate with aggressiveness, metastasis, and prognosis. Notable lncRNAs, such as H19, MALAT1, and DOCK9-AS2, dysregulate oncogenic pathways and represent potential biomarkers. Conclusions: Advances in therapeutics suggest inhibiting oncogenic lncRNAs or restoring tumor-suppressive lncRNAs via RNA interference, antisense oligonucleotides, or CRISPR/Cas9 editing. New technologies, including single-cell RNA sequencing and spatial transcriptomics, will improve understanding of heterogeneous lncRNA–microRNA networks in TC and support precision medicine. LncRNAs signify both molecular drivers and clinical targets for thyroid cancer. Full article

Aggressive thyroid carcinomas—anaplastic (ATC) and poorly differentiated (PDTC)—are rare but highly lethal malignant entities. Their immunophenotypical characterization is still incomplete, and no standardized diagnostic algorithms have been used. Our study retrospectively analyzes 40 thyroidectomy cases as follows: 12 ATC and 28 PDTC from 2014 to 2024 by evaluating clinical data, histopathological aspects, molecular analysis for presence of BRAFV600E and TERTC228/250T mutations, as well as immunohistochemical expression of BRAF_V600E, total BRAF, K-RAS, TERT, PAX-8, TTF-1, P53, and Ki-67. BRAF_V600E was present in 70% of cases, with higher prevalence in ATC. Total BRAF correlated positively with K-RAS and TERT and negatively with BRAF_V600E. TERT abnormal expression was highly prevalent in over 90% of cases, while loss of TTF-1 and PAX-8 is associated with anaplastic transformation. Ki-67 proliferative index had significantly higher values in ATC, thus supporting its role as a marker for aggressiveness. On univariate analysis, higher Ki-67 indices and lymph node invasion are independent predictor factors for the presence of metastases. However, on multivariate analysis, they both lose significance. Upon multivariate analysis, loss of TTF-1 and tumor necrosis were significant predictors for anaplastic histotype. Specific BRAF_V600E immunohistochemistry may be a good screening tool for the BRAF_V600E mutation. Molecularly, there is a relatively frequent association of the BRAFV600E mutation and TERTC228, mainly in the PDTC subgroup. Patterns of marker expression suggest that BRAF or RAF activation with subsequent loss of TTF-1 or PAX-8, TERT upregulation, and TP53 alteration are frequent occurrences in aggressive thyroid carcinomas. The association between TTF-1 loss and anaplastic transformation, presence of necrosis alongside BRAF_V600E, underlines their diagnostic potential in subclassifying aggressive thyroid carcinomas. Full article

Organoid and spheroid technologies have rapidly become pivotal in thyroid cancer research, offering models that are more physiologically relevant than traditional two-dimensional culture. In the study of papillary and anaplastic thyroid carcinomas, two subtypes that differ both histologically and clinically, three-dimensional (3D) models offer unparalleled insights into tumor biology, therapeutic vulnerabilities, and resistance mechanisms. These models maintain essential tumor characteristics such as cellular diversity, spatial structure, and interactions with the microenvironment, making them extremely valuable for disease modeling and drug testing. This review emphasizes recent progress in the development and use of thyroid cancer organoids and spheroids, focusing on their role in replicating disease features, evaluating targeted therapies, and investigating epithelial–mesenchymal transition (EMT), cancer stem cell behavior, and treatment resistance. Patient-derived organoids have shown potential in capturing individualized drug responses, supporting precision oncology strategies for both differentiated and aggressive subtypes. Additionally, new platforms, such as thyroid organoid-on-a-chip systems, provide dynamic, high-fidelity models for functional studies and assessments of endocrine disruption. Despite ongoing challenges, such as standardization, limited inclusion of immune and stromal components, and culture reproducibility, advancements in microfluidics, biomaterials, and machine learning have enhanced the clinical and translational potential of these systems. Organoids and spheroids are expected to become essential in the future of thyroid cancer research, particularly in bridging the gap between laboratory discoveries and patient-focused therapies. Full article

Thyroid cancer, the most frequently occurring endocrine neoplasm, comprises a heterogeneous group of histological subtypes, spanning from the indolent papillary thyroid carcinoma (PTC) to the rapidly progressive and lethal anaplastic thyroid carcinoma (ATC). Although conventional therapies, such as surgery and radioactive iodine (RAI), are effective for differentiated thyroid cancers, treatment resistance and poor prognosis remain major challenges in advanced and undifferentiated forms. In current times, growing attention has been directed toward the potential of Natural Killer (NK) cells as a promising immunotherapeutic avenue. These innate immune cells are capable of direct cytotoxicity against tumor cells, but their efficiency is frequently compromised by the immunosuppressive tumor microenvironment (TME), which inhibits NK cell activation, infiltration, and persistence. This review explores the dynamic interaction between NK cells and the TME in thyroid cancer, detailing key mechanisms of immune evasion, including the impact of suppressive cytokines, altered chemokine landscapes, and inhibitory ligand expression. We further discuss latest advancements in NK cell-based immunotherapies, including strategies for ex vivo expansion, genetic modification, and combinatorial approaches with checkpoint inhibitors or cytokines. Additionally, emerging modalities, such as NK cell-derived extracellular vesicles, are addressed. By combining mechanistic insights with advancing therapeutic techniques, this review provides a comprehensive perspective on NK cell-based interventions and their future potential in improving outcomes for patients with thyroid cancer. Full article

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with poor prognosis and limited treatment options. Precision oncology seeks personalized therapies that selectively modulate tumor behavior, which is critical for improving patient outcomes. In this study, we evaluated the therapeutic potential of human dental pulp stem cell-derived extracellular vesicles (hDPSC-EVs) in three ATC cell lines (8505C, HTH83, KTC-2). Fluorescence and confocal microscopy confirmed the efficient, time-dependent internalization of hDPSC-EVs by ATC cells, with increased fluorescence intensity over 48 h. Functional assays revealed the selective inhibition of migration and invasion in a cell line-dependent manner, without affecting cell proliferation, viability, or tumorigenic traits, indicating a non-cytotoxic, context-specific modulation of tumor behavior. After 72 h of EV treatment, targeted qPCR of 92 cancer-related genes showed the strongest response in 8505C cells (24 genes; 16 up, 8 down), moderate changes in KTC-2 (16 genes; 14 up, 2 down), and few alterations in HTH83 (6 genes; 4 up, 2 down). Across all lines, FN1 emerged as a context-dependent target, downregulated in 8505C but upregulated in the other two. No broad pathway enrichment was observed, indicating the fine-tuning of key networks rather than wholesale reprogramming. Despite variations across cell lines, hDPSC-EVs consistently demonstrated no impact on cell proliferation and no evidence of cytotoxicity or tumorigenic behavior, with no adverse outcomes. These findings provide preclinical evidence for hDPSC-EVs as a promising, safe, and targeted therapeutic platform in precision oncology, particularly for aggressive cancers, like ATC, warranting further exploration in preclinical and clinical studies. Full article

Aggressive thyroid carcinomas are rare malignancies characterized by a high impact on patient’s lives and poor prognosis. The available literature is scarce presenting divergent data concerning the clinical outcomes, prognostic factors and variable mutational signature studies. We aim to collect data from the literature and assemble a systematic review. The literature from 2007 until May 2025 was searched using PubMed. Studies bearing data concerning clinical aspects, prognostic outcomes, or molecular characteristics of differentiated high-grade (DHGTC), poorly differentiated (PDTC), and anaplastic thyroid carcinomas (ATC) were retrieved. Original articles in English, ethically conducted on human patients, were selected. From 688 articles, 39 were included. DHGTC has a good 5-year survival rate (5YSR) of 76%, 23.18% metastasis rate, 42.23%, lymph node involvement (LNI), 61.44% extrathyroidal extension (ETE), majority being diagnosed in stage III. PDTC has an intermediate 5YSR of 65.71%, 21.17% distant metastasis, 32.22% LNI, and 55.19% ETE, majority diagnosed in stage III. ATC has a grim 2-year survival rate of 11.15%, 42.15% metastasis, 44.14%, LNI, and 58.51% ETE, majority presented in stage IV-B. Mutational profiling shows that each carcinoma has its unique set of molecular alterations. Most positive prognostic comes for DHGTC, then PDTC, and finally, ATC. Full article

Thyroid cancer (TC) invariably remains the most prevalent endocrine cancer in the world. Major histological forms of TC include papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic thyroid carcinoma (ATC), each of which has a unique clinical and molecular profile. The incidence rate of TC is higher in females, and unfortunately, it has tended to increase over the last several years. Yet the treatment of advanced or aggressive TC forms has improved recently because of developments in immunotherapy and targeted medicines, including PD-1 inhibitors and tyrosine kinase inhibitors (e.g., lenvatinib, sorafenib). Imaging, fine-needle aspiration biopsies, and molecular testing are implemented in the diagnostic process, e.g., in search of mutations that might affect prognosis and provide the most successful treatment option. Chemotherapy, immunotherapy, radioactive iodine therapy (RAI), surgery (such as a total thyroidectomy), and molecularly targeted therapies are currently standard treatment modalities in TC. Optimizing patient outcomes requires better diagnostic precision and individualized treatment regimens based on the genetic profile and tumor subtype. To improve survival and quality of life, it is critical to comprehend the complex etiology of TC and the changing therapeutic landscape. Full article

Anaplastic thyroid carcinoma (ATC) is the rarest and most aggressive form of thyroid cancer, marked by a poor prognosis and resistance to conventional treatments. Like many malignancies, ATC has a complex genetic landscape, with numerous mutations driving tumor initiation, progression, and therapeutic resistance. However, recent advances in molecular research have expanded our understanding of these genetic alterations, paving the way for new targeted treatment strategies. Currently, therapies targeting specific genetic mutations, such as BRAF and MEK, show promise, but their effectiveness is limited to patients harboring these mutations. To explore broader therapeutic possibilities, we conducted a comprehensive literature review using the PubMed database and Google to identify studies on key genetic mutations in ATC. By leveraging these molecular insights, we aim to highlight potential therapeutic avenues that could enhance treatment options and improve patient outcomes. Full article

Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations—one germline and one somatic—and analyze the broader prevalence and significance of FLCN in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline FLCN mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic FLCN inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic FLCN mutation in an oncocytic poorly differentiated thyroid carcinoma, which exhibited extensive angioinvasion, high proliferative activity, and concurrent TP53 and RB1 mutations. The tumor progressed with metastatic disease despite multimodal treatment. Thyroid carcinomas revealed FLCN alterations in 1.1% of cases. Pathogenic mutations were rare but associated with oncocytic morphology, while homozygous deletions occurred more frequently in genomically unstable tumors, including anaplastic thyroid carcinoma. These findings suggest FLCN mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of FLCN coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including FLCN in genetic testing could improve tumor detection and characterization, particularly in BHD patients who may benefit from routine thyroid screening. Further studies are needed to clarify FLCN’s role in thyroid cancer pathogenesis. Full article

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer. Tumor cells have been shown to activate alternative signaling pathways, making treatments less effective. One of the major proteins involved in the progression of ATC is the proto-oncogene KRAS that belongs to a group of small guanosine triphosphate (GTP)-binding proteins. Despite its recognized importance in cancer malignancy, KRAS is considered non-druggable and has never been studied in the field of ATC. In this context, a new synthetic molecule, BAY-293, has recently been developed that selectively inhibits the KRAS–SOS-1 interaction. Based on these findings, the aim of this study was to evaluate for the first time the antitumor effect of BAY-293 using in vitro and in vivo models of ATC. The in vitro model included different thyroid cancer (TC) cell lines used to study the effect of BAY-293 on the modulation of mitogen-activated protein kinase (MAPK) pathways, apoptosis, and cell migration. To confirm the in vitro findings and better mimic the complex tumor microenvironment, an in vivo orthotopic model of ATC was used. The results of the study indicate that BAY-293, both in vitro and in vivo, effectively blocked the KRAS/MAPK/ERK pathway and β-catenin, which act as downstream effectors essential for cell migration, and increased the apoptotic process by slowing the progression of ATC. In conclusion, this study demonstrated that KRAS/SOS-1 inhibition could be a promising therapeutic target for the treatment of ATC and highlighted BAY-293 as an innovative molecule that needs further research to fully evaluate its efficacy in the field of thyroid cancer. Full article

Background: Small papillary thyroid carcinomas with the largest dimension of 10 mm are slow-growing and self-limiting tumors, most of which have no potential for progression, rarely becoming clinically evident carcinomas or undergoing regressive changes. Their anaplastic transformation, primarily in the thyroid gland or into lymph node metastasis, is extremely rare. Case Presentation: A 66-year-old female patient was admitted to our hospital for diagnostics and treatment of a large tumor on the left neck side. Preoperative imaging and cytological findings of the neck tumor suggested metastasis of papillary thyroid carcinoma. Total thyroidectomy and metastasectomy were performed. In the final diagnosis, anaplastic transformation of the papillary thyroid carcinoma’s metastasis in the neck was confirmed. Opposite to advanced dedifferentiation of metastasis, primary tumor foci in the thyroid were regressed and replaced with sclerosis and microcalcification. The synchronous co-occurrence of incidental primary thyroid carcinoma and anaplastic thyroid carcinoma originating from ectopic cervical thyroid tissue was considered diagnostically. Conclusions: The case highlights the necessity of regular monitoring of the thyroid and neck lymph nodes for patients under active surveillance, including those with small calcified tumor foci. This paper also comprehensively reviews the existing literature on this topic. Full article

Background/Objectives MC4R expression and its role in colorectal and anaplastic thyroid cancers, where resistance to therapy and lack of standard treatments remain significant challenges, are poorly understood. This study aimed to investigate MC4R as a potential therapeutic target in these cancers using the selective antagonist ML00253764 (ML), alone and in combination with vinorelbine (VNR) and irinotecan (or its active metabolite SN-38). Methods: Human colorectal adenocarcinoma HT-29, Caco-2, and anaplastic thyroid carcinoma 8305C cell lines were used. MC4R expression was assessed by Real-Time PCR with validated primers (Assay ID Hs00271877_s1), immunofluorescence, and Western blotting. Proliferation and apoptosis assays were conducted with ML, and synergy with VNR and SN-38 was evaluated by Combination Index and Loewe methods. ERK1/2 phosphorylation was measured using an ELISA assay. In vivo studies were conducted by injecting tumor cells into Athymic Nude-Foxn1nu mice, treated with ML, VNR, irinotecan, or their combinations. Results: MC4R expression was confirmed in all cell lines. ML treatment inhibited MC4R, producing antiproliferative and pro-apoptotic effects, with IC₅₀ values of 7667 ± 2144.6 nM (8305C), 806.4 ± 321.8 nM (HT-29), and 2993 ± 1135.2 nM (Caco-2). In combination with VNR and SN-38, ML exhibited significant synergy in vitro and reduced tumor volume in vivo without causing weight loss or adverse effects in mice. Conclusions This study identifies ML as a promising therapeutic agent that, when combined with chemotherapy, may offer a novel strategy for treating colorectal and anaplastic thyroid cancers. Full article