A novel multimodal diagnostic framework integrating hyperspectral imaging and deep learning for predicting RET gene mutations in medullary thyroid carcinoma.

Hyalinizing trabecular tumor of the thyroid: A comprehensive review of clinicopathological features, diagnostic dilemmas, and emerging molecular insights.

Calcitonin and procalcitonin: Revisiting the overlooked role of C cells.

A uncommon neuroendocrine cancer that arises from thyroid parafollicular C cells, medullary thyroid carcinoma (MTC) makes up 1-5% of all thyroid malignancies. Because of its aggressive nature, early lymphatic dissemination, and poor response to traditional treatments, MTC contributes disproportionately to thyroid cancer- related death despite its low frequency. It can happen occasionally or as a component of hereditary disorders such multiple endocrine neoplasia types 2A and 2B, which are frequently linked to RET proto-oncogene mutations. Variable imaging and cytological features can make diagnosis difficult, therefore biochemical indicators like serum calcitonin are crucial for precise identification. We describe the case of a 67-year-old woman who had a history of right breast cancer and who had a right-sided neck enlargement that was painless. While fine-needle aspiration cytology showed results compatible with medullary thyroid cancer, ultrasonography showed characteristics suggestive of a benign thyroid nodule. The patient had a central neck lymph node dissection along with a total thyroidectomy. A clearly defined tumor limited to the right thyroid lobe was discovered during surgery, and the postoperative course was uncomplicated with clinical improvement at discharge. This case emphasizes how difficult it is to diagnose medullary thyroid cancer, especially when radiological results are deceptive. It highlights the need of keeping a high level of suspicion as well as the function of biochemicalmarkers and cytology in diagnosis. While improvements in molecular genetics and targeted medicines continue to improve outcomes in advanced and metastatic illness, early surgical intervention continues to be the cornerstone of management.

Analysis of clinical and histopathological features in concurrent papillary and medullary thyroid carcinoma.

One of the challenges in tumor molecular profiling for therapeutic decisions is the unavailability of tumor tissue or its inadequacy to provide high-quality nucleic acids. Although tissue biopsy remains the "gold-standard," analysis of circulating tumor DNA (ctDNA) may offer an alternative to characterize mutations necessary to initiate systemic therapy with selective inhibitors in eligible patients. This study aimed to identify cases of sporadic medullary thyroid carcinoma (sMTC) in which plasma ctDNA analysis may be useful for RET gene testing when tumor tissue is unavailable. We conducted a retrospective cohort study analyzing plasma from 36 patients affected by RET-mutated sMTC. Patients were divided into three cohorts (1) 18 patients with progressive sMTC; (2) nine patients with stable disease under treatment with a multikinase inhibitor; and (3) nine patients with metastatic but stable disease without treatment. For patients in cohort 1, we studied plasma collected at the time of progression just before the initiation of systemic therapy, while in cohorts 2 and 3, we studied last plasma available at follow-up. The RET driver mutation was analyzed in ctDNA using specific digital droplet PCR assays. The RET driver mutation was detected in 16/36 (44.4%, CI 27.9-61.9) ctDNA samples, with a statistically significant difference among the three cohorts 16/18 (88.9%, CI 65.3-98.6) in cohort 1 and 0/9 (0%, CI 0-33.6) in cohorts 2 and 3 (p < 0.001) with a mean variant allele frequency of 5.4%. The presence of detectable RET-mutated ctDNA was associated with disease progression (p < 0.001), higher percentage of metastatic sites with > five lesions (i.e., tumor burden; p = 0.001), and higher levels of serum calcitonin (Ct) (p = 0.009), and carcinoembryonic antigen (p = 0.038). Our study demonstrates that ctDNA analysis may be a valid approach to genotype sMTC patients. Thus, liquid biopsy-based RET mutation profiling may be beneficial in advanced and progressive sMTC cases when primary tumor tissue is unavailable or inadequate for high-quality nucleic acid extraction, enabling RET-inhibitor therapy, if needed, according to specific indications. However, to obtain reliable results, ctDNA molecular profiling should be performed when tumor burden is high and the disease is progressing.

The cytological characteristics of high-grade medullary thyroid carcinoma (HG-MTC) remain insufficiently defined. This study aimed to elucidate these features and assess their potential in estimating HG-MTC. Cytological and histological specimens from 12 patients with HG-MTC and 36 patients with low-grade (LG) MTC were analyzed. Amyloid was observed in 50.0% of LG-MTC nodules but in only 8.3% of HG-MTC nodules (p < 0.05). Necrotic materials were observed in only one HG-MTC nodule. The frequencies of intracytoplasmic mucin (25.0%), pseudoinclusions (66.7%), mitotic figures (58.3%), and cannibalism (25.0%) in HG-MTC nodules were significantly higher than those in LG-MTC nodules (p < 0.05). Nuclear grooves, fine chromatin pattern, and irregularly shaped nuclei were observed in 41.7%, 41.7%, and 25.0% of HG-MTC nodules, respectively. None of them were observed in LG-MTC nodules (p < 0.05). When at least one of the six cytological features including mitotic figures, nuclear grooves, fine chromatin pattern, irregularly shaped nuclei, intracytoplasmic mucin, and cannibalism was present, the sensitivity and specificity for HG-MTC diagnosis were 91.7% and 83.3%, respectively. Mitotic figures, nuclear grooves, fine chromatin pattern, irregularly shaped nuclei, intracellular mucin, and cannibalism are cytological findings suggestive of HG-MTC. Except for pseudoinclusions, PTC-like nuclear features can be considered important diagnostic clues for HG-MTC.

Medullary thyroid carcinoma (MTC) is a rare thyroid cancer arising from parafollicular C cells belonging to the heterogeneous class of neuroendocrine neoplasms. Mutations in the RET and RAS genes are detected in approximately 50% to 80% of sporadic MTCs, while other genetic alterations are relatively uncommon. Only a few transcriptomic studies of this neoplasia have been performed, and the biology and the molecular mechanisms underlying its progression remain largely unknown. In this study, we performed transcriptome profiling of a cohort comprising 72 MTC specimens from patients with different genetic backgrounds. The presented data highlighted the molecular heterogeneity of MTCs and the need for personalized treatment strategies. For this reason, the obtained profiles could offer novel perspectives into the molecular landscape of this neoplasm within the scientific community.

BCAR3 has been implicated in various cancers, yet its role in thyroid cancer (TC) remains unclear. This study aimed to investigate the methylation status, functional effects, and underlying mechanisms of BCAR3 in TC. BCAR3 methylation was analyzed using matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry in 422 TC and 371 benign thyroid nodule samples. Expression levels were assessed via immunohistochemistry, qPCR, and Western blot. Functional assays including proliferation, migration, and invasion were performed after BCAR3 knockdown. Rescue experiments using a PI3K activator were conducted to examine pathway mechanisms. BCAR3 was significantly hypomethylated in TC compared to benign tissues (p < 0.001), with CpG_6 most strongly associated with TC risk (odds ratio, OR = 1.73, p < 0.001). Notably, BCAR3 hypomethylation was more pronounced in cases with larger tumor size and advanced disease stage. Furthermore, BCAR3 methylation showed differential patterns across TC subtypes, with medullary thyroid carcinoma exhibiting the lowest methylation levels. BCAR3 expression was upregulated in TC tissues and cell lines (p < 0.05). Mechanistically, BCAR3 knockdown reduced phosphorylation of AKT/mTOR and altered expression of epithelial-to-mesenchymal transition (EMT) marker, characterized by an increase in E-cadherin and decreases in Vimentin and N-cadherin, and consequently suppressed proliferation, migration, and invasion (p < 0.05). Rescue experiments with a PI3K activator showed a trend towards restoration of these effects, although not to the level of the control groups. BCAR3 hypomethylation contributes to TC cells' proliferation, migration, and invasion by promoting AKT/mTOR activation and EMT. These findings highlight the potential of BCAR3 methylation as both a biomarker and a therapeutic target in TC.

Comment on "Evaluating the necessity of prophylactic lateral neck dissection in medullary thyroid carcinoma based on preoperative calcitonin levels: a multicenter retrospective cohort study".

Artificial intelligence (AI) and machine learning (ML) are reshaping cancer research and care. In pediatric oncology, early evidence-most robust in imaging-suggests value for diagnosis, risk stratification, and assessment of treatment response. Pediatric endocrine tumors are rare and heterogeneous, including intra- and extra-adrenal paraganglioma (PGL), adrenocortical tumors (ACT), differentiated and medullary thyroid carcinoma (DTC/MTC), and gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Here, we provide a pediatric-first, entity-structured synthesis of AI/ML applications in endocrine tumors, paired with a methods-for-clinicians primer and a pediatric endocrine tumor guardrails checklist mapped to contemporary reporting/evaluation standards. We also outline a realistic EU-anchored roadmap for translation that leverages existing infrastructures (EXPeRT, ERN PaedCan). We find promising-yet preliminary-signals for early non-remission/recurrence modeling in pediatric DTC and interpretable survival prediction in pediatric ACT. For PGL and GEP-NEN, evidence remains adult-led (biochemical ML screening scores; CT/PET radiomics for metastatic risk or peptide receptor radionuclide therapy response) and serves primarily as methodological scaffolding for pediatrics. Cross-cutting insights include the centrality of calibration and validation hierarchy and the current limits of explainability (radiomics texture semantics; saliency ≠ mechanism). Translation is constrained by small datasets, domain shift across age groups and sites, limited external validation, and evolving regulatory expectations. We close with pragmatic, clinically anchored steps-benchmarks, multi-site pediatric validation, genotype-aware evaluation, and equity monitoring-to accelerate safe, equitable adoption in pediatric endocrine oncology.

Selpercatinib is a selective inhibitor of rearranged during transfection (RET) kinase and is indicated for patients with RET fusion-positive non-small cell lung cancer, advanced RET fusion-positive solid tumors, and thyroid cancer. This report describes a patient who developed renal tubular damage resulting in renal loss of electrolytes and polyuria four weeks after the start of selpercatinib. To our knowledge, tubular damage is a rare selpercatinib-induced toxicity. This report contributes to the growing literature about selpercatinib-related adverse events and their management. A 74-year-old male with RET mutation-positive medullary thyroid cancer, presented with thirst, hyponatremia, hypomagnesemia, hypocalcemia, and polyuria. The hyponatremia deteriorated to symptomatic hyponatremia (112 mmol/L) and required intensive care unit admission. Selpercatinib treatment (160mg bi-daily) was interrupted, and plasma was collected for therapeutic drug monitoring (TDM). The patient was hospitalized for fluid supplementation and correction of electrolytes. The association with selpercatinib seemed likely due to a Naranjo score of 9 (out of 13). Following dose interruption and supportive care, electrolyte disturbances and polyuria resolved. After recovery, selpercatinib was rechallenged at a dose of 80mg bi-daily based on TDM. No recurrence of electrolyte disturbances or renal toxicity was observed, and the patient maintained stable disease. Our report indicates an association between selpercatinib plasma concentration and renal tubular damage, and emphasizes the importance of recognizing selpercatinib-induced tubular injury. This report also provides guidance for the management of these renal manifestations and for rechallenge guided by TDM, highlighting a potential role for TDM in dose determinations after selpercatinib-induced renal toxicity.

Medullary thyroid carcinoma (MTC) is a rare malignant tumour of the thyroid gland that originates from parafollicular cells. Although rare, MTC is aggressive, so early detection is important for improving prognosis. The accuracy of fine-needle aspiration cytology (FNAC) for diagnosing MTC is still controversial. The data of 20 patients who underwent thyroid FNAC with histological follow-up to diagnose MTC between 2016 and 2024 were retrospectively collected from The First Affiliated Hospital of Soochow University. Cytological findings, histological features, and serological testing were reviewed, and causes of misdiagnosis were evaluated. The diagnostic accuracy of FNAC was 90% (18/20). Two patients were initially misdiagnosed with suspected papillary thyroid carcinoma, while eighteen patients were accurately diagnosed in the first instance with suspected MTC. Cytopathological analysis revealed plasmacytoid and spindle-like characteristics with 'salt and pepper' chromatin distributed in the nuclei, with occasional giant tumour cells and frequent deposition of pink-stained amyloid in the background. In addition, serum calcitonin and carcinoembryonic antigen were elevated to varying degrees. Fine-needle aspiration is a highly valuable method for the preoperative diagnosis of MTC.

Multifocality in sporadic medullary thyroid carcinoma is associated with low tumor grade and no difference in somatic driver mutations or overall survival when compared with unifocal tumors.

The Role of External Beam Radiation Therapy in Thyroid Cancer Management: A Scoping Review.

Insights into the stability of serum calcitonin and a comparison of three serum calcitonin immunoassays.

The shifting landscape of germline RET pathogenic variants with the introduction of panel testing.

Introduction: Ki-67 has shown promise as a predictive and diagnostic marker in solid tumours. The Ki-67 index is a wellestablished proliferation marker that has been studied in various tumours, including follicular neoplasms of the thyroid. Its role in thyroid pathology, especially in differentiating between Follicular Thyroid Adenoma (FTA) and Follicular Thyroid Carcinoma (FTC), has garnered significant clinical interest. Aim: To evaluate the diagnostic and prognostic utility of the Ki-67 labeling index (Ki-67 LI) in follicular neoplasms of the thyroid. Materials and Methods: A comprehensive search of records in the databases PubMed, Embase, and Scopus, along with manual citation searching, was conducted using MeSH terms and keywords related to ‘Ki-67 antigen’ and ‘FTC.’ Peerreviewed literature evaluating Ki-67 as a diagnostic or prognostic marker in follicular thyroid neoplasms published in English was included. Non English publications, reviews, case reports, and editorials, as well as research focusing solely on other thyroid cancers, including anaplastic or medullary carcinomas, were excluded during the screening process. The quality assessment was conducted using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) Cochrane tool and the Quality in Prognosis Studies (QUIPS) for diagnostic and prognostic studies, respectively. A narrative synthesis and subgroup analysis of the extracted data were performed due to the heterogeneity in effect measures of Ki-67 labeling index and the outcomes. The parameters of prognostic outcomes assessed included the proportion of metastasis, recurrence, nodal involvement, survival rates, and mortality rates. The parameters of diagnostic outcomes involved the mean/median Ki-67 index to differentiate benign from malignant neoplasms. Results: A total of six eligible studies were included in this review. Follicular carcinomas demonstrated significantly higher Ki-67 labeling indices compared to adenomas. High values of Ki-67 are associated with malignancy, tumour aggressiveness, recurrence, and metastasis. The subgroup analysis indicated that the likelihood of poor prdeognosis for follicular thyroid neoplasms is approximately doubled at a cut-off of about 5% for the Ki-67 LI. Conclusion: This review includIntroduction: Ki-67 has shown promise as a predictive and diagnostic marker in solid tumours. The Ki-67 index is a wellestablished proliferation marker that has been studied in various tumours, including follicular neoplasms of the thyroid. Its role in thyroid pathology, especially in differentiating between Follicular Thyroid Adenoma (FTA) and Follicular Thyroid Carcinoma (FTC), has garnered significant clinical interest. Aim: To evaluate the diagnostic and prognostic utility of the Ki-67 labeling index (Ki-67 LI) in follicular neoplasms of the thyroid. Materials and Methods: A comprehensive search of records in the databases PubMed, Embase, and Scopus, along with manual citation searching, was conducted using MeSH terms and keywords related to ‘Ki-67 antigen’ and ‘FTC.’ Peerreviewed literature evaluating Ki-67 as a diagnostic or prognostic marker in follicular thyroid neoplasms published in English was included. Non English publications, reviews, case reports, and editorials, as well as research focusing solely on other thyroid cancers, including anaplastic or medullary carcinomas, were excluded during the screening process. The quality assessment was conducted using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) Cochrane tool and the Quality in Prognosis Studies (QUIPS) for diagnostic and prognostic studies, respectively. A narrative synthesis and subgroup analysis of the extracted data were performed due to the heterogeneity in effect measures of Ki-67 labeling index and the outcomes. The parameters of prognostic outcomes assessed included the proportion of metastasis, recurrence, nodal involvement, survival rates, and mortality rates. The parameters of diagnostic outcomes involved the mean/median Ki-67 index to differentiate benign from malignant neoplasms. Results: A total of six eligible studies were included in this review. Follicular carcinomas demonstrated significantly higher Ki-67 labeling indices compared to adenomas. High values of Ki-67 are associated with malignancy, tumour aggressiveness, recurrence, and metastasis. The subgroup analysis indicated that the likelihood of poor prdeognosis for follicular thyroid neoplasms is approximately doubled at a cut-off of about 5% for the Ki-67 LI. Conclusion: This review included six studies involving retrospective analysis. There are variations in the techniques of immunohistochemical analysis, cell counting methods, and cut-off values chosen for the Ki-67 index among the included studies. Due to a lack of consensus regarding the reliability and standardisation of this biomarker, Ki-67 LI cannot replace standard histology. Regardless of a specific threshold, high Ki67 levels effectively differentiate carcinomas from adenomas and indicate a poor prognosis.ed six studies involving retrospective analysis. There are variations in the techniques of immunohistochemical analysis, cell counting methods, and cut-off values chosen for the Ki-67 index among the included studies. Due to a lack of consensus regarding the reliability and standardisation of this biomarker, Ki-67 LI cannot replace standard histology. Regardless of a specific threshold, high Ki67 levels effectively differentiate carcinomas from adenomas and indicate a poor prognosis.

Highly-selected sporadic, apparently unifocal cN0 MTC may benefit from unilateral surgery. A proof of concept in a high-volume institution.

Sprayable pH-sensitive near-infrared fluorophore for rapid, bright, specific, and safe visualization of human thyroid cancer in orthotopic mouse models.