Thyroid cancer is the most common endocrine malignancy. Recent developments in molecular biological techniques have led to a better understanding of the pathogenesis and clinical behavior of thyroid neoplasms. This has culminated in the updating of thyroid tumor classification, including the re-categorization of existing and introduction of new entities. In this review, we discuss various molecular biomarkers possessing diagnostic, prognostic, predictive and therapeutic roles in thyroid cancer. A comprehensive account of epigenetic dysregulation, including DNA methylation, the function of various microRNAs and long non-coding RNAs, germline mutations determining familial occurrence of medullary and non-medullary thyroid carcinoma, and single nucleotide polymorphisms predisposed to thyroid tumorigenesis has been provided. In addition to novel immunohistochemical markers, including those for neuroendocrine differentiation, and next-generation immunohistochemistry (BRAF V600E, RAS, TRK, and ALK), the relevance of well-established markers, such as Ki-67, in current clinical practice has also been discussed. A tumor microenvironment (PD-L1, CD markers) and its influence in predicting responses to immunotherapy in thyroid cancer and the expanding arena of techniques, including liquid biopsy based on circulating nucleic acids and plasma-derived exosomes as a non-invasive technique for patient management, are also summarized.

Background: A theranostic probe for accurate staging and treatment is crucial for the management of medullary thyroid cancers (MTCs). The abundance of stroma in most of thyroid cancers, including MTC, opens new avenues for selecting cancer-associated fibroblasts (CAFs) as new molecular imaging and therapeutic targets. [ ⁶⁸ Ga]Ga-labeled fibroblast activation protein inhibitor (FAPi) molecules have gained importance as alternative molecular imaging agents in the imaging of thyroid cancers. The purpose of this study was to compare the detection efficiency of primary and metastatic lesions of MTCs between [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi and [ ⁶⁸ Ga]Ga-DOTANOC positron emission tomography (PET) radiotracers. Materials and Methods: In this retrospective study, [ ⁶⁸ Ga]Ga-DOTANOC and [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi PET/CT (computed tomography) images were compared using patient-based and lesion-based analysis in patients with MTC for follow-up assessment. The quantitative assessment included comparing standardized uptake values corrected for lean body mass (SULpeak) and tumor-to-background ratios (TBR). The findings on both scans were validated with the morphological findings of the diagnostic CT. Results: Twenty-seven patients (21 males and 6 females) with a mean age of 42.4 ± 13.2 years (range 14–66 years) were included in the study. [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi had similar sensitivities as that of [ ⁶⁸ Ga]Ga-DOTANOC PET/CT for detecting primary tumors (100% [18 of 18] vs. 94.4% [17 of 18], p = 0.979) involved lymph nodes (98.3% [118 of 120] vs. 95% [114 of 120], p = 0.288), and brain metastases (100%). [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi demonstrated significantly higher sensitivities than [ ⁶⁸ Ga]Ga-DOTANOC PET/CT for detecting lung nodules (93.5% [87 of 93] vs. 68.9% [64 of 93], p < 0.0001), liver (100% [105 of 105] vs. 46.4% [49 of 105], p < 0.0001), bone (92.4% [110 of 119] vs. 76.5% [91 of 119], p = 0.001), and pleural metastases 98.2% versus 0%. Higher uptake values and TBR values were reported with [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi compared with that of [ ⁶⁸ Ga]Ga-DOTANOC. Conclusion: [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi outperformed [ ⁶⁸ Ga]Ga-DOTANOC PET/CT in the detection of distant metastases with both patient-based and lesion-based analysis in MTCs.

Thyroid carcinomas (TC) are rare in the pediatric population; however, they constitute the most common endocrine malignancy. Despite some similarities with adult carcinomas, they have distinct clinical behavior and responses to therapy due to their unique pathology and molecular characteristics. The age cut-off used for defining the pediatric age group has been variable across different studies, and the universally accepted recommendations influence accurate interpretation of the available data. Moreover, factors such as radiation exposure and germline mutations have greater impact in children than in adults. Papillary TC is the most common and the most evaluated pediatric TC. Others, including follicular, poorly differentiated and medullary carcinomas, are rarer and have limited available literature. Most studies are from the West. Asian studies are primarily from Japan, with few from China, India, Saudi Arabia and Republic of Korea. This review provides a comprehensive account of the well-established and novel biomarkers in the field, including point mutations, fusions, miRNA, and thyroid differentiation genes. Familial and syndromic associations are also discussed. Current management guidelines for pediatric patients are largely derived from those for adults. An awareness of the molecular landscape is essential to acknowledge the uniqueness of these tumors and establish specific diagnostic and therapeutic guidelines.

Aim: The study aimed to analyze the long-term outcomes of [ ¹⁷⁷ Lu]Lu-DOTAGA.FAPi dimer therapy in individuals diagnosed with radioiodine-resistant (RAI-R) follicular cell-derived thyroid cancer. Materials and Methods: In this retrospective study, 73 patients with RAI-R follicular thyroid carcinoma who had undergone multiple lines of previous treatments were included. Following [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi positron emission tomography–computed tomography scan, among the 73 patients, 65 received [ ¹⁷⁷ Lu]Lu-DOTAGA.FAPi dimer monotherapy with a median activity of 5.5 GBq per cycle at 8-week intervals. The remaining eight patients underwent tandem [ ¹⁷⁷ Lu]Lu/[ ²²⁵ Ac]Ac-DOTAGA.FAPi dimer therapy, consisting of a median of two cycles of [ ¹⁷⁷ Lu]Lu-DOTAGA.FAPi dimer followed by one cycle of [ ²²⁵ Ac]Ac-DOTAGA.FAPi dimer, also at 8-week intervals. The primary endpoint included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included PERCIST criteria response assessment and safety assessment according to Common Terminology Criteria for Adverse Events (V5.0). Results: We enrolled 37 female and 36 male patients, with a mean age of 54.3 years (range: 27 − 80 years). The patients received a median cumulative activity of 22.2 GBq (range, 4 GBq–55.5 GBq) of [ ¹⁷⁷ Lu]Lu-DOTAGA-FAPi dimer over one to nine cycles, with a median of three cycles. Among 73 patients, 20 died and 16 deaths were due to thyroid cancer. Nineteen patients experienced disease progression, with an estimated median PFS of 29 months [CI 14–34 months]. The estimated median OS was 32 months [CI 21–40 months]. Four patients (5.4%) encountered grade III anemia, primarily linked to bone metastasis in three cases and neck tumor mass bleed in one. Grade III thrombocytopenia occurred in three patients (4%). No grade III renal or hepatotoxicity was observed. Conclusion: In this study, [ ¹⁷⁷ Lu]Lu-DOTAGA.FAPi dimer therapy showed promising safety and efficacy in aggressive, radioiodine-resistant thyroid cancer, achieving a median PFS and OS of 29 and 32 months, respectively, with manageable adverse events. Confirmation of our findings is needed from prospective clinical trials comparing [ ¹⁷⁷ Lu]Lu-DOTAGA.FAPi dimer therapy to other treatments.