Rare thyroid malignancies ［including anaplastic thyroid carcinoma (ATC) , medullary thyroid carcinoma (MTC), primary thyroid lymphoma (PTL), primary squamous cell carcinoma of thyroid (PSCCT), poorly differentiated thyroid carcinoma (PDTC) , and primary thyroid sarcoma (PTS)］constitute less than 10% of all thyroid malignancies but account for over 50% of thyroid cancer-related deaths, posing a major clinical challenge. These malignancies are characterized by high aggressiveness, diagnostic difficulty, high rates of metastasis at initial presentation, limited treatment options, and poor prognosis. The key challenges in current management include diagnostic delays, inaccurate staging, and a lack of standardized treatment guidelines. Although the prognosis for many patients has improved in recent years with the advent of targeted drugs and innovations in surgical techniques and concepts, the overall survival rate has not shown significant improvement. To address the diagnosis and treatment of these patients, it is imperative to establish a surgeon-led multidisciplinary team (MDT) approach and a comprehensive standardized management system throughout the entire diagnosis and treatment process for rare thyroid malignancies. Future efforts should focus on conducting larger-scale, higher-quality clinical research to acquire a deeper understanding of the clinical characteristics of these diseases, investigate the response and resistance mechanisms of targeted therapies, and promote the development of highly selective kinase inhibitors and immunotherapeutic agents, thereby improving treatment outcomes for patients with rare thyroid malignancies.

The overall prognosis of thyroid cancer is favorable. However, once it progresses to advanced disease, it becomes a major threat to patient survival. Diagnosis and treatment of advanced thyroid cancer involve complex, multidisciplinary and multimodal processes. In 2024, the European Society of Endocrine Surgeons (ESES) convened an expert panel to address issues related to the definition, preoperative management, and therapeutic strategies for advanced thyroid cancer, culminating in a consensus statement that reflects the heightened attention of European and North American experts to this entity. The consensus defines advanced thyroid cancer across three domains—local, regional, and distant metastatic disease—and explicitly includes anaplastic thyroid carcinoma (ATC) within the advanced category. It emphasizes comprehensive preoperative evaluation using multimodal imaging, endoscopy, and molecular testing, together with optimization of comorbidities and nutritional status. Multidisciplinary team (MDT) care is central to crafting individualized treatment plans. Therapeutic strategies are anchored in achieving the greatest possible curative-intent resection of the primary tumor and metastatic foci, integrated with targeted therapy, radiotherapy, and neoadjuvant therapy as appropriate. For differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and ATC, surgery remains pivotal, with careful attention to balancing local control and quality of life. Molecular testing guides the rational use of targeted agents, including multikinase inhibitors (MKIs) and therapies directed at RET, BRAF, and NTRK alterations. Overall, the consensus provides a structured framework for defining and managing advanced thyroid cancer and underscores the roles of precision medicine and MDT care in improving survival and quality of life.

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, and a subset of subtypes exhibits moderate to high aggressiveness; accurate recognition is pivotal for prognostic assessment and individualized management. The fifth edition of the World Health Organization (WHO) classification emphasizes an integrated histologic-molecular diagnostic paradigm and, for the first time, explicitly designates high-risk histologic subtypes, including the tall cell subtype, hobnail subtype, and columnar cell subtype. Although the diffuse sclerosing subtype and the solid/trabecular subtype are categorized as intermediate risk, they likewise carry a considerable risk of metastasis. Distinct molecular profiles characterize these subtypes: the diffuse sclerosing subtype frequently harbors RET fusions; the tall cell subtype commonly shows BRAF V600E and TERT promoter mutations; and the hobnail subtype is closely associated with TP53 mutations. High-grade PTC, defined by tumor necrosis and a high mitotic rate, demonstrates biological behavior approaching that of poorly differentiated thyroid carcinoma. Standardized pathologic diagnosis requires adequate sampling in combination with immunohistochemistry and molecular testing to minimize misdiagnosis or underdiagnosis. Molecular subtyping further informs risk stratification and selection of targeted therapies. Overall, the diagnosis of rare PTC subtypes is transitioning from morphology alone to integrated molecular pathology, thereby laying the foundation for precision medicine and individualized treatment.

Poorly differentiated thyroid carcinoma (PDTC) is a rare pathological subtype of thyroid carcinoma whose morphological characteristics and biological behavior are intermediate between differentiated thyroid carcinoma and anaplastic carcinoma. PDTC is highly invasive, and is prone to recurrence and metastasis. Its diagnostic criteria are not yet unified, and the“Turin Criteria”are widely adopted internationally. Extrathyroidal invasion and distant metastasis are independent risk factors affecting the prognosis of PDTC. Currently, there is no consensus on the treatment strategies for PDTC. Surgery is the primary treatment modality for PDTC, while adjuvant therapies such as radioactive iodine therapy, external beam radiation therapy, and targeted therapy remain controversial.

Locally advanced thyroid carcinoma (LATC) accounts for 5%-15% of thyroid cancers and often involves adjacent critical nerves, vessels, and organs, resulting in surgical challenges and poor prognosis. Histologic subtypes include papillary thyroid carcinoma, follicular carcinoma, oncocytic carcinoma, poorly differentiated thyroid carcinoma (PDTC), anaplastic thyroid carcinoma (ATC), and high-grade medullary thyroid carcinoma (MTC).At the molecular level, activation of driver genes such as BRAF, RAS, and RET, together with mutations in TP53 and the TERT promoter, is closely associated with the aggressive behavior of LATC. Neoadjuvant therapy has emerged as a novel strategy, aiming to downstage tumors preoperatively, increase resectability, improve functional preservation, and prolong survival. Multitarget tyrosine kinase inhibitors (mTKIs), such as anlotinib and lenvatinib, and highly selective targeted agents, such as RET inhibitors (selpercatinib and pralsetinib), have demonstrated high objective response rates (ORR)in LATC neoadjuvant therapy, with some cases achieving R0 resection. For ATC with BRAF V600E mutation, preoperative therapy with dabrafenib plus trametinib has significantly improved survival. In the field of immunotherapy, programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, either as monotherapy or in combination with targeted therapy, have shown potential efficacy in ATC and PDTC. Although evidence of efficacy is accumulating, optimal timing and management of adverse effects remain to be clarified. Future multicenter clinical studies are needed to establish individualized neoadjuvant therapy systems based on molecular subtyping, thereby advancing LATC toward precision and standardized treatment.

The whole-course management of medullary thyroid carcinoma (MTC) relies heavily on dynamic monitoring of serum calcitonin (Ctn) and carcinoembryonic antigen (CEA). During the diagnostic and therapeutic stages, a comprehensive strategy of “Ctn as the primary indicator, CEA as a complementary marker, with imaging and genetic testing as supplements” should be established, providing crucial evidence for determining the extent of surgery, assessing metastatic risk, and guiding individualized interventions. In postoperative follow-up, patients with a Ctn doubling time (DT) of less than 6 months have a 10-year survival rate of only approximately 25%, while a shortened CEA DT indicates an increased risk of visceral metastasis. The synergistic monitoring system of Ctn and CEA runs through the entire process of diagnosis, surgery, and prognostic management of MTC, and serves as a cornerstone for optimizing individualized therapeutic strategies.

Metastatic thyroid tumor (MTT) refers to a secondary thyroid malignancy originating from other organ cancers through hematogenous spread, lymphatic dissemination, or direct invasion. Common primary tumors include renal cell carcinoma, lung cancer, breast cancer, gastrointestinal malignancies, and melanoma. Clinical manifestations of MTT lack specificity, often mimicking primary thyroid carcinoma, with presentations such as thyroid nodules or cervical masses. Hematogenous spread is the most frequent metastatic route, followed by lymphatic spread and direct invasion. At the molecular level, alterations such as BRAF, KRAS, and EML4-ALK mutations and signaling pathway abnormalities are implicated. Diagnosis relies on imaging, fine-needle aspiration (FNA), and immunohistochemical markers. Thyroglobulin (Tg), thyroid transcription factor-1 (TTF-1), carbonic anhydrase Ⅸ (CAⅨ), Napsin A, PAX8, GATA3, and S-100 are valuable in differentiating primary from metastatic tumors. Treatment strategies depend on the type of primary tumor and the extent of metastasis. Surgery can improve local control and relieve compressive symptoms, while resection of isolated metastases combined with treatment of the primary lesion may prolong survival. Systemic therapies include chemotherapy, radiotherapy, targeted therapy, and immunotherapy, with some patients benefiting from molecularly guided regimens. Prognosis varies substantially with the primary tumor: patients with renal cell carcinoma have relatively better survival, whereas those with lung cancer, gastrointestinal malignancies, or melanoma exhibit poorer outcomes. Overall, the management of MTT requires a multidisciplinary approach integrating pathology and molecular testing to achieve individualized therapy and improved patient survival.

Medullary thyroid carcinoma (MTC) is a distinct subtype of thyroid carcinoma with higher malignancy than differentiated thyroid carcinoma and regional lymph node metastasis can occur at an early stage. The incidence of superior mediastinal lymph node metastasis is reported to be 18.2%-27.5%. However, such metastases usually lack specific symptoms and are often overlooked due to obstruction by the sternum and clavicle, which limits the detection of lesions by routine ultrasound examination. Therefore, effective diagnostic and assessment modalities are of particular importance. Contrast-enhanced CT of the neck and chest can provide a reliable evaluation of superior mediastinal lymph node metastasis in MTC and its relationship with adjacent critical structures. The novel 68Ga-labeled CTR-FAPI positron emission tomography/computed tomography (68Ga-CTR-FAPI PET/CT) has shown promising diagnostic performance in detecting nodal and distant metastases of MTC. When superior mediastinal lymph node metastasis is present, standardized dissection of the superior mediastinum is currently the only potentially curative approach and has a direct impact on prognosis. Common surgical approaches include transcervical direct dissection, thoracotomy, transcervical endoscopic-assisted dissection，thoracoscopic dissection，and combined transcervical endoscopic-assisted thoracoscopic dissection. Endoscopic surgery offers the advantages of magnification, illumination and extended visualization, helping to overcome the limitations of open surgery imposed by the sternum and clavicle while avoiding the trauma of thoracotomy. For appropriately selected patients, transcervical endoscopic-assisted thoracoscopic or combined approaches can achieve standardized and minimally invasive superior mediastinal lymph node dissection with clinical value warranting further exploration and promotion. In addition, with the advent of novel targeted therapies, especially highly selective RET inhibitors such as pralsetinib and selpercatinib for RET mutations, new therapeutic opportunities have emerged for patients with MTC who were previously unsuitable for complete surgical resection. Preoperative neoadjuvant therapy guided by the patient’s tumor mutation profile may yield favorable outcomes.

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive thyroid malignancy with an extremely poor prognosis, and the median survival time is only 4-6 months. Traditional therapeutic modalities, including surgery, radiotherapy, and chemotherapy, provide limited overall efficacy. With advances in molecular biology, the genomic landscape of ATC has been gradually elucidated. Common alterations include BRAF V600E, TP53 mutations, TERT promoter mutations, and gene fusions involving NTRK, RET, and ALK, affecting signaling pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR. Targeted therapies against specific alterations (e.g., dabrafenib plus trametinib, larotrectinib, selpercatinib, pralsetinib) have markedly improved survival in selected patients. In the field of immunotherapy, programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors (e.g., spartalizumab, pembrolizumab), administered alone or in combination with targeted therapy or radiotherapy, have shown promising efficacy. Combined immunotherapy and targeted therapy, such as the PD-L1 inhibitor atezolizumab with vemurafenib and cobimetinib, has significantly prolonged survival in patients harboring BRAF V600E mutations. Supportive care, including airway management, nutritional support, and management of adverse effects, remains essential. Multidisciplinary collaboration and individualized precision therapy are central to optimizing ATC management. Future research should focus on mechanisms of resistance and therapeutic strategies for patients without BRAF mutations.

Mixed thyroid malignancies are rare tumors characterized by the coexistence of two or more distinct histological types within the same thyroid gland. Common forms include papillary thyroid carcinoma (PTC) combined with medullary thyroid carcinoma (MTC), PTC combined with follicular thyroid carcinoma (FTC), MTC combined with FTC, and differentiated thyroid carcinoma (DTC) combined with anaplastic thyroid carcinoma (ATC). The components may display tightly interwoven, partially separated, or spatially independent patterns, leading to the formation of mixed tumors, composite tumors, or collision tumors. The underlying pathogenesis remains unclear, with major hypotheses including the incidental theory, microenvironmental alteration theory, and stem cell theory. Diagnosis relies on imaging studies, fine-needle aspiration or core needle biopsy combined with immunohistochemistry and genetic testing (e.g., BRAF, RET mutations), with postoperative pathology serving as the diagnostic gold standard. Treatment strategies should be guided by the most aggressive component. Surgery is the primary modality and is often combined with radioactive iodine therapy, thyroid hormone suppression, targeted therapy, or immunotherapy. Tumors containing an MTC component require dynamic monitoring of serum calcitonin (Ctn) and carcinoembryonic antigen (CEA), whereas those with an ATC component often necessitate multimodal chemoradiotherapy and targeted therapy. Prognosis depends on the most malignant component: PTC-FTC subtypes generally have favorable outcomes, while those involving ATC or sarcomatous components are associated with extremely poor survival. Overall, mixed thyroid malignancies exhibit marked clinical heterogeneity, necessitating individualized management and long-term follow-up.

Oncocytic carcinoma of the thyroid (OCA) is a rare malignant tumor arising from thyroid follicular cells, characterized by cytoplasm enriched with abundant eosinophilic granules. It exhibits highly aggressive behavior and a high risk of recurrence, posing major challenges in clinical management. Research has demonstrated that mitochondrial DNA mutations and alterations in the MAPK pathway (RAS/RAF/MEK/ERK) are critically involved in tumorigenesis, while activation of the PI3K/AKT/mTOR pathway contributes to invasiveness and therapeutic resistance. Diagnosis primarily relies on fine-needle aspiration (FNA), but the heterogeneity of Hürthle cells limits its accuracy. The integration of molecular marker detection and imaging modalities can improve diagnostic reliability. Surgical resection remains the cornerstone of treatment, with total thyroidectomy recommended in cases of large tumors or lymph node metastasis. The efficacy of radioactive iodine (RAI) therapy is limited due to poor iodine uptake. In recent years, multikinase inhibitors (MKIs) and immune checkpoint inhibitors have shown therapeutic potential in advanced or recurrent cases. Prognosis is closely correlated with tumor size, lymph node involvement, and vascular invasion, necessitating long-term surveillance with serum thyroglobulin measurement and imaging follow-up. Multidisciplinary team (MDT) management plays an essential role in optimizing individualized treatment strategies. Overall, diagnostic and therapeutic approaches for OCA are advancing toward precision and integration, with molecular studies and emerging targeted therapies offering new opportunities to improve survival and quality of life.

Intrathyroid thymic carcinoma (ITTC) is an extremely rare malignant tumor arising from ectopic thymic tissue within the thyroid, with histological features resembling thymic epithelial tumors. It predominantly affects middle-aged and elderly individuals and typically presents as a painless cervical mass. Imaging lacks specificity, and ITTC is often misdiagnosed as primary thyroid squamous cell carcinoma or anaplastic carcinoma. Definitive diagnosis relies on pathology and immunophenotyping; positivity for CD5, CD117, and p63/p40, along with negativity for thyroglobulin (Tg) and thyroid transcription factor-1 (TTF-1), provides critical diagnostic value. The Ki-67 index, combined with the extent of necrosis and mitotic activity, can be used for risk assessment. Surgical resection with R0 margins remains the cornerstone of treatment, with routine central lymph node dissection recommended, while lateral neck dissection is reserved for cases with confirmed metastasis or high-risk factors. Postoperative radiotherapy may improve local control in high-risk patients. In recurrent or progressive cases, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have shown potential efficacy in patients with high expression, and targeted therapies are under investigation. Overall, the precise management of ITTC requires integration of morphology, immunohistochemistry, and molecular data, with individualized treatment planning formulated by a multidisciplinary team (MDT). Future multicenter prospective studies are needed to clarify the optimal indications for radiotherapy, immunotherapy, and targeted therapy, and to validate the clinical value of molecular subtyping and dynamic monitoring.

Primary thyroid lymphoma (PTL) is a rare form of extranodal lymphoma of the thyroid, accounting for 1%-5% of thyroid malignancies. It occurs predominantly in middle-aged and elderly women, with more than 80% of cases associated with Hashimoto’s thyroiditis. Patients typically present with a rapidly enlarging thyroid mass within a short period, often accompanied by compressive symptoms or B symptoms. Its clinical manifestations resemble those of anaplastic thyroid carcinoma or thyroiditis, leading to frequent misdiagnosis. Histologically, diffuse large B-cell lymphoma (DLBCL) is the most common subtype, followed by mucosa-associated lymphoid tissue (MALT) lymphoma, with significant differences in aggressiveness and prognosis between subtypes. Ultrasound-guided core needle biopsy combined with immunohistochemistry (e.g., CD20, Ki-67) and fluorescence in situ hybridization (FISH) for MYC, BCL2, and BCL6 constitutes the diagnostic gold standard. Treatment strategies are based on pathological subtype and disease stage. DLBCL is usually managed with R-CHOP chemotherapy combined with radiotherapy, while localized MALT lymphoma confined to the thyroid may be cured with definitive radiotherapy. Surgery is mainly reserved for urgent airway management or diagnostically challenging cases. Prognostic assessment relies on the International Prognostic Index (IPI), serum lactate dehydrogenase (LDH) levels, and positron emission tomography-computed tomography (PET/CT). Advanced age, DLBCL subtype, high IPI score, and TP53 mutation are adverse prognostic factors. Overall, PTL is highly sensitive to radiotherapy and chemotherapy; early-stage MALT lymphoma has an excellent prognosis, whereas aggressive DLBCL carries a poorer outcome. Multidisciplinary collaboration is essential to improve therapeutic efficacy and enhance patient survival and quality of life.

Sporadic medullary thyroid carcinoma (MTC) accounts for approximately 75%~80% of all MTC cases and frequently presents with lymph node or distant metastases at an early stage, leading to considerable variability in prognosis. Genetic studies have shown that about 60% of cases harbor RET somatic mutations, with the RET M918T mutation being the most common, indicating strong tumor aggressiveness; RAS mutations are generally mutually exclusive with RET alterations. Serum calcitonin (Ctn) is the most sensitive and specific biomarker, and preoperative levels can predict the risk of lymph node metastasis. The doubling times of Ctn and carcinoembryonic antigen (CEA) serve as key prognostic indicators. Ultrasonography combined with CT or MRI enhances the detection of metastatic lesions, while 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and 68Ga-somatostatin receptor imaging are valuable for recurrence surveillance. Surgery remains the cornerstone of treatment, with most guidelines recommending total thyroidectomy with central lymph node dissection. In carefully selected low-risk patients, unilateral lobectomy may be considered, while lateral neck dissection should be individualized. For advanced or unresectable cases, targeted therapy has become an important option, with RET inhibitors demonstrating superior efficacy. Prognostic evaluation should integrate genetic mutation status and dynamic changes in Ctn and CEA to guide individualized follow-up and treatment. In the future, precision medicine strategies based on molecular features are expected to improve survival outcomes and quality of life in patients with sporadic MTC.