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
1,204 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:
1,204 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:
2026-08-13 | Papillary thyroid carcinoma with fibromatosis/fasciitis-like stromal component is a rare subtype of papillary carcinoma with moderate aggressiveness: a single-center retrospective cross-sectional study of 725 patients.
Papillary thyroid carcinoma with fibromatosis/fasciitis-like stroma (PTC/WF/FLS) is a rare subtype with poorly defined clinical and biological behavior. We observed an increasing number of cases and a relatively high rate of capsular invasion, suggesting potential local recurrence and postoperative relapse, which warrant further investigation. The objective of this study is to delineate the invasive and metastatic capabilities of this subtype through the investigation of its clinicobiological parameters. According to the 2022 World Health Organization (WHO) Classification of Thyroid Tumors, 725 patients with thyroid cancer collected between 2017 and 2021 were classified into a PTC/WF/FLS observation group, high-risk group (HRG), and low-risk group (LRG). Age, sex, tumor location, lesion number, tumor size, family history of cancer, genetic mutations, and tumor microenvironment were compared among the three groups, and their effects on lymph node metastasis and local invasion of the capsule, blood vessels, and nerves were analyzed. The PTC/WF/FLS, HRG, and LRG showed no significant differences in age, sex, tumor location, lesion number, genetic mutations, or tumor microenvironment. In early-stage disease (T1), the PTC/WF/FLS group had the highest capsular invasion rate compared with the HRG and LRG (16.28%, 5.53%, and 7.51%, respectively; P=0.003). The association with a family history of cancer was also higher in the PTC/WF/FLS group than in the HRG and LRG (9.24%, 4.91%, and 3.44%, respectively; P=0.04). Propensity-matched and stratified analyses showed that the VI-region lymph node metastasis rate in the PTC/WF/FLS group was intermediate between those in the HRG and LRG, although the between-group differences were not significant (P=0.10 and P=0.97, respectively). PTC/WF/FLS is a rare, moderately aggressive subtype of papillary carcinoma. It shows a strong tendency toward capsular invasion and lymphatic metastasis, even at an early stage (T1), which may increase the risk of early local recurrence and postoperative relapse.
2026-07-29 | Targeted therapies in the management of advanced medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that contributes disproportionately to thyroid cancer-related mortality. Historically, systemic treatment options for advanced MTC were limited due to poor responsiveness to radioactive iodine and conventional chemotherapy. The development of targeted therapies has significantly transformed disease management. This narrative review summarizes current evidence on targeted therapies for advanced MTC, including multikinase inhibitors (MKIs), selective RET inhibitors, and emerging treatment strategies. Literature on efficacy, safety, resistance mechanisms, and novel therapeutic approaches was evaluated. First-generation MKIs, including vandetanib and cabozantinib, demonstrated clinical benefit by targeting RET and angiogenic pathways, though off-target toxicities limited tolerability. More recently, selective RET inhibitors, such as selpercatinib and pralsetinib, have shown high response rates and improved safety profiles, establishing them as preferred first-line therapies for RET-mutant MTC. However, pralsetinib's recent market withdrawal due to regulatory challenges highlights the need for additional options. Emerging therapies, including BOS172738, SY-5007, and peptide receptor radionuclide therapy, show promising early results. Resistance mechanisms, including gatekeeper and solvent front mutations, remain a challenge. Advances in clinical biomarkers and novel approaches, such as CAR-T cell therapy, may further support personalized treatment. Targeted therapies have reshaped the management of advanced MTC, with selective RET inhibitors offering improved efficacy and tolerability. Continued research is essential to overcome resistance, expand therapeutic options, and improve patient outcomes.
2026-07-28 | Imidazole-Functionalized Thieno[3,2-c]Quinoline Hybrids in Aggressive Medullary Thyroid Cancer Cell Models: Biological Evaluation and in Silico Insights.
Background/Objectives: Medullary thyroid carcinoma (MTC) is a rare and aggressive endocrine malignancy frequently associated with RET alterations and dysregulation of RET-associated signaling pathways. In previous studies, first-generation nitro-substituted thieno[3,2-c]quinolines 1 showed promising antiproliferative activity in TT(RETC634R) cells, while subsequent imidazole-based optimization generated second-generation derivatives 2 with broad-spectrum antiproliferative activity in the NCI-60 human tumor cell line panel. Since thyroid cancer models are not included in the NCI-60 platform, the present study aimed to evaluate the antiproliferative potential of these optimized derivatives in clinically relevant MTC cellular models. Methods: Imidazole-functionalized thieno[3,2-c]quinoline derivatives (2a-j) were evaluated against TT(RETC634R) and MZ-CRC-1(RETM918T) cells. The most active compounds were further characterized through induced fit docking (IFD), MM-GBSA calculations, and molecular dynamics (MD) simulations on representative molecular targets. In silico ADME/Toxicity profiling was also performed to assess their developability. Results: Several derivatives exhibited potent activity in both MTC cell models, with multiple compounds achieving submicromolar potency. Compounds 2b and 2g emerged as the most active derivatives in TT(RETC634R) cells, whereas compounds 2d and 2i displayed the most favorable profile in the aggressive MZ-CRC-1(RETM918T) model, thereby extending the biological applicability of the scaffold to an additional clinically relevant RET-mutant context. Computational studies supported RET as the most plausible molecular target for all selected lead compounds, while favorable PI3Kα interaction profiles were predicted for selected derivatives, suggesting distinct target engagement profiles within the series. The most promising derivatives also exhibited an overall favorable predicted ADME/Toxicity profile. Conclusions: The present findings support the success of imidazole-based optimization of the thieno[3,2-c]quinoline scaffold and identify thieno[3,2-c]quinolines 2 as promising lead structures for the future development of novel anti-MTC agents. Further biological and mechanistic investigations will be necessary to better clarify the molecular mechanisms underlying their antiproliferative activity and to guide future lead optimization studies.
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.
2026-07-25 | Papillary Thyroid Cancer With Cutaneous Metastasis: A Case Report and Literature Review.
Cutaneous metastasis of papillary thyroid carcinoma is rare, which may present as slowly growing nodules, erythematous papules, or ulcerative nodules. The pathophysiological mechanisms of skin metastasis in thyroid cancer remain unclear. Skin metastasis of thyroid papillary carcinoma represents a poor prognostic factor in previous studies, and whether there exist relative genes still needs to be further investigated. Eight years after a radical surgery for left-sided thyroid cancer, a 29-year-old female presented to our dermatology department after discovering a patch of hyperpigmentation on the right side of her neck for 2 years. The dermatologist performed a biopsy of the neck skin mass under local anesthesia, and the gross specimen consisted of a piece of skin tissue measuring 0.4 cm × 0.3 cm × 0.3 cm, with a gray-black area of 0.4 cm on the surface. Microscopic examination, along with the clinical history, suggested metastasis of papillary thyroid carcinoma. Further immunohistochemical analysis showed results consistent with metastasis of papillary thyroid carcinoma, with tumor cells expressing TTF-1 (positive), TG (-), Ki67 (-), PAX-8 (+), GCDFP (-), ER (-), PR (20%), and GATA-3 (-). Skin metastases account for a relatively small proportion of metastatic thyroid cancer and can be easily misdiagnosed. Patients with skin lesions, especially in the head and neck area, that appear during the follow-up of thyroid cancer should be carefully selected and diagnosed.
2026-08-13 | Papillary thyroid carcinoma with fibromatosis/fasciitis-like stromal component is a rare subtype of papillary carcinoma with moderate aggressiveness: a single-center retrospective cross-sectional study of 725 patients.
Papillary thyroid carcinoma with fibromatosis/fasciitis-like stroma (PTC/WF/FLS) is a rare subtype with poorly defined clinical and biological behavior. We observed an increasing number of cases and a relatively high rate of capsular invasion, suggesting potential local recurrence and postoperative relapse, which warrant further investigation. The objective of this study is to delineate the invasive and metastatic capabilities of this subtype through the investigation of its clinicobiological parameters. According to the 2022 World Health Organization (WHO) Classification of Thyroid Tumors, 725 patients with thyroid cancer collected between 2017 and 2021 were classified into a PTC/WF/FLS observation group, high-risk group (HRG), and low-risk group (LRG). Age, sex, tumor location, lesion number, tumor size, family history of cancer, genetic mutations, and tumor microenvironment were compared among the three groups, and their effects on lymph node metastasis and local invasion of the capsule, blood vessels, and nerves were analyzed. The PTC/WF/FLS, HRG, and LRG showed no significant differences in age, sex, tumor location, lesion number, genetic mutations, or tumor microenvironment. In early-stage disease (T1), the PTC/WF/FLS group had the highest capsular invasion rate compared with the HRG and LRG (16.28%, 5.53%, and 7.51%, respectively; P=0.003). The association with a family history of cancer was also higher in the PTC/WF/FLS group than in the HRG and LRG (9.24%, 4.91%, and 3.44%, respectively; P=0.04). Propensity-matched and stratified analyses showed that the VI-region lymph node metastasis rate in the PTC/WF/FLS group was intermediate between those in the HRG and LRG, although the between-group differences were not significant (P=0.10 and P=0.97, respectively). PTC/WF/FLS is a rare, moderately aggressive subtype of papillary carcinoma. It shows a strong tendency toward capsular invasion and lymphatic metastasis, even at an early stage (T1), which may increase the risk of early local recurrence and postoperative relapse.
2026-07-29 | Targeted therapies in the management of advanced medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that contributes disproportionately to thyroid cancer-related mortality. Historically, systemic treatment options for advanced MTC were limited due to poor responsiveness to radioactive iodine and conventional chemotherapy. The development of targeted therapies has significantly transformed disease management. This narrative review summarizes current evidence on targeted therapies for advanced MTC, including multikinase inhibitors (MKIs), selective RET inhibitors, and emerging treatment strategies. Literature on efficacy, safety, resistance mechanisms, and novel therapeutic approaches was evaluated. First-generation MKIs, including vandetanib and cabozantinib, demonstrated clinical benefit by targeting RET and angiogenic pathways, though off-target toxicities limited tolerability. More recently, selective RET inhibitors, such as selpercatinib and pralsetinib, have shown high response rates and improved safety profiles, establishing them as preferred first-line therapies for RET-mutant MTC. However, pralsetinib's recent market withdrawal due to regulatory challenges highlights the need for additional options. Emerging therapies, including BOS172738, SY-5007, and peptide receptor radionuclide therapy, show promising early results. Resistance mechanisms, including gatekeeper and solvent front mutations, remain a challenge. Advances in clinical biomarkers and novel approaches, such as CAR-T cell therapy, may further support personalized treatment. Targeted therapies have reshaped the management of advanced MTC, with selective RET inhibitors offering improved efficacy and tolerability. Continued research is essential to overcome resistance, expand therapeutic options, and improve patient outcomes.
2026-07-28 | Imidazole-Functionalized Thieno[3,2-c]Quinoline Hybrids in Aggressive Medullary Thyroid Cancer Cell Models: Biological Evaluation and in Silico Insights.
Background/Objectives: Medullary thyroid carcinoma (MTC) is a rare and aggressive endocrine malignancy frequently associated with RET alterations and dysregulation of RET-associated signaling pathways. In previous studies, first-generation nitro-substituted thieno[3,2-c]quinolines 1 showed promising antiproliferative activity in TT(RETC634R) cells, while subsequent imidazole-based optimization generated second-generation derivatives 2 with broad-spectrum antiproliferative activity in the NCI-60 human tumor cell line panel. Since thyroid cancer models are not included in the NCI-60 platform, the present study aimed to evaluate the antiproliferative potential of these optimized derivatives in clinically relevant MTC cellular models. Methods: Imidazole-functionalized thieno[3,2-c]quinoline derivatives (2a-j) were evaluated against TT(RETC634R) and MZ-CRC-1(RETM918T) cells. The most active compounds were further characterized through induced fit docking (IFD), MM-GBSA calculations, and molecular dynamics (MD) simulations on representative molecular targets. In silico ADME/Toxicity profiling was also performed to assess their developability. Results: Several derivatives exhibited potent activity in both MTC cell models, with multiple compounds achieving submicromolar potency. Compounds 2b and 2g emerged as the most active derivatives in TT(RETC634R) cells, whereas compounds 2d and 2i displayed the most favorable profile in the aggressive MZ-CRC-1(RETM918T) model, thereby extending the biological applicability of the scaffold to an additional clinically relevant RET-mutant context. Computational studies supported RET as the most plausible molecular target for all selected lead compounds, while favorable PI3Kα interaction profiles were predicted for selected derivatives, suggesting distinct target engagement profiles within the series. The most promising derivatives also exhibited an overall favorable predicted ADME/Toxicity profile. Conclusions: The present findings support the success of imidazole-based optimization of the thieno[3,2-c]quinoline scaffold and identify thieno[3,2-c]quinolines 2 as promising lead structures for the future development of novel anti-MTC agents. Further biological and mechanistic investigations will be necessary to better clarify the molecular mechanisms underlying their antiproliferative activity and to guide future lead optimization studies.
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.
2026-07-25 | Papillary Thyroid Cancer With Cutaneous Metastasis: A Case Report and Literature Review.
Cutaneous metastasis of papillary thyroid carcinoma is rare, which may present as slowly growing nodules, erythematous papules, or ulcerative nodules. The pathophysiological mechanisms of skin metastasis in thyroid cancer remain unclear. Skin metastasis of thyroid papillary carcinoma represents a poor prognostic factor in previous studies, and whether there exist relative genes still needs to be further investigated. Eight years after a radical surgery for left-sided thyroid cancer, a 29-year-old female presented to our dermatology department after discovering a patch of hyperpigmentation on the right side of her neck for 2 years. The dermatologist performed a biopsy of the neck skin mass under local anesthesia, and the gross specimen consisted of a piece of skin tissue measuring 0.4 cm × 0.3 cm × 0.3 cm, with a gray-black area of 0.4 cm on the surface. Microscopic examination, along with the clinical history, suggested metastasis of papillary thyroid carcinoma. Further immunohistochemical analysis showed results consistent with metastasis of papillary thyroid carcinoma, with tumor cells expressing TTF-1 (positive), TG (-), Ki67 (-), PAX-8 (+), GCDFP (-), ER (-), PR (20%), and GATA-3 (-). Skin metastases account for a relatively small proportion of metastatic thyroid cancer and can be easily misdiagnosed. Patients with skin lesions, especially in the head and neck area, that appear during the follow-up of thyroid cancer should be carefully selected and diagnosed.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
lenvatinib [Lenvima] | small molecules | FDA | 2012-12-27 | 2015-02-13 | Eisai, Inc. |
ribavirin elaidate | small molecules | FDA | 2011-09-02 | — | Translational Therapeutics, Inc. |
cabozantinib [Cabometyx] | small molecules | FDA | 2010-11-29 | 2021-09-17 | Exelixis, Inc. |
N-Methyl-2-[3-[((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]benzamide | small molecules | FDA | 2007-05-04 | — | Pfizer, Inc. |
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