Revolutionizing Thyroid Cancer Diagnosis: The Role of THADA-IGF2BP3 Fusions in Identifying Indolent Neoplasms

Dear Editor, The Bethesda System for reporting thyroid cytopathology stratifies thyroid lesions into six categories based on their fine needle aspiration cytology (FNAC) results. FNAs with intermediate scores are categorized as Bethesda III or IV and represent indeterminate lesions that have posed challenges to clinicians for years. With technological advancements in molecular testing of thyroid lesions, molecular information is increasingly used to determine phenotypes and aid in understanding the patients’ prognosis.[1] As data on molecular alterations are more readily accessible, recent studies have elucidated the role of particular gene mutations in thyroid tumorigenesis. One such alteration of interest is THADA-IGF2BP3 fusion. Hypothesized to be the prime driver of mutation in around 5% of malignant thyroid neoplasms, this gene alteration has been garnering significant academic scrutiny.[2] On that premise, we review the role of THADA-IGF2BP3 gene fusions in identifying indolent neoplasms and how this gene fusion has revolutionized thyroid cytology diagnosis. We also provide valuable insights into the relationship between THADA-IGF2BP3 fusions and thyroid tumor behavior. Zand et al.[3] investigated THADA-IGF2BP3 molecular fusions in relation to fine needle aspiration (FNA) categorization, surgical pathology diagnosis, and other molecular alterations detected by ThyroSeq genomic classifier (GC) testing. A total of 249 FNAC specimens that were diagnosed as Bethesda III or Bethesda IV by ThyroSeqV3 were included, and various parameters (patient demographics, FNA diagnosis, ThyroSeq V3 results, and surgical pathology follow-up) were analyzed. Notably, THADA-IGF2BP3 fusions were associated solely with the eight cases that showed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on surgical pathology follow-up. This finding of 100% association of THADA-IGF2BP3 alteration with NIFTP further corroborates the preexisting literary evidence that THADA-IGF2BP3 fusion indicates indolent behavior.[4] Additionally, the finding underscores how THADA-IGF2BP3 fusion could be developed as a molecular marker for detecting low-risk thyroid lesions. Moreover, this lays the groundwork for molecular diagnosis to play an even more important role in guiding the management protocol of patients with THADA-IGF2BP3 fusion. It could enable clinicians to make enlightened choices while tailoring a more targeted treatment plan, including determining the extent of surgery and the need for adjuvant radioactive therapy, maximizing the efficiency of the process. However, it is essential to address limitations and potential areas of further research. The study’s retrospective nature and small sample size reduce the generalizability of the results to a broader population with indeterminate thyroid lesions observed on FNA. As the concluding remarks of the article state, there is a need for multicentric studies with larger sample sizes and prospective data collection methods to establish a definite association between THADA-IGF2BP3 fusions and NIFTP. Additionally, while the study makes a histopathological analysis of every case, it cannot take into account any recurrences that may arise in the patients after the study’s conclusion. These limitations, however, in no way undermine the massively commendable results of the study. To strengthen the study, a deeper exploration of the biological mechanisms underlying the oncogenic potential of the THADA-IGF2BP3 fusion would be beneficial. Understanding the pathways involved could offer further insights into targeted therapeutic strategies. Gubbiotti et al.[4] conducted THADA-IGF2BP3 gene fusion detection via ThyroSeqV3® analysis in 34 thyroid FNA samples. They found that THADA-IGF2BP3 fusions can be seen in malignant, low-risk, and benign thyroid neoplasms, where malignant neoplasms show a lack of aggressive features. Therefore, such entities can be classified as the clinically low-risk type. Morariu et al.[5] in their study, tested 30 thyroid samples for THADA-IGF2BP3 fusion on n ThyroSeq v3 GC. They found that 77% of these fusion-positive thyroid nodules were thyroid malignancies requiring surgery, either papillary carcinoma or NIFTP. However, these malignancies were low-risk, predominantly encapsulated FVPTCs, and thus can likely be adequately treated with lobectomy.[5] In conclusion, all these studies represent a significant advancement in the field of cytopathology by increasing our understanding of the involvement of THADA-IGF2BP3 fusions in NIFTP. This opens up exciting avenues of research in the discipline of thyroid cytopathology. Despite the methodological constraints, the study’s findings can facilitate the development of personalized treatment plans beneficial for clinicians and patients. Continued research efforts in this regard are essential to tap into the potential of molecular diagnostics in the dynamic field of cancer care. Integrating THADA-IGF2BP3 fusion testing into existing molecular diagnostic panels, particularly for Bethesda category III and IV lesions, could enhance the accuracy of preoperative diagnosis. This would enable more tailored surgical management, potentially reducing the number of unnecessary surgeries for indeterminate thyroid nodules. Furthermore, incorporating this marker alongside established genetic markers for NIFTP, such as rat sarcoma mutations and other oncogenic fusions, could refine the diagnostic criteria and improve patient outcomes. Author contributions MM took part in manuscript drafting. Dr. GK was involved in conceptualization, manuscript drafting, editing and revision. Dr. BS, Dr. SG and Dr. SS were involved in the critical revision. Data availability statement The data that support the findings of this study are available on request from the corresponding author. The data is not publicly available due to privacy or ethical restrictions. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.