RARE DISEASE
Rare thyroid carcinoma
Rare thyroid carcinoma
Rare thyroid carcinoma
Drug discovery
4
drugs
With orphan designations
Overview
Rare thyroid carcinomas encompass aggressive, poorly differentiated malignancies such as anaplastic (ATC), medullary (MTC), Hürthle cell, and primary thyroid lymphomas/sarcomas. These tumors represent <5% of thyroid cancers, exhibit rapid progression, and often present with advanced disease. Prognosis varies widely, with ATC having exceptionally poor survival (median ~6 months) and MTC linked to hereditary syndromes in 25% of cases [1][6][16][20].
Population
Anaplastic thyroid cancer (ATC) accounts for 1-2% of thyroid malignancies, primarily affecting individuals >60 years [1][6].
Medullary thyroid cancer (MTC) represents 2-5% of cases, with 25% arising from RET proto-oncogene mutations [1][8].
Higher incidence observed in non-Hispanic white populations and females (3:1 ratio) [2][7].
Burden
Global DALYs increased 29.98% from 1990-2019, with South Asia experiencing the highest mortality [9][19].
ATC contributes disproportionately to thyroid cancer deaths (median survival 6 months; 5-year survival <20%) [1][6].
Treatment costs escalate with advanced disease management, including palliative airway interventions and targeted therapies [1][6][19].
Therapies
ATC: Multimodal approach with surgery (when resectable), combined chemoradiation, and BRAF/MEK inhibitors (dabrafenib/trametinib) for BRAF V600E-mutated tumors [3][6].
MTC: Tyrosine kinase inhibitors (cabozantinib, vandetanib) for metastatic disease; prophylactic thyroidectomy for RET mutation carriers [8][16].
Emerging therapies: Immune checkpoint inhibitors, NTRK/RET inhibitors, and clinical trial enrollment emphasized for advanced cases [3][8][16].
Categories: rare endocrine diseases, rare neoplastic diseases
Research Papers
1,219 drug discovery papers about Rare thyroid carcinoma, with 2 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,219 drug discovery papers about Rare thyroid carcinoma, with 2 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | [Special tumor entities : New results at the 2026 ASCO Annual Meeting].
Rare tumor entities in the head and neck region are biologically heterogeneous, frequently only investigated in small cohorts, and therapeutically challenging. The current article critically contextualizes clinically relevant studies presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting on salivary gland, thyroid, and nasopharyngeal cancer and cutaneous squamous cell carcinoma. In adenoid cystic carcinoma, several molecularly targeted strategies have shown early activity, including MYB degradation, NOTCH inhibition, and a B7-H4-directed antibody-drug conjugate. In other salivary gland cancers, HER2-directed therapy and androgen receptor blockade were relevant. In thyroid cancer, selective tyrosine kinase inhibition and multimodal concepts for anaplastic carcinoma confirmed the importance of molecular diagnostics and repeated assessment of operability. In nasopharyngeal cancer, cadonilimab in combination with chemotherapy prolonged progression-free survival after failure of immunotherapy. In cutaneous squamous cell carcinoma, definitive irradiation with cemiplimab and adjuvant immunotherapy were investigated. Overall, the data support biomarker-based and interdisciplinary treatment pathways; however, given the small, often single-arm studies, the data should be interpreted with caution.
2026-09-24 | Management of ectopic Cushing syndrome in medullary thyroid carcinoma: from case reports to systematic literature review.
Ectopic Cushing's syndrome (ECS) secondary to medullary thyroid carcinoma (MTC) is a rare endocrine manifestation associated with aggressive disease and considerable morbidity from severe hypercortisolism. We conducted a systematic review of PubMed and Web of Science from inception to January 25, 2026, in accordance with PRISMA guidelines, to identify all published cases of ECS due to MTC. Data were extracted on clinical presentation, RET mutational status, treatments, outcomes, and causes of death. In addition, we described four previously unreported patients from "C. I. Parhon" National Institute in Bucharest, Romania, analyzed independently from the systematic review dataset. The systematic review identified 99 published cases of ECS caused by MTC. The mean age at diagnosis was 46.3 years (range 12-84), with male predominance (69.7%). Among cases with available genetic data, most were sporadic 32/43 cases (74.4%), frequently harboring somatic RET M918T mutation. MTC stage at diagnosis was available in 90 cases, of which 48 patients (53.3%) presented with distant metastases. ECS and MTC were diagnosed concomitantly in 45/89 patients (50.6%), while MTC preceded ECS in 43/89 patients (48.3%), with a median delay of 42 months. Hypercortisolism manifestations predominated and often masked locoregional thyroid disease. Thyroid surgery was the initial therapeutic approach in 62/77 cases (80.5%). Hypercortisolism was difficult to control and often refractory to multiple treatment strategies. Bilateral adrenalectomy was required in 33 patients, including 12 in whom it served as rescue treatment following failure of medical therapy. Selective RET inhibitors, particularly selpercatinib, have recently emerged as a promising treatment option, with all five reported cases demonstrating rapid biochemical improvement and radiologic responses. Among cases with available outcome data, mortality was primarily driven by complications of uncontrolled hypercortisolism and progressive metastatic MTC. Complementing the systematic review, regarding the four cases from our center, we have observed substantial disease burden, with thyroid surgery performed in every patient. Two cases received vandetanib producing favorable biochemical (calcitonin) and radiologic responses. Hypercortisolism proved challenging to manage, with three patients failing to achieve remission despite multimodal therapy, including surgery, targeted therapy, adrenalectomy, or medical treatment. ECS secondary to MTC is an exceptionally rare and highly morbid manifestation that occurs predominantly in metastatic sporadic MTC. Management of both tumor burden and hypercortisolism is complex and often requires multimodal therapy. Emerging data suggests that selective RET inhibitors may lead to simultaneous control of both tumor progression and cortisol excess in RET-mutated disease, although current data remain limited to case reports. The four institutional cases offer additional real-world clinical context and are presented separately from the systematic review to maintain methodological rigor.
2026-09-17 | Anaplastic Thyroid Carcinoma, Squamous Cell Carcinoma Pattern: Cytological Diagnosis According to the WHO 5th Edition Classification.
Anaplastic thyroid carcinoma (ATC) with squamous cell carcinoma pattern is a rare and highly aggressive thyroid malignancy that presents significant diagnostic challenges on cytology. According to the WHO 5th edition classification (2022), primary squamous cell carcinoma of the thyroid is no longer regarded as a distinct entity and is currently classified as a morphologic pattern/subtype of ATC.
2026-09-07 | C-Cell Lesions and Medullary Thyroid Carcinoma: A Review.
Advances in genetic studies, tumor grading, and targeted therapy have improved diagnosis and management of medullary thyroid carcinoma (MTC). This rare neuroendocrine neoplasm is linked to hereditary MEN2 syndromes driven by germline RET mutations, while sporadic tumors frequently harbor somatic RET or RAS alterations. The disease develops from proliferation of neoplastic C-cells. Histologically, MTC often demonstrates diverse morphologies; classic MTC features include nests of neuroendocrine cells associated with stromal amyloid. Immunohistochemical expression of calcitonin, CEA, chromogranin, and synaptophysin aid in diagnosis. Recently established grading criteria based on mitotic activity, Ki-67 proliferation index, and tumor necrosis have improved prognostic evaluation and risk stratification. Genetic sequencing and selective RET inhibitors have also enhanced precision-based management and outcomes in advanced RET-mutated tumors.
2026-08-28 | A rare, invasive, and challenging cancer in childhood: diffuse sclerosing variant of papillary thyroid carcinoma.
Pediatric thyroid cancers are rare, with papillary thyroid carcinoma (PTC) being the most common type. The diffuse sclerosing variant (DSV) is a rarer subtype associated with frequent recurrence and extensive lymphatic involvement. Among 51 pediatric patients treated for thyroid carcinoma at our tertiary center over a 20-year period, three were diagnosed with DSV-PTC. We present this retrospective case series to highlight its clinical course and diagnostic challenges. Three patients (aged 8-17) presented with neck swelling; one also exhibited high fever and neck pain. While thyroid function tests were normal, serum thyroglobulin levels were significantly elevated. Imaging revealed diverse presentations: a solitary nodule, diffuse enlargement mimicking an abscess, and diffuse inflammation. Following fine-needle aspiration confirmation of PTC, all patients underwent total thyroidectomy and central and bilateral lymph node dissection. Histopathology confirmed DSV-PTC in all cases. Every patient presented with diffuse lymph node metastasis; two showed extrathyroidal extension, and one had distant pulmonary metastasis. Genetic analysis identified a BRAF V600E alteration in one case and RET translocations in the other two, confirmed by fluorescence in situ hybridization (FISH) after negative broad next-generation sequencing (NGS) panels. All patients required revision surgery for residual tissue followed by radioactive iodine (RAI) therapy. At follow-up (13-28 months), outcomes ranged from stable disease and additional RAI requirement to complete remission without relapse. Although based on a small case series, our findings suggest that DSV-PTC can behave aggressively in pediatric patients and can mimic benign inflammatory conditions, leading to potential diagnostic delays. Early recognition and a comprehensive multimodal approach, including extensive surgery and RAI, appear vital for managing this challenging variant.
proteins
2026-06-26 | Papillary thyroid carcinoma discovered in a patient on semaglutide therapy for metabolic syndrome: a case presentation and review of current evidence.
Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is widely used for the management of type 2 diabetes, metabolic syndrome, and obesity. Concerns regarding its potential association with thyroid cancer, particularly medullary thyroid carcinoma, have emerged, although current human evidence remains inconclusive. Reports of papillary thyroid carcinoma (PTC) while using semaglutide therapy are exceedingly rare. We describe a 40-year-old man with metabolic syndrome and obesity who had been treated with semaglutide for several years before discontinuation. A routine chest computed tomography (CT) performed for an unrelated diaphragmatic hernia identified a suspicious thyroid lesion, later confirmed by ultrasound as a 1 × 1 cm irregular hypoechoic nodule in the left lobe with several small ipsilateral lymph nodes demonstrating suspicious features. Fine-needle aspiration cytology revealed classic PTC (Bethesda VI). The patient underwent total thyroidectomy with left selective neck dissection and central compartment dissection. Histopathology confirmed a unifocal classic variant PTC, 16 mm in size, with negative margins, no lymph node involvement, and no extrathyroidal extension. After an uncomplicated postoperative course, he was prescribed levothyroxine for TSH suppression and discharged. This case of PTC discovered concomitantly while the patient was on semaglutide therapy highlights an important clinical scenario but does not provide evidence of causation. The totality of available human data continues to support the safety of semaglutide with respect to thyroid cancer risk. Further long-term surveillance and high-quality epidemiological studies remain warranted.
2026-02-14 | Peptide receptor radionuclide therapy in neuroendocrine tumours: advances, combination strategies, and future directions.
Peptide receptor radionuclide therapy (PRRT) has established itself as a pivotal component in the management of advanced, somatostatin receptor (SSTR)-positive neuroendocrine tumours (NETs). The NETTER-1 phase III trial demonstrated that [177Lu]Lu-DOTATATE significantly prolongs progression-free survival (PFS) and improves quality of life in patients with midgut NETs refractory to somatostatin analogues, leading to regulatory approval by both EMA (2017) and FDA (2018). The recent NETTER-2 phase III trial further extended these findings by supporting the first-line use of PRRT in Grade 2 and 3 gastroentero-pancreatic (GEP)-NETs (Ki-67 ≥ 10 ≤ 55%). Beyond standard β-emitting therapy, several developments are reshaping the field: the clinical adoption of SSTR antagonists such as radiolabelled JR-11 and LM3, targeted α-particle-emitting therapies (225Ac, 212Pb, 213Bi) for resistant disease, and rational combination strategies with chemotherapy, DNA-repair inhibitors, and immunotherapy. Parallel innovation in radiopharmaceutical chemistry has yielded new peptide ligands, including cholecystokinin-2 receptor (CCK2R)-targeted compounds such as DOTA-MGS5, which show promise for rare NETs such as medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). This review summarises clinical evidence, translational advances, and future perspectives for PRRT as a cornerstone of precision nuclear oncology. Emphasis is placed on expanding indications, integrating α-emitters, improving safety and dosimetry, and developing novel theragnostic ligands that enable personalised treatment strategies for NETs patients.
2026-01-30 | Atypical presentation and association of medullary thyroid carcinoma: reports from a tertiary care center in Northwest India.
Medullary thyroid carcinoma (MTC) constitutes 5-10% of thyroid malignancies but accounts for 15% of thyroid cancer-related mortality. Twenty percent of MTC are hereditary and are part of familial MTC or multiple endocrine neoplasia (MEN) syndromes. Classical MTC presents as a nodular goiter with or without lymphadenopathy, or occasionally diarrhea and metastatic symptoms. Several patients in our cohort had unusual features that delayed diagnosis. The standard management remains surgical resection, with tyrosine kinase inhibitors (TKIs) in RET mutation-positive or RET mutation-negative metastatic cases and/or Lutathera peptide receptor radionuclide therapy (PRRT) used in disseminated disease, and external beam radiotherapy for locally aggressive or infiltrative retaining a limited role. However, some patients developed therapy-related complications or exhibited resistance to treatment. Of the 80 MTC patients reviewed, this case series highlights 10 atypical presentations in nine cases : 3 unusual tumors along with MTC, namely chondrosarcoma, carcinoma prostrate, and ectopic Cushing's syndrome; 4 unusual associations or presenting manifestations: pneumoconiosis masquerading as lung metastasis, Marfanoid habitus in MEN-2A and VHL spectrum disease, 1 with skull metastasis, and 2 cases with TKI-related complications in the form of glomerulonephritis and one patient displayed Marfanoid habitus with a RET mutation but without MEN2B or fibrillin gene mutation, while another developed bowel perforation secondary to lenvatinib therapy emphasizing diagnostic and therapeutic challenges and rare tumor associations. This series underscores the heterogeneity of MTC and the need for thorough evaluation and personalized management. Greater clinician awareness of MTC's diverse presentations is essential to improve early diagnosis and optimize treatment outcomes. Diverse and atypical clinical presentations can obscure the diagnosis of MTC. Management of MTC remains complex due to therapy-related complications and resistance. Molecular diagnostics enable better risk stratification and personalized care.
2025-10-25 | Anatomical-biochemical discordance and prognostic role of bone metastases in advanced MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE.
Medullary thyroid carcinoma (MTC) is a rare malignancy with limited treatment options in the metastatic setting. While peptide receptor radionuclide therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTA-TATE has been well established in gastroenteropancreatic neuroendocrine tumors, its clinical utility in MTC remains under investigation. We retrospectively analyzed 18 patients with advanced, somatostatin receptor-positive MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE. Treatment decisions-including in patients with low somatostatin receptor (SSTR) expression or first-line PRRT indication-were made by a multidisciplinary tumor board. Anatomical response was assessed using RECIST 1.1 on [⁶⁸Ga]Ga-DOTA-TATE PET/CT after two cycles. Biochemical and clinical outcomes were also recorded. Progression-free survival (PFS) was evaluated using Kaplan-Meier and Cox regression. Median PFS was 37.0 months. Radiologic disease control -defined as partial response (PR) or stable disease (SD) -was achieved in 78%, and biochemical response (≥ 50% decrease in calcitonin) in 44% of patients. Patients with bone metastases had significantly shorter PFS (24.6 vs. 47.0 months, p = 0.027). Longer PFS was also observed in those receiving higher cumulative dose, those with larger solitary tumors, and those treated in the first-line setting, although these trends did not reach statistical significance. Discordance between anatomical and biochemical response was observed in 50% of cases, highlighting limitations of calcitonin-based monitoring. PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE is a well-tolerated treatment option for selected patients with advanced MTC, including those receiving first-line therapy and those with low SSTR expression. In our limited cohort, bone metastases were associated with shorter PFS, and discordant imaging/biochemical responses are common. Functional imaging-guided selection and individualized response assessment are essential for optimal management.
2024-11-30 | Parathyroid hormone-based algorithm reduces complications after total thyroidectomy.
Hypocalcemia after total thyroidectomy is a frequent complication that can be predicted and best managed by the postoperative measurement of parathyroid hormone levels. This study included consecutive patients who underwent total thyroidectomy between 2017 and 2022. Hypocalcemia was defined as serum calcium <8.0 mg/dL and hypoparathyroidism as parathyroid hormone <15 pg/mL. After comparing serum calcium levels on postoperative day 1 and intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy in the first period, an algorithm involving routine postoperative oral calcium and alfacalcidol administration in patients with intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy <20 pg/mL was developed and tested during the second period. The rates of symptomatic hypocalcemia, readmission for hypocalcemia, and permanent hypoparathyroidism were compared between the 2 periods. In the first period, 1,965 total thyroidectomies (1,548 women; mean age, 51 years) were performed, including 617 patients (31%) with central neck dissection for thyroid carcinoma. Of 314 patients (16%) who experienced symptomatic hypocalcemia, only 183 (58%) could be predicted using serum calcium levels on postoperative day 1 <8.0 mg/dL. This rate increased to 96% (301 patients) when using intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy and serum calcium levels on postoperative day 1 (P < .001). Intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy alone could predict symptomatic hypocalcemia in 90% (282) of patients. Hypoparathyroidism was permanent in 20 patients (1%), with a greater predictive value of intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy over serum calcium levels on postoperative day 1 (18/20 [90%] vs 8/20 [40%], P < .01). Using the intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy-based algorithm and preventive calcium supplementation in the second period of the study, 1,420 total thyroidectomies (1,106 women; mean age, 50 years) were performed, including 392 (28%) cases with central neck dissection for thyroid carcinoma. Only 2.3% (32) patients developed a symptomatic hypocalcemia compared with 16% during the first period (P < .001). Thirty-eight patients (2.7%) experienced readmission after total thyroidectomy before implementation of the supplementation protocol in our study compared with 2 patients (0.01%) after we began using the protocol (P < .001). There was no significant difference in permanent hypoparathyroidism between the 2 periods (1.3% vs 1%) (P = .8). The parathyroid hormone-based algorithm determined by intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy and routine preventive administration of oral calcium/calcitriol reduced the risk of symptomatic hypocalcemia and readmission after total thyroidectomy.
cell therapies
2026-07-23 | Updated Dutch 2026 pediatric differentiated thyroid carcinoma guideline: aligning with Europe.
Pediatric differentiated thyroid carcinoma (DTC) is a rare disease, creating challenges for standardized care across Europe. The Netherlands published its first national pediatric DTC guideline in 2020. The 2022 European Thyroid Association (ETA) guideline introduced differences that required reconciliation with national practice. This article presents the 2026 update of the Dutch guideline, harmonized with European recommendations while retaining context-specific adaptations. The 2020 Dutch guideline was systematically compared with the ETA 2022 guideline. Differences were discussed by the national pediatric DTC working group and addressed in a structured consensus meeting to agree on revisions and adaptations relevant to the Dutch context. Most European recommendations were adopted. Key national adaptations include performing total thyroidectomy without prior histology in Bethesda V-VI nodules with a proven BRAF mutation, expanded use of molecular diagnostics in selected nodules, and referral for genetic counseling in confirmed cases. In addition, less extensive surgery and selective omission of radioactive iodine therapy in low-risk patients were recommended, based on shared decision-making. Follow-up with neck ultrasound was limited to an initial 3-month assessment, with subsequent imaging only in case of rising thyroglobulin or anti-thyroglobulin concentrations. The 2026 Dutch guideline aligns with European recommendations while preserving context-specific adaptations. It provides a framework for consistent, patient-centered care and supports standardized clinical practice in the Netherlands, offering a model for harmonized pediatric DTC management across Europe.
2026-02-06 | Patient-Derived in Vitro Models Reveal Insights into Medullary Thyroid Cancer Microenvironment and Resistance to Tyrosine Kinase Inhibitors.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with a 10-year mortality rate up to 50%. Current therapies for metastatic MTC comprise various tyrosine-kinase inhibitors, but resistance often appears due to the need for lifelong treatments. Like in other tumors, genetic, epigenetic, post-transcriptional, post-translational, and cell-cell interaction events influence drug response. However, progress in understanding MTC biology is limited by the lack of reliable in vivo and in vitro models. This study aims to develop a patient-derived model faithfully reproducing the microenvironmental alterations present in MTC. We applied a two-step protocol consisting of a first phase in which primary cells are cultivated as multicellular spheroids and a second phase in which they are switched to adherent cultures. After evaluation of the genetic background by targeted Next Generation Sequencing, we characterized our cells phenotype by examining a panel of stem/progenitor-related markers, the secretory abilities by ELISAs, the drug response by proliferation assays, the in vivo angiogenic and invasiveness by the use of zebrafish model, the in vitro invasivity by Matrigel Dome assays and the spatial variation of stem/progenitor marker in both 3D cell models and tissue samples by confocal microscopy. Our model allowed the establishment of eight MTC patient-derived cell lines with different genetic backgrounds. The cultures faithfully reproduced the changes in stem and progenitor markers that we detected in our cohort of MTC tissue samples and could be successfully xenotransplanted in zebrafish model, showing both angiogenetic and invasive properties. Drug screening assays revealed the potential of our model for the study of patient-specific responses, as we were able to identify different candidate regulators of the sensitivity to currently available therapies for MTC. Our two-step protocol successfully generated primary MTC lines that maintain high plasticity, can be cultivated for several passages, and recreate the heterogeneity observed in patients' tissues. Our model will offer a robust platform for preclinical drug testing and mechanistic studies, addressing a longstanding gap in MTC research. It enables exploration of tumor microenvironment interactions and personalized therapeutic responses, supporting progress beyond current genomic-driven frameworks.
2026-01-21 | Pediatric follicular thyroid carcinoma: a clinicopathologic study treated at a single institution during a 30-year period.
PURPOSE: Pediatric follicular thyroid carcinoma (FTC) is an exceptionally rare entity, and its management has largely been extrapolated from adult protocols. Recent revisions of the WHO classification have redefined FTC subtypes, but pediatric studies based on the new criteria are lacking. This study aimed to evaluate the clinicopathological features of pediatric FTC using the updated WHO classification and to compare outcomes with pediatric papillary thyroid carcinoma (PTC). METHODS: Medical records of patients < 19 years who underwent thyroidectomy between 1989 and 2019 at Ito Hospital were reviewed. Pathological diagnosis was reassessed according to the most recent WHO classification. Twenty-four FTC and 134 PTC cases were identified. Clinical characteristics, histological findings, and outcomes were analyzed. RESULTS: Pediatric FTC accounted for 15.2% of pediatric DTC, a significantly higher proportion than in adults (5.9%). Median age was 16 years; female-to-male ratio was 7:1. Subtypes were minimally invasive (25%), encapsulated angioinvasive (46%), and widely invasive (29%). Extensive vascular invasion (VI ≥ 4) was observed in 7 patients (29%). Solid, trabecular, or insular growth pattern were observed in 21 patients (87.5%). VI was associated with distant metastasis, but no patients experienced disease-specific death during median follow-up of 6.2 years. In contrast, PTC patients showed significantly higher recurrence rates (p < 0.05). CONCLUSION: Pediatric FTC demonstrates excellent prognosis, but its pathological spectrum differs from previous reports under older classifications. VI remains the key determinant of metastatic risk. These findings suggest the need for risk-adapted strategies tailored to pediatric FTC, with avoidance of overtreatment in low-risk cases.
2025-08-26 | B7-H3 and CSPG4-targeted CAR T cells as potent effectors in anaplastic thyroid cancer.
Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with poor survival and no available effective therapy. This unmet clinical need led us to investigate chimeric antigen receptor (CAR) T cells s as potential treatment option for this malignant disease. As target tumor antigens of our CAR T cell therapy, we selected the chondroitin sulfate proteoglycan 4 (CSPG4) and the B7-homolog 3 (B7-H3), as they are both highly and homogeneously expressed on different types of thyroid carcinoma cell lines and tissues, including ATC. Importantly, both CSPG4 and B7-H3 have a low distribution on normal tissues, thus limiting 'on-target off-tumor' CAR T-related toxicities. We generated CSPG4-specific and B7-H3-specific CAR T cells by utilizing a second-generation CAR construct comprised of a CD28 costimulatory domain and tested their antitumor activity in vitro and in an orthotopic xenograft murine model of ATC. We demonstrated that thyroid cancer cells are specifically recognized and effectively eradicated in vitro by CSPG4-targeted and B7-H3-targeted CAR T cells. Additionally, both CAR T cell types were able to mediate significant control or complete eradication of primary ATC tumors when mice were treated with CSPG4 CAR T cells or B7-H3 CAR T cells, respectively. Overall, in this study we identified CSPG4 and B7-H3 as valuable target antigens in thyroid cancer and demonstrated that CAR T cell immunotherapy can be a valuable therapeutic option for ATC patients. Our findings provide the translational basis for exploring CAR T cell immunotherapies targeting CSPG4 and B7-H3 with ATC patients who do not respond or relapse after first line treatment.
2025-07-30 | Risk-adapted therapy in pediatric thyroid cancer: initial experience from a national reference program by the MET group.
Pediatric differentiated thyroid carcinoma (pedDTC) is rare but increasingly prevalent, requiring multidisciplinary care to ensure optimal outcomes. In 2021, the pediatric national reference program of the German Malignant Endocrine Tumor (MET) registry was established to standardize the management of pedDTC, with a particular focus on radioactive iodine (RAI) use and minimizing treatment variability. This study evaluated the program's first 3.5 years, including 43 inquiries concerning 39 patients with confirmed or suspected pedDTC. A weekly national expert tumor board provided individualized recommendations based on multidisciplinary input and risk stratification. Data were analyzed for demographic trends, therapeutic decisions, and short-term outcomes. Among 34 patients with confirmed pedDTC, RAI use was reduced or omitted in 70.6% of cases, particularly among low-risk patients, in alignment with the American Thyroid Association 2015 guidelines. Surgical strategies were modified in 61.5% of cases to balance disease control with treatment-related morbidity. No systemic medical therapy was recommended during initial management. At a mean follow-up of 0.7 years, all patients were alive; persistent disease was observed in 15.4%. The national reference program has successfully introduced a structured, individualized approach to the management of pedDTC in Germany. Ongoing data collection and longer follow-up will be essential to assess the long-term impact of this centralized, risk-adapted model.
antibodies
2026-09-07 | Single-Cell Transcriptome of Anaplastic Thyroid Cancer Reveals Immunosuppressive Tumor Microenvironment Remodeling.
Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy responsible for most thyroid cancer-related deaths. To elucidate molecular and immunological characteristics distinguishing ATC from aggressive papillary thyroid cancer (PTC), we performed single-cell RNA sequencing on three ATC and three lethal PTC samples. ATC tumor cells exhibited enhanced inflammatory and immune-related gene expression, and co-activation of MAPK and PI3K pathways. Notably, p53 pathway activity was suppressed in ATC, alongside activation of angiogenic and immune-evasion programs, indicating a shift from proliferation-driven to immune-evasion-oriented signaling. Transcriptional network analysis revealed E2F family activation, including E2F1, E2F7, and E2F8, suggesting CDK-RB-E2F axis dysregulation drives tumor dedifferentiation and proliferation, whereby p53 suppression unleashes E2F-dependent transcriptional reprogramming. Immunoprofiling revealed CD8+ T cells in ATC showed elevated exhaustion signatures and high expression of inhibitory immune checkpoint molecules, accompanied by enhanced Treg-CD8+ T cell interactions, indicating a dual-layered immunosuppressive mechanism involving both T-cell exhaustion and enhanced Treg-mediated suppression. In addition, we identified antigen-presenting CAFs with altered CD4+ T-cell interactions. These findings delineate a comprehensive single-cell landscape of ATC and demonstrate coordinated alterations in tumor-intrinsic signaling and the tumor microenvironment during dedifferentiation, provide a foundation for developing rational combination immunotherapies tailored to the molecular and immunological landscape of thyroid cancer.
2026-07-28 | Case report: Concurrent primary thyroid MALT lymphoma and lymph node metastatic thyroid micropapillary carcinoma in Hashimoto's thyroiditis: a diagnostic and therapeutic challenge.
Primary thyroid lymphoma (PTL) is an extremely rare malignancy, and its prognosis primarily depends on factors such as histological type and clinical stage. Papillary thyroid carcinoma(PTC) is the most common pathological type of thyroid cancer. Papillary thyroid microcarcinoma(PTMC) accounts for a significant proportion of PTCs and generally has a favorable prognosis;however, central lymph node metastasis (CLNM) occurs in approximately 10-30% of cases. Thecoexistence of PTL and metastatic PTMC is exceedingly rare, with only a few reports in the literature. Hashimoto thyroiditis (HT) is a common risk factor for both PTL and PTC. We present a case of HT diagnosed concurrently with PTL and PTMC, accompanied by level VI CLNM. We systematically reviewed the patient's clinical presentation, imaging findings, laboratory results, histopathological features, treatment, and follow-up. A 40-year-old woman presented with neck discomfort. Ultrasonography revealed a solid hypoechoic nodule in the right thyroid lobe with irregular and slightly lobulated margins. The patientdeclined fine-needle aspiration cytology and opted for direct surgery. The patient underwent right thyroid lobectomy with isthmusectomy and biopsy of the right central compartment (level VI) lymph nodes. Postoperative pathology confirmed the coexistence of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), with pathological features suggestive of large B-cell transformation, and PTMC, with carcinoma identified in one of ten resected level VI lymph nodes (1/10). Immunohistochemistry showed that the lymphoma cells were positive for CD20, CD79a, Pax-5, and Bcl-2 and negative for CD5, CD10, and Cyclin D1. The patient received four cycles (six infusions) of a single-agent, obinutuzumab, as post-surgical therapy. The patient has now completed the full treatment course, remains in a stable condition, and shows no evidence of recurrence. The coexistence of PTL and PTMC is exceptionally rare and poses a significant risk of misdiagnosis. Comprehensive preoperative evaluation and precise histopathological examination are crucial for accurate diagnosis. Although PTMC generally has an excellent prognosis, central lymph node metastasis can occur in a subset of patients. Careful evaluation of suspicious cervical lymph nodes and individualized postoperative surveillance are therefore warranted. Therapeutic decision-making requires a balanced consideration of lymphoma stage and thyroid carcinoma risk stratification, underscoring the importance of a multidisciplinary approach.
2026-06-02 | B7-H3 (CD276) as a candidate therapeutic target in medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak, or absent. Statistical analyses were conducted using descriptive statistics and Fisher's exact test. The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 in any evaluable samples. B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.
2026-05-15 | Intrathyroid thymic carcinoma: A comprehensive review of clinicopathological features and therapeutic strategies.
Intrathyroid thymic carcinoma (ITTC) is an exceptionally rare primary thyroid malignancy with thymic epithelial differentiation, generally characterized by relatively indolent biological behavior. However, significant knowledge gaps persist in ITTC diagnosis, and a consensus on an optimal treatment strategy for ITTC is lacking. This review synthesizes the current knowledge on ITTC, focusing on its clinicopathological features, molecular landscape, prognostic factors, and therapeutic approaches, to raise clinical awareness of this rare entity and guide individualized management. ITTC predominantly affects adults, with a slight female predilection. Pretreatment diagnosis in imaging and cytology of ITTC is challenging. Histopathologically, ITTC is indistinguishable from thymic squamous cell carcinoma (TSCC), and no specific molecular alterations have been identified to date. Lymph node metastasis and the presence of symptoms at diagnosis serve as adverse prognostic indicators in ITTC patients. While surgery remains the priority treatment for ITTC, patients' responses to adjuvant radiotherapy and/or chemotherapy are variable, underscoring the need for further investigation into the role of systemic antineoplastic therapies. Notably, checkpoint inhibitors targeting PD-L1 or PD-1 represent a promising avenue for ITTC patients with advanced disease.
2026-05-04 | The Molecular Landscape of CASTLE: A Rare Thymus-like Head and Neck Cancer.
Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignancy arising in the thyroid or neck, with an uncertain cellular origin that complicates both diagnosis and treatment. To better understand its molecular underpinnings and identify potential therapeutic avenues, we conducted integrated whole-exome and transcriptome sequencing on six CASTLE and six thymic carcinoma samples. Whole-exome sequencing (WES) was performed on all 12 samples, while RNA sequencing was successful for 1 CASTLE and 6 thymic carcinoma samples. Our analysis included somatic mutation profiling, mutational signature deconvolution, differential gene expression, and characterization of tumor microenvironment for the cases with available data, with comparisons to genomic data from other thyroid cancers. CASTLE tumors demonstrated a higher median tumor mutational burden than thymic carcinoma and lacked the common BRAF and RAS mutations typically found in thyroid cancers. They harbored alterations in genes such as TRHDE, cilia-associated genes (ANKS6, CFAP46, DNAH6), and Wnt signaling components (TRRAP, BCL9L), as well as mutational signatures suggestive of mismatch repair deficiency and oxidative damage. MSIsensor-pro analysis of the WES data provided support for the potential for mismatch repair deficiency in a subset of CASTLE samples. Exploratory transcriptomic analysis from a single CASTLE case showed downregulation of thyroid follicular markers and an "immune-hot", lymphocyte-rich microenvironment, closely resembling that of thymic carcinoma. While these findings require validation in larger cohorts, they support a thymic origin for CASTLE and establish its molecular distinction from follicular-derived thyroid cancers. The immunogenic tumor landscape suggests that immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, may be a promising therapeutic strategy, alongside emerging targets for precision oncology.
other
2024-05-28 | LINC00887 Acts as an Enhancer RNA to Promote Medullary Thyroid Carcinoma Progression by Binding with FOXQ1.
Medullary thyroid carcinoma (MTC) is a rare but aggressive endocrine malignancy that originates from the parafollicular C cells of the thyroid gland. Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from enhancer regions, which are critical regulators of tumorigenesis. However, the roles and regulatory mechanisms of eRNAs in MTC remain poorly understood. This study aims to identify key eRNAs regulating the malignant phenotype of MTC and to uncover transcription factors involved in the regulation of key eRNAs. GSE32662 and GSE114068 were used for the identification of differentially expressed genes, eRNAs, enhancers and enhancer-regulated genes in MTC. Metascape and the transcription factor affinity prediction method were used for gene function enrichment and transcription factor prediction, respectively. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to assess the binding of histone H3 lysine 27 acetylation (H3K27ac)-enriched regions to anti- H3K27ac. RIP-qPCR was used to detect the binding between FOXQ1 and LINC00887. CCK8 and Transwell were performed to measure the proliferation and invasion of MTC cells, respectively. Intracellular reactive oxygen species (ROS) levels were quantified using a ROS assay kit. Four eRNAs (H1FX-AS1, LINC00887, MCM3AP-AS1 and A1BG-AS1) were screened, among which LINC00887 was the key eRNA promoting the proliferation and invasion of MTC cells. A total of 135 genes controlled by LINC00887-regulated enhancers were identified; among them, BCL2, PRDX1, SFTPD, TPO, GSS, RAD52, ZNF580, and ZFP36L1 were significantly enriched in the "ROS metabolic process" term. As a transcription factor regulating genes enriched in the "ROS metabolic process" term, FOXQ1 could recruit LINC00887. Overexpression of FOXQ1 restored LINC00887 knockdown-induced downregulation of GSS and ZFP36L1 transcription in MTC cells. Additionally, FOXQ1 overexpression counteracted the inhibitory effects of LINC00887 knockdown on the proliferation and invasion of MTC cells and the promotion of intracellular ROS accumulation induced by LINC00887 knockdown. LINC00887 was identified as a key eRNA promoting the malignant phenotype of MTC cells. The involvement of FOXQ1 was essential for LINC00887 to play a pro-tumorigenic role in MTC. Our findings suggest that the FOXQ1/LINC00887 axis is a potential therapeutic target for MTC.
2024-02-22 | Delving into the Role of lncRNAs in Papillary Thyroid Cancer: Upregulation of LINC00887 Promotes Cell Proliferation, Growth and Invasion.
Papillary thyroid carcinoma (PTC) is the most common histological category of thyroid cancer. In recent years, there has been an increasing number of studies on lncRNAs in PTC. Long intergenic non-protein coding RNA 887 (LINC00887) is a critical oncogene in developing other cancers. LINC00887 is upregulated in PTC samples but its role in PTC is currently unclear. This study aimed to investigate the impact the disruption of LINC00887 expression has on PTC progression. We performed a CRISPR/Cas9 strategy for the truncation of LINC00887 in BCPAP and TPC1 cell lines. Functional assays showed that LINC00887 knockdown in both TPC1 and BCPAP cells reduced cell proliferation, colony formation and migration, delayed the cell cycle, and increased apoptosis. These results strengthened the role of LINC00887 in cancer and showed for the first time that this lncRNA could be a potential oncogene in PTC, acting as a tumor promoter. Modulation of the immune system may be one of the etiopathogenic mechanisms of LINC00887 in PTC, as shown by the observed influence of this lncRNA on PD-L1 expression. In addition, the biological pathways of LINC00887 identified to date, such as EMT, the Wnt/β-catenin signaling pathway or the FRMD6-Hippo signaling pathway may also be relevant regulatory mechanisms operating in PTC.
2023-06-28 | Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers.
Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC. We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis. Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.
2022-06-02 | A signature of circadian rhythm genes in driving anaplastic thyroid carcinoma malignant progression.
Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer. Recently, dysregulation of circadian rhythm genes was demonstrated to play an essential role in tumor progression, while its exact role and mechanism in ATC remained poorly clear. 4 ATC-related datasets were integrated to screen for differentially expressed circadian rhythm genes (DE-CRGs). Thereafter, Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) and network enrichment analysis were conducted to investigate the dynamic characteristics of circadian rhythm genes. Next, Lasso-logistic model and immunohistochemistry were applied for determining the candidates. Finally, cell biological experiments and gene set enrichment analysis (GSEA) were used to confirm the roles of NPAS2 in ATC. 25 DE-CRGs were firstly identified in ATC. These DE-CRGs mainly regulated mitotic nuclear division, cytokinesis and DNA replication signals. Notably, NPAS2, CSNK1E, NAMPT, TYMS, SERPINE1, TOP2A, JUN, EGR3 and HEBP1 were identified as the dynamic signature in the malignant progression of ATC, which were confirmed by prognostic analysis. Furthermore, NPAS2 was found to be significantly up-regulated in ATC through clinical samples and cell experiments. Silencing NPAS2 effectively inhibited the proliferation, migration and invasion of ATC cells. GSEA showed that high expression of NPAS2 was mainly associated with cell cycle and focal adhesion, and silencing of NPAS2 suppressed these signals in our experiments. In summary, we found a dynamic 9-DE-CRGs signature in ATC. And the aberrant expression of NPAS2 drove the malignant phenotypes of ATC, which facilitated to deepen our understanding of the roles of circadian rhythm genes in ATC.
2022-03-25 | CSPG4 Is a Potential Therapeutic Target in Anaplastic Thyroid Cancer.
Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4+ T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting ∼10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.
small molecules
2026-09-30 | [Special tumor entities : New results at the 2026 ASCO Annual Meeting].
Rare tumor entities in the head and neck region are biologically heterogeneous, frequently only investigated in small cohorts, and therapeutically challenging. The current article critically contextualizes clinically relevant studies presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting on salivary gland, thyroid, and nasopharyngeal cancer and cutaneous squamous cell carcinoma. In adenoid cystic carcinoma, several molecularly targeted strategies have shown early activity, including MYB degradation, NOTCH inhibition, and a B7-H4-directed antibody-drug conjugate. In other salivary gland cancers, HER2-directed therapy and androgen receptor blockade were relevant. In thyroid cancer, selective tyrosine kinase inhibition and multimodal concepts for anaplastic carcinoma confirmed the importance of molecular diagnostics and repeated assessment of operability. In nasopharyngeal cancer, cadonilimab in combination with chemotherapy prolonged progression-free survival after failure of immunotherapy. In cutaneous squamous cell carcinoma, definitive irradiation with cemiplimab and adjuvant immunotherapy were investigated. Overall, the data support biomarker-based and interdisciplinary treatment pathways; however, given the small, often single-arm studies, the data should be interpreted with caution.
2026-09-24 | Management of ectopic Cushing syndrome in medullary thyroid carcinoma: from case reports to systematic literature review.
Ectopic Cushing's syndrome (ECS) secondary to medullary thyroid carcinoma (MTC) is a rare endocrine manifestation associated with aggressive disease and considerable morbidity from severe hypercortisolism. We conducted a systematic review of PubMed and Web of Science from inception to January 25, 2026, in accordance with PRISMA guidelines, to identify all published cases of ECS due to MTC. Data were extracted on clinical presentation, RET mutational status, treatments, outcomes, and causes of death. In addition, we described four previously unreported patients from "C. I. Parhon" National Institute in Bucharest, Romania, analyzed independently from the systematic review dataset. The systematic review identified 99 published cases of ECS caused by MTC. The mean age at diagnosis was 46.3 years (range 12-84), with male predominance (69.7%). Among cases with available genetic data, most were sporadic 32/43 cases (74.4%), frequently harboring somatic RET M918T mutation. MTC stage at diagnosis was available in 90 cases, of which 48 patients (53.3%) presented with distant metastases. ECS and MTC were diagnosed concomitantly in 45/89 patients (50.6%), while MTC preceded ECS in 43/89 patients (48.3%), with a median delay of 42 months. Hypercortisolism manifestations predominated and often masked locoregional thyroid disease. Thyroid surgery was the initial therapeutic approach in 62/77 cases (80.5%). Hypercortisolism was difficult to control and often refractory to multiple treatment strategies. Bilateral adrenalectomy was required in 33 patients, including 12 in whom it served as rescue treatment following failure of medical therapy. Selective RET inhibitors, particularly selpercatinib, have recently emerged as a promising treatment option, with all five reported cases demonstrating rapid biochemical improvement and radiologic responses. Among cases with available outcome data, mortality was primarily driven by complications of uncontrolled hypercortisolism and progressive metastatic MTC. Complementing the systematic review, regarding the four cases from our center, we have observed substantial disease burden, with thyroid surgery performed in every patient. Two cases received vandetanib producing favorable biochemical (calcitonin) and radiologic responses. Hypercortisolism proved challenging to manage, with three patients failing to achieve remission despite multimodal therapy, including surgery, targeted therapy, adrenalectomy, or medical treatment. ECS secondary to MTC is an exceptionally rare and highly morbid manifestation that occurs predominantly in metastatic sporadic MTC. Management of both tumor burden and hypercortisolism is complex and often requires multimodal therapy. Emerging data suggests that selective RET inhibitors may lead to simultaneous control of both tumor progression and cortisol excess in RET-mutated disease, although current data remain limited to case reports. The four institutional cases offer additional real-world clinical context and are presented separately from the systematic review to maintain methodological rigor.
2026-09-17 | Anaplastic Thyroid Carcinoma, Squamous Cell Carcinoma Pattern: Cytological Diagnosis According to the WHO 5th Edition Classification.
Anaplastic thyroid carcinoma (ATC) with squamous cell carcinoma pattern is a rare and highly aggressive thyroid malignancy that presents significant diagnostic challenges on cytology. According to the WHO 5th edition classification (2022), primary squamous cell carcinoma of the thyroid is no longer regarded as a distinct entity and is currently classified as a morphologic pattern/subtype of ATC.
2026-09-07 | C-Cell Lesions and Medullary Thyroid Carcinoma: A Review.
Advances in genetic studies, tumor grading, and targeted therapy have improved diagnosis and management of medullary thyroid carcinoma (MTC). This rare neuroendocrine neoplasm is linked to hereditary MEN2 syndromes driven by germline RET mutations, while sporadic tumors frequently harbor somatic RET or RAS alterations. The disease develops from proliferation of neoplastic C-cells. Histologically, MTC often demonstrates diverse morphologies; classic MTC features include nests of neuroendocrine cells associated with stromal amyloid. Immunohistochemical expression of calcitonin, CEA, chromogranin, and synaptophysin aid in diagnosis. Recently established grading criteria based on mitotic activity, Ki-67 proliferation index, and tumor necrosis have improved prognostic evaluation and risk stratification. Genetic sequencing and selective RET inhibitors have also enhanced precision-based management and outcomes in advanced RET-mutated tumors.
2026-08-28 | A rare, invasive, and challenging cancer in childhood: diffuse sclerosing variant of papillary thyroid carcinoma.
Pediatric thyroid cancers are rare, with papillary thyroid carcinoma (PTC) being the most common type. The diffuse sclerosing variant (DSV) is a rarer subtype associated with frequent recurrence and extensive lymphatic involvement. Among 51 pediatric patients treated for thyroid carcinoma at our tertiary center over a 20-year period, three were diagnosed with DSV-PTC. We present this retrospective case series to highlight its clinical course and diagnostic challenges. Three patients (aged 8-17) presented with neck swelling; one also exhibited high fever and neck pain. While thyroid function tests were normal, serum thyroglobulin levels were significantly elevated. Imaging revealed diverse presentations: a solitary nodule, diffuse enlargement mimicking an abscess, and diffuse inflammation. Following fine-needle aspiration confirmation of PTC, all patients underwent total thyroidectomy and central and bilateral lymph node dissection. Histopathology confirmed DSV-PTC in all cases. Every patient presented with diffuse lymph node metastasis; two showed extrathyroidal extension, and one had distant pulmonary metastasis. Genetic analysis identified a BRAF V600E alteration in one case and RET translocations in the other two, confirmed by fluorescence in situ hybridization (FISH) after negative broad next-generation sequencing (NGS) panels. All patients required revision surgery for residual tissue followed by radioactive iodine (RAI) therapy. At follow-up (13-28 months), outcomes ranged from stable disease and additional RAI requirement to complete remission without relapse. Although based on a small case series, our findings suggest that DSV-PTC can behave aggressively in pediatric patients and can mimic benign inflammatory conditions, leading to potential diagnostic delays. Early recognition and a comprehensive multimodal approach, including extensive surgery and RAI, appear vital for managing this challenging variant.
proteins
2026-06-26 | Papillary thyroid carcinoma discovered in a patient on semaglutide therapy for metabolic syndrome: a case presentation and review of current evidence.
Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is widely used for the management of type 2 diabetes, metabolic syndrome, and obesity. Concerns regarding its potential association with thyroid cancer, particularly medullary thyroid carcinoma, have emerged, although current human evidence remains inconclusive. Reports of papillary thyroid carcinoma (PTC) while using semaglutide therapy are exceedingly rare. We describe a 40-year-old man with metabolic syndrome and obesity who had been treated with semaglutide for several years before discontinuation. A routine chest computed tomography (CT) performed for an unrelated diaphragmatic hernia identified a suspicious thyroid lesion, later confirmed by ultrasound as a 1 × 1 cm irregular hypoechoic nodule in the left lobe with several small ipsilateral lymph nodes demonstrating suspicious features. Fine-needle aspiration cytology revealed classic PTC (Bethesda VI). The patient underwent total thyroidectomy with left selective neck dissection and central compartment dissection. Histopathology confirmed a unifocal classic variant PTC, 16 mm in size, with negative margins, no lymph node involvement, and no extrathyroidal extension. After an uncomplicated postoperative course, he was prescribed levothyroxine for TSH suppression and discharged. This case of PTC discovered concomitantly while the patient was on semaglutide therapy highlights an important clinical scenario but does not provide evidence of causation. The totality of available human data continues to support the safety of semaglutide with respect to thyroid cancer risk. Further long-term surveillance and high-quality epidemiological studies remain warranted.
2026-02-14 | Peptide receptor radionuclide therapy in neuroendocrine tumours: advances, combination strategies, and future directions.
Peptide receptor radionuclide therapy (PRRT) has established itself as a pivotal component in the management of advanced, somatostatin receptor (SSTR)-positive neuroendocrine tumours (NETs). The NETTER-1 phase III trial demonstrated that [177Lu]Lu-DOTATATE significantly prolongs progression-free survival (PFS) and improves quality of life in patients with midgut NETs refractory to somatostatin analogues, leading to regulatory approval by both EMA (2017) and FDA (2018). The recent NETTER-2 phase III trial further extended these findings by supporting the first-line use of PRRT in Grade 2 and 3 gastroentero-pancreatic (GEP)-NETs (Ki-67 ≥ 10 ≤ 55%). Beyond standard β-emitting therapy, several developments are reshaping the field: the clinical adoption of SSTR antagonists such as radiolabelled JR-11 and LM3, targeted α-particle-emitting therapies (225Ac, 212Pb, 213Bi) for resistant disease, and rational combination strategies with chemotherapy, DNA-repair inhibitors, and immunotherapy. Parallel innovation in radiopharmaceutical chemistry has yielded new peptide ligands, including cholecystokinin-2 receptor (CCK2R)-targeted compounds such as DOTA-MGS5, which show promise for rare NETs such as medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). This review summarises clinical evidence, translational advances, and future perspectives for PRRT as a cornerstone of precision nuclear oncology. Emphasis is placed on expanding indications, integrating α-emitters, improving safety and dosimetry, and developing novel theragnostic ligands that enable personalised treatment strategies for NETs patients.
2026-01-30 | Atypical presentation and association of medullary thyroid carcinoma: reports from a tertiary care center in Northwest India.
Medullary thyroid carcinoma (MTC) constitutes 5-10% of thyroid malignancies but accounts for 15% of thyroid cancer-related mortality. Twenty percent of MTC are hereditary and are part of familial MTC or multiple endocrine neoplasia (MEN) syndromes. Classical MTC presents as a nodular goiter with or without lymphadenopathy, or occasionally diarrhea and metastatic symptoms. Several patients in our cohort had unusual features that delayed diagnosis. The standard management remains surgical resection, with tyrosine kinase inhibitors (TKIs) in RET mutation-positive or RET mutation-negative metastatic cases and/or Lutathera peptide receptor radionuclide therapy (PRRT) used in disseminated disease, and external beam radiotherapy for locally aggressive or infiltrative retaining a limited role. However, some patients developed therapy-related complications or exhibited resistance to treatment. Of the 80 MTC patients reviewed, this case series highlights 10 atypical presentations in nine cases : 3 unusual tumors along with MTC, namely chondrosarcoma, carcinoma prostrate, and ectopic Cushing's syndrome; 4 unusual associations or presenting manifestations: pneumoconiosis masquerading as lung metastasis, Marfanoid habitus in MEN-2A and VHL spectrum disease, 1 with skull metastasis, and 2 cases with TKI-related complications in the form of glomerulonephritis and one patient displayed Marfanoid habitus with a RET mutation but without MEN2B or fibrillin gene mutation, while another developed bowel perforation secondary to lenvatinib therapy emphasizing diagnostic and therapeutic challenges and rare tumor associations. This series underscores the heterogeneity of MTC and the need for thorough evaluation and personalized management. Greater clinician awareness of MTC's diverse presentations is essential to improve early diagnosis and optimize treatment outcomes. Diverse and atypical clinical presentations can obscure the diagnosis of MTC. Management of MTC remains complex due to therapy-related complications and resistance. Molecular diagnostics enable better risk stratification and personalized care.
2025-10-25 | Anatomical-biochemical discordance and prognostic role of bone metastases in advanced MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE.
Medullary thyroid carcinoma (MTC) is a rare malignancy with limited treatment options in the metastatic setting. While peptide receptor radionuclide therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTA-TATE has been well established in gastroenteropancreatic neuroendocrine tumors, its clinical utility in MTC remains under investigation. We retrospectively analyzed 18 patients with advanced, somatostatin receptor-positive MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE. Treatment decisions-including in patients with low somatostatin receptor (SSTR) expression or first-line PRRT indication-were made by a multidisciplinary tumor board. Anatomical response was assessed using RECIST 1.1 on [⁶⁸Ga]Ga-DOTA-TATE PET/CT after two cycles. Biochemical and clinical outcomes were also recorded. Progression-free survival (PFS) was evaluated using Kaplan-Meier and Cox regression. Median PFS was 37.0 months. Radiologic disease control -defined as partial response (PR) or stable disease (SD) -was achieved in 78%, and biochemical response (≥ 50% decrease in calcitonin) in 44% of patients. Patients with bone metastases had significantly shorter PFS (24.6 vs. 47.0 months, p = 0.027). Longer PFS was also observed in those receiving higher cumulative dose, those with larger solitary tumors, and those treated in the first-line setting, although these trends did not reach statistical significance. Discordance between anatomical and biochemical response was observed in 50% of cases, highlighting limitations of calcitonin-based monitoring. PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE is a well-tolerated treatment option for selected patients with advanced MTC, including those receiving first-line therapy and those with low SSTR expression. In our limited cohort, bone metastases were associated with shorter PFS, and discordant imaging/biochemical responses are common. Functional imaging-guided selection and individualized response assessment are essential for optimal management.
2024-11-30 | Parathyroid hormone-based algorithm reduces complications after total thyroidectomy.
Hypocalcemia after total thyroidectomy is a frequent complication that can be predicted and best managed by the postoperative measurement of parathyroid hormone levels. This study included consecutive patients who underwent total thyroidectomy between 2017 and 2022. Hypocalcemia was defined as serum calcium <8.0 mg/dL and hypoparathyroidism as parathyroid hormone <15 pg/mL. After comparing serum calcium levels on postoperative day 1 and intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy in the first period, an algorithm involving routine postoperative oral calcium and alfacalcidol administration in patients with intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy <20 pg/mL was developed and tested during the second period. The rates of symptomatic hypocalcemia, readmission for hypocalcemia, and permanent hypoparathyroidism were compared between the 2 periods. In the first period, 1,965 total thyroidectomies (1,548 women; mean age, 51 years) were performed, including 617 patients (31%) with central neck dissection for thyroid carcinoma. Of 314 patients (16%) who experienced symptomatic hypocalcemia, only 183 (58%) could be predicted using serum calcium levels on postoperative day 1 <8.0 mg/dL. This rate increased to 96% (301 patients) when using intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy and serum calcium levels on postoperative day 1 (P < .001). Intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy alone could predict symptomatic hypocalcemia in 90% (282) of patients. Hypoparathyroidism was permanent in 20 patients (1%), with a greater predictive value of intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy over serum calcium levels on postoperative day 1 (18/20 [90%] vs 8/20 [40%], P < .01). Using the intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy-based algorithm and preventive calcium supplementation in the second period of the study, 1,420 total thyroidectomies (1,106 women; mean age, 50 years) were performed, including 392 (28%) cases with central neck dissection for thyroid carcinoma. Only 2.3% (32) patients developed a symptomatic hypocalcemia compared with 16% during the first period (P < .001). Thirty-eight patients (2.7%) experienced readmission after total thyroidectomy before implementation of the supplementation protocol in our study compared with 2 patients (0.01%) after we began using the protocol (P < .001). There was no significant difference in permanent hypoparathyroidism between the 2 periods (1.3% vs 1%) (P = .8). The parathyroid hormone-based algorithm determined by intraoperative parathyroid hormone levels 20 minutes after total thyroidectomy and routine preventive administration of oral calcium/calcitriol reduced the risk of symptomatic hypocalcemia and readmission after total thyroidectomy.
cell therapies
2026-07-23 | Updated Dutch 2026 pediatric differentiated thyroid carcinoma guideline: aligning with Europe.
Pediatric differentiated thyroid carcinoma (DTC) is a rare disease, creating challenges for standardized care across Europe. The Netherlands published its first national pediatric DTC guideline in 2020. The 2022 European Thyroid Association (ETA) guideline introduced differences that required reconciliation with national practice. This article presents the 2026 update of the Dutch guideline, harmonized with European recommendations while retaining context-specific adaptations. The 2020 Dutch guideline was systematically compared with the ETA 2022 guideline. Differences were discussed by the national pediatric DTC working group and addressed in a structured consensus meeting to agree on revisions and adaptations relevant to the Dutch context. Most European recommendations were adopted. Key national adaptations include performing total thyroidectomy without prior histology in Bethesda V-VI nodules with a proven BRAF mutation, expanded use of molecular diagnostics in selected nodules, and referral for genetic counseling in confirmed cases. In addition, less extensive surgery and selective omission of radioactive iodine therapy in low-risk patients were recommended, based on shared decision-making. Follow-up with neck ultrasound was limited to an initial 3-month assessment, with subsequent imaging only in case of rising thyroglobulin or anti-thyroglobulin concentrations. The 2026 Dutch guideline aligns with European recommendations while preserving context-specific adaptations. It provides a framework for consistent, patient-centered care and supports standardized clinical practice in the Netherlands, offering a model for harmonized pediatric DTC management across Europe.
2026-02-06 | Patient-Derived in Vitro Models Reveal Insights into Medullary Thyroid Cancer Microenvironment and Resistance to Tyrosine Kinase Inhibitors.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with a 10-year mortality rate up to 50%. Current therapies for metastatic MTC comprise various tyrosine-kinase inhibitors, but resistance often appears due to the need for lifelong treatments. Like in other tumors, genetic, epigenetic, post-transcriptional, post-translational, and cell-cell interaction events influence drug response. However, progress in understanding MTC biology is limited by the lack of reliable in vivo and in vitro models. This study aims to develop a patient-derived model faithfully reproducing the microenvironmental alterations present in MTC. We applied a two-step protocol consisting of a first phase in which primary cells are cultivated as multicellular spheroids and a second phase in which they are switched to adherent cultures. After evaluation of the genetic background by targeted Next Generation Sequencing, we characterized our cells phenotype by examining a panel of stem/progenitor-related markers, the secretory abilities by ELISAs, the drug response by proliferation assays, the in vivo angiogenic and invasiveness by the use of zebrafish model, the in vitro invasivity by Matrigel Dome assays and the spatial variation of stem/progenitor marker in both 3D cell models and tissue samples by confocal microscopy. Our model allowed the establishment of eight MTC patient-derived cell lines with different genetic backgrounds. The cultures faithfully reproduced the changes in stem and progenitor markers that we detected in our cohort of MTC tissue samples and could be successfully xenotransplanted in zebrafish model, showing both angiogenetic and invasive properties. Drug screening assays revealed the potential of our model for the study of patient-specific responses, as we were able to identify different candidate regulators of the sensitivity to currently available therapies for MTC. Our two-step protocol successfully generated primary MTC lines that maintain high plasticity, can be cultivated for several passages, and recreate the heterogeneity observed in patients' tissues. Our model will offer a robust platform for preclinical drug testing and mechanistic studies, addressing a longstanding gap in MTC research. It enables exploration of tumor microenvironment interactions and personalized therapeutic responses, supporting progress beyond current genomic-driven frameworks.
2026-01-21 | Pediatric follicular thyroid carcinoma: a clinicopathologic study treated at a single institution during a 30-year period.
PURPOSE: Pediatric follicular thyroid carcinoma (FTC) is an exceptionally rare entity, and its management has largely been extrapolated from adult protocols. Recent revisions of the WHO classification have redefined FTC subtypes, but pediatric studies based on the new criteria are lacking. This study aimed to evaluate the clinicopathological features of pediatric FTC using the updated WHO classification and to compare outcomes with pediatric papillary thyroid carcinoma (PTC). METHODS: Medical records of patients < 19 years who underwent thyroidectomy between 1989 and 2019 at Ito Hospital were reviewed. Pathological diagnosis was reassessed according to the most recent WHO classification. Twenty-four FTC and 134 PTC cases were identified. Clinical characteristics, histological findings, and outcomes were analyzed. RESULTS: Pediatric FTC accounted for 15.2% of pediatric DTC, a significantly higher proportion than in adults (5.9%). Median age was 16 years; female-to-male ratio was 7:1. Subtypes were minimally invasive (25%), encapsulated angioinvasive (46%), and widely invasive (29%). Extensive vascular invasion (VI ≥ 4) was observed in 7 patients (29%). Solid, trabecular, or insular growth pattern were observed in 21 patients (87.5%). VI was associated with distant metastasis, but no patients experienced disease-specific death during median follow-up of 6.2 years. In contrast, PTC patients showed significantly higher recurrence rates (p < 0.05). CONCLUSION: Pediatric FTC demonstrates excellent prognosis, but its pathological spectrum differs from previous reports under older classifications. VI remains the key determinant of metastatic risk. These findings suggest the need for risk-adapted strategies tailored to pediatric FTC, with avoidance of overtreatment in low-risk cases.
2025-08-26 | B7-H3 and CSPG4-targeted CAR T cells as potent effectors in anaplastic thyroid cancer.
Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with poor survival and no available effective therapy. This unmet clinical need led us to investigate chimeric antigen receptor (CAR) T cells s as potential treatment option for this malignant disease. As target tumor antigens of our CAR T cell therapy, we selected the chondroitin sulfate proteoglycan 4 (CSPG4) and the B7-homolog 3 (B7-H3), as they are both highly and homogeneously expressed on different types of thyroid carcinoma cell lines and tissues, including ATC. Importantly, both CSPG4 and B7-H3 have a low distribution on normal tissues, thus limiting 'on-target off-tumor' CAR T-related toxicities. We generated CSPG4-specific and B7-H3-specific CAR T cells by utilizing a second-generation CAR construct comprised of a CD28 costimulatory domain and tested their antitumor activity in vitro and in an orthotopic xenograft murine model of ATC. We demonstrated that thyroid cancer cells are specifically recognized and effectively eradicated in vitro by CSPG4-targeted and B7-H3-targeted CAR T cells. Additionally, both CAR T cell types were able to mediate significant control or complete eradication of primary ATC tumors when mice were treated with CSPG4 CAR T cells or B7-H3 CAR T cells, respectively. Overall, in this study we identified CSPG4 and B7-H3 as valuable target antigens in thyroid cancer and demonstrated that CAR T cell immunotherapy can be a valuable therapeutic option for ATC patients. Our findings provide the translational basis for exploring CAR T cell immunotherapies targeting CSPG4 and B7-H3 with ATC patients who do not respond or relapse after first line treatment.
2025-07-30 | Risk-adapted therapy in pediatric thyroid cancer: initial experience from a national reference program by the MET group.
Pediatric differentiated thyroid carcinoma (pedDTC) is rare but increasingly prevalent, requiring multidisciplinary care to ensure optimal outcomes. In 2021, the pediatric national reference program of the German Malignant Endocrine Tumor (MET) registry was established to standardize the management of pedDTC, with a particular focus on radioactive iodine (RAI) use and minimizing treatment variability. This study evaluated the program's first 3.5 years, including 43 inquiries concerning 39 patients with confirmed or suspected pedDTC. A weekly national expert tumor board provided individualized recommendations based on multidisciplinary input and risk stratification. Data were analyzed for demographic trends, therapeutic decisions, and short-term outcomes. Among 34 patients with confirmed pedDTC, RAI use was reduced or omitted in 70.6% of cases, particularly among low-risk patients, in alignment with the American Thyroid Association 2015 guidelines. Surgical strategies were modified in 61.5% of cases to balance disease control with treatment-related morbidity. No systemic medical therapy was recommended during initial management. At a mean follow-up of 0.7 years, all patients were alive; persistent disease was observed in 15.4%. The national reference program has successfully introduced a structured, individualized approach to the management of pedDTC in Germany. Ongoing data collection and longer follow-up will be essential to assess the long-term impact of this centralized, risk-adapted model.
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2026-09-07 | Single-Cell Transcriptome of Anaplastic Thyroid Cancer Reveals Immunosuppressive Tumor Microenvironment Remodeling.
Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy responsible for most thyroid cancer-related deaths. To elucidate molecular and immunological characteristics distinguishing ATC from aggressive papillary thyroid cancer (PTC), we performed single-cell RNA sequencing on three ATC and three lethal PTC samples. ATC tumor cells exhibited enhanced inflammatory and immune-related gene expression, and co-activation of MAPK and PI3K pathways. Notably, p53 pathway activity was suppressed in ATC, alongside activation of angiogenic and immune-evasion programs, indicating a shift from proliferation-driven to immune-evasion-oriented signaling. Transcriptional network analysis revealed E2F family activation, including E2F1, E2F7, and E2F8, suggesting CDK-RB-E2F axis dysregulation drives tumor dedifferentiation and proliferation, whereby p53 suppression unleashes E2F-dependent transcriptional reprogramming. Immunoprofiling revealed CD8+ T cells in ATC showed elevated exhaustion signatures and high expression of inhibitory immune checkpoint molecules, accompanied by enhanced Treg-CD8+ T cell interactions, indicating a dual-layered immunosuppressive mechanism involving both T-cell exhaustion and enhanced Treg-mediated suppression. In addition, we identified antigen-presenting CAFs with altered CD4+ T-cell interactions. These findings delineate a comprehensive single-cell landscape of ATC and demonstrate coordinated alterations in tumor-intrinsic signaling and the tumor microenvironment during dedifferentiation, provide a foundation for developing rational combination immunotherapies tailored to the molecular and immunological landscape of thyroid cancer.
2026-07-28 | Case report: Concurrent primary thyroid MALT lymphoma and lymph node metastatic thyroid micropapillary carcinoma in Hashimoto's thyroiditis: a diagnostic and therapeutic challenge.
Primary thyroid lymphoma (PTL) is an extremely rare malignancy, and its prognosis primarily depends on factors such as histological type and clinical stage. Papillary thyroid carcinoma(PTC) is the most common pathological type of thyroid cancer. Papillary thyroid microcarcinoma(PTMC) accounts for a significant proportion of PTCs and generally has a favorable prognosis;however, central lymph node metastasis (CLNM) occurs in approximately 10-30% of cases. Thecoexistence of PTL and metastatic PTMC is exceedingly rare, with only a few reports in the literature. Hashimoto thyroiditis (HT) is a common risk factor for both PTL and PTC. We present a case of HT diagnosed concurrently with PTL and PTMC, accompanied by level VI CLNM. We systematically reviewed the patient's clinical presentation, imaging findings, laboratory results, histopathological features, treatment, and follow-up. A 40-year-old woman presented with neck discomfort. Ultrasonography revealed a solid hypoechoic nodule in the right thyroid lobe with irregular and slightly lobulated margins. The patientdeclined fine-needle aspiration cytology and opted for direct surgery. The patient underwent right thyroid lobectomy with isthmusectomy and biopsy of the right central compartment (level VI) lymph nodes. Postoperative pathology confirmed the coexistence of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), with pathological features suggestive of large B-cell transformation, and PTMC, with carcinoma identified in one of ten resected level VI lymph nodes (1/10). Immunohistochemistry showed that the lymphoma cells were positive for CD20, CD79a, Pax-5, and Bcl-2 and negative for CD5, CD10, and Cyclin D1. The patient received four cycles (six infusions) of a single-agent, obinutuzumab, as post-surgical therapy. The patient has now completed the full treatment course, remains in a stable condition, and shows no evidence of recurrence. The coexistence of PTL and PTMC is exceptionally rare and poses a significant risk of misdiagnosis. Comprehensive preoperative evaluation and precise histopathological examination are crucial for accurate diagnosis. Although PTMC generally has an excellent prognosis, central lymph node metastasis can occur in a subset of patients. Careful evaluation of suspicious cervical lymph nodes and individualized postoperative surveillance are therefore warranted. Therapeutic decision-making requires a balanced consideration of lymphoma stage and thyroid carcinoma risk stratification, underscoring the importance of a multidisciplinary approach.
2026-06-02 | B7-H3 (CD276) as a candidate therapeutic target in medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak, or absent. Statistical analyses were conducted using descriptive statistics and Fisher's exact test. The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 in any evaluable samples. B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.
2026-05-15 | Intrathyroid thymic carcinoma: A comprehensive review of clinicopathological features and therapeutic strategies.
Intrathyroid thymic carcinoma (ITTC) is an exceptionally rare primary thyroid malignancy with thymic epithelial differentiation, generally characterized by relatively indolent biological behavior. However, significant knowledge gaps persist in ITTC diagnosis, and a consensus on an optimal treatment strategy for ITTC is lacking. This review synthesizes the current knowledge on ITTC, focusing on its clinicopathological features, molecular landscape, prognostic factors, and therapeutic approaches, to raise clinical awareness of this rare entity and guide individualized management. ITTC predominantly affects adults, with a slight female predilection. Pretreatment diagnosis in imaging and cytology of ITTC is challenging. Histopathologically, ITTC is indistinguishable from thymic squamous cell carcinoma (TSCC), and no specific molecular alterations have been identified to date. Lymph node metastasis and the presence of symptoms at diagnosis serve as adverse prognostic indicators in ITTC patients. While surgery remains the priority treatment for ITTC, patients' responses to adjuvant radiotherapy and/or chemotherapy are variable, underscoring the need for further investigation into the role of systemic antineoplastic therapies. Notably, checkpoint inhibitors targeting PD-L1 or PD-1 represent a promising avenue for ITTC patients with advanced disease.
2026-05-04 | The Molecular Landscape of CASTLE: A Rare Thymus-like Head and Neck Cancer.
Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignancy arising in the thyroid or neck, with an uncertain cellular origin that complicates both diagnosis and treatment. To better understand its molecular underpinnings and identify potential therapeutic avenues, we conducted integrated whole-exome and transcriptome sequencing on six CASTLE and six thymic carcinoma samples. Whole-exome sequencing (WES) was performed on all 12 samples, while RNA sequencing was successful for 1 CASTLE and 6 thymic carcinoma samples. Our analysis included somatic mutation profiling, mutational signature deconvolution, differential gene expression, and characterization of tumor microenvironment for the cases with available data, with comparisons to genomic data from other thyroid cancers. CASTLE tumors demonstrated a higher median tumor mutational burden than thymic carcinoma and lacked the common BRAF and RAS mutations typically found in thyroid cancers. They harbored alterations in genes such as TRHDE, cilia-associated genes (ANKS6, CFAP46, DNAH6), and Wnt signaling components (TRRAP, BCL9L), as well as mutational signatures suggestive of mismatch repair deficiency and oxidative damage. MSIsensor-pro analysis of the WES data provided support for the potential for mismatch repair deficiency in a subset of CASTLE samples. Exploratory transcriptomic analysis from a single CASTLE case showed downregulation of thyroid follicular markers and an "immune-hot", lymphocyte-rich microenvironment, closely resembling that of thymic carcinoma. While these findings require validation in larger cohorts, they support a thymic origin for CASTLE and establish its molecular distinction from follicular-derived thyroid cancers. The immunogenic tumor landscape suggests that immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, may be a promising therapeutic strategy, alongside emerging targets for precision oncology.
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2024-05-28 | LINC00887 Acts as an Enhancer RNA to Promote Medullary Thyroid Carcinoma Progression by Binding with FOXQ1.
Medullary thyroid carcinoma (MTC) is a rare but aggressive endocrine malignancy that originates from the parafollicular C cells of the thyroid gland. Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from enhancer regions, which are critical regulators of tumorigenesis. However, the roles and regulatory mechanisms of eRNAs in MTC remain poorly understood. This study aims to identify key eRNAs regulating the malignant phenotype of MTC and to uncover transcription factors involved in the regulation of key eRNAs. GSE32662 and GSE114068 were used for the identification of differentially expressed genes, eRNAs, enhancers and enhancer-regulated genes in MTC. Metascape and the transcription factor affinity prediction method were used for gene function enrichment and transcription factor prediction, respectively. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to assess the binding of histone H3 lysine 27 acetylation (H3K27ac)-enriched regions to anti- H3K27ac. RIP-qPCR was used to detect the binding between FOXQ1 and LINC00887. CCK8 and Transwell were performed to measure the proliferation and invasion of MTC cells, respectively. Intracellular reactive oxygen species (ROS) levels were quantified using a ROS assay kit. Four eRNAs (H1FX-AS1, LINC00887, MCM3AP-AS1 and A1BG-AS1) were screened, among which LINC00887 was the key eRNA promoting the proliferation and invasion of MTC cells. A total of 135 genes controlled by LINC00887-regulated enhancers were identified; among them, BCL2, PRDX1, SFTPD, TPO, GSS, RAD52, ZNF580, and ZFP36L1 were significantly enriched in the "ROS metabolic process" term. As a transcription factor regulating genes enriched in the "ROS metabolic process" term, FOXQ1 could recruit LINC00887. Overexpression of FOXQ1 restored LINC00887 knockdown-induced downregulation of GSS and ZFP36L1 transcription in MTC cells. Additionally, FOXQ1 overexpression counteracted the inhibitory effects of LINC00887 knockdown on the proliferation and invasion of MTC cells and the promotion of intracellular ROS accumulation induced by LINC00887 knockdown. LINC00887 was identified as a key eRNA promoting the malignant phenotype of MTC cells. The involvement of FOXQ1 was essential for LINC00887 to play a pro-tumorigenic role in MTC. Our findings suggest that the FOXQ1/LINC00887 axis is a potential therapeutic target for MTC.
2024-02-22 | Delving into the Role of lncRNAs in Papillary Thyroid Cancer: Upregulation of LINC00887 Promotes Cell Proliferation, Growth and Invasion.
Papillary thyroid carcinoma (PTC) is the most common histological category of thyroid cancer. In recent years, there has been an increasing number of studies on lncRNAs in PTC. Long intergenic non-protein coding RNA 887 (LINC00887) is a critical oncogene in developing other cancers. LINC00887 is upregulated in PTC samples but its role in PTC is currently unclear. This study aimed to investigate the impact the disruption of LINC00887 expression has on PTC progression. We performed a CRISPR/Cas9 strategy for the truncation of LINC00887 in BCPAP and TPC1 cell lines. Functional assays showed that LINC00887 knockdown in both TPC1 and BCPAP cells reduced cell proliferation, colony formation and migration, delayed the cell cycle, and increased apoptosis. These results strengthened the role of LINC00887 in cancer and showed for the first time that this lncRNA could be a potential oncogene in PTC, acting as a tumor promoter. Modulation of the immune system may be one of the etiopathogenic mechanisms of LINC00887 in PTC, as shown by the observed influence of this lncRNA on PD-L1 expression. In addition, the biological pathways of LINC00887 identified to date, such as EMT, the Wnt/β-catenin signaling pathway or the FRMD6-Hippo signaling pathway may also be relevant regulatory mechanisms operating in PTC.
2023-06-28 | Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers.
Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC. We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis. Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.
2022-06-02 | A signature of circadian rhythm genes in driving anaplastic thyroid carcinoma malignant progression.
Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer. Recently, dysregulation of circadian rhythm genes was demonstrated to play an essential role in tumor progression, while its exact role and mechanism in ATC remained poorly clear. 4 ATC-related datasets were integrated to screen for differentially expressed circadian rhythm genes (DE-CRGs). Thereafter, Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) and network enrichment analysis were conducted to investigate the dynamic characteristics of circadian rhythm genes. Next, Lasso-logistic model and immunohistochemistry were applied for determining the candidates. Finally, cell biological experiments and gene set enrichment analysis (GSEA) were used to confirm the roles of NPAS2 in ATC. 25 DE-CRGs were firstly identified in ATC. These DE-CRGs mainly regulated mitotic nuclear division, cytokinesis and DNA replication signals. Notably, NPAS2, CSNK1E, NAMPT, TYMS, SERPINE1, TOP2A, JUN, EGR3 and HEBP1 were identified as the dynamic signature in the malignant progression of ATC, which were confirmed by prognostic analysis. Furthermore, NPAS2 was found to be significantly up-regulated in ATC through clinical samples and cell experiments. Silencing NPAS2 effectively inhibited the proliferation, migration and invasion of ATC cells. GSEA showed that high expression of NPAS2 was mainly associated with cell cycle and focal adhesion, and silencing of NPAS2 suppressed these signals in our experiments. In summary, we found a dynamic 9-DE-CRGs signature in ATC. And the aberrant expression of NPAS2 drove the malignant phenotypes of ATC, which facilitated to deepen our understanding of the roles of circadian rhythm genes in ATC.
2022-03-25 | CSPG4 Is a Potential Therapeutic Target in Anaplastic Thyroid Cancer.
Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4+ T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting ∼10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.
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Drug Discovery Landscape
4 orphan drug designations for Rare thyroid carcinoma, including 2 approved therapies.
4 orphan drug designations for Rare thyroid carcinoma, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
lenvatinib [Lenvima] | small molecules | FDA | Approved | Eisai, Inc. |
ribavirin elaidate | small molecules | FDA | — | Translational Therapeutics, Inc. |
cabozantinib [Cabometyx] | small molecules | FDA | Approved | Exelixis, Inc. |
N-Methyl-2-[3-[((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]benzamide | small molecules | FDA | Pfizer, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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