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Open research questions in Thyroid Cancer Diagnosis and Treatment

65 unresolved questions extracted from the limitations and future-work sections of 508 Thyroid Cancer Diagnosis and Treatment papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • This guideline establishes a standardized and integra- tive framework for the ultrasound-based management of thyroid tumors. It encompasses conventional imag- ing, refined TI-RADS stratification, advanced techniques such as contrast-enhanced ultrasound and elastography, and evidence-based recommendations for ultrasound- guided fine-needle aspiration biopsy. By harmoniz- ing imaging protocols and decision-making pathways, the guideline aims to enhance diagnostic consistency, optimize risk assessment, and promote precise clinical management. Wei et al. Holistic Integrative Oncology (2026) 5:51 Page 7 of 8 Looking ahead, the integration of artificial intelligence for automated nodule detection and characterization, the development of molecular and contrast-enhanced ultrasound biomarkers for noninvasive risk prediction, and the refinement of elastographic and fusion imaging techniques hold promise for further improving diag- nostic accuracy and personalizing therapeutic strategies [19–21]. The continuous evolution of these technologies, coupled with multi-institutional validation and guideline updates, will support more proactive, individualized, and minimally invasive approaches to thyroid nodule evalua- tion and care. These advances are expected to strengthen the role of ultrasound in thyroid tumor management and contribute to better patient outcomes. Authors’ contributions XW: Conceptualized and designed the study, led the literature retrieval and analysis, drafted the manuscript, critically reviewed the intellectual content, oversaw overall project management and coordination, critically reviewed the intellectual content, acquired funding, provided administrative, technical, or material support. AL, WW, XJ, JW, ML, WC, PL, QL, YW, JZ, JZ: Contributed to the conception and design of the study, critically reviewed the intellectual content, assisted in literature retrieval, provided valuable suggestions on the article structure, and contributed to multiple revisions and editing of the manuscript. All authors have read and approved the manuscript.

    CACA technical guidelines for ultrasound imaging diagnosis of thyroid tumors · 2026 · DOI

  • Future investigations will focus on elucidating the precise manner in which DLEU2 regulates ELAVL1 expression. Our experimental results confirmed that DLEU2 directly bound to ELAVL1 in the cytoplasm and enhanced its expres- sion; however, the precise underlying regulatory mecha- nism remains to be elucidated. However, there are no reports on whether DLEU2 influences the malignant phe- notype of PTC through interactions with RBPs.

    DLEU2 promotes the migration and invasion of papillary thyroid carcinoma cells through the ELAVL1/RCC2 axis · 2026 · DOI

  • Therefore, AUC, calibration performance, and clinical net benefit could not be evaluated in this version. Third, the statistical analysis of the current study was limited by the available data.

    Development and clinical validation of an artificial intelligence based model for thyroid nodule malignancy risk assessment using C-TIRADS guidelines · 2026 · DOI

  • Despite the availability of an international TG standard (certified reference material CRM-457), complete assay standardisation and interchangeability remain unachieved Camel-derived polyclonal anti-TG antibodies have been rarely explored in immunoradiometric assay (IRMA) formats.

    Analytical and Clinical Evaluation of a Camel Polyclonal Antibody-Based IRMA for Serum Thyroglobulin Measurement Compared with ECLIA in Thyroid Cancer Patients · 2026 · DOI

  • incorporating prospective designs, TIRADS classification, and molecular testing are recommended to further refine diagnostic accuracy and clinical decision-making in these populations.

    Prevalence and Diagnostic Assessment of Thyroid Nodules in a Rural District Hospital: Bethesda Classification and FNAB Correlations · 2026 · DOI

  • FNMTC comprises a genetically heterogeneous and underrecognized group of follicular-cell-derived neoplasms, most commonly presenting as multifocal PTC, and includes both syndromic forms associated with extra-thyroidal tumors and nonsyndromic forms in which thyroid carcinoma predominates.

    Recognizing Familial Thyroid Neoplasia: The Pathologist’s Role in Diagnosis and Management · 2026 · DOI

  • Nonetheless, high tracer uptake (exceeding the liver) in selected lesions might identify possible candidates for 177LuPSMA-617 therapy, warranting further research.

    A prospective, exploratory study of 18F-PSMA-1007 PET/CT in patients with medullary thyroid cancer · 2026 · DOI

  • Background Medullary thyroid carcinoma (MTC) carries a disproportionately high mortality among thyroid malignancies, and the risk is even greater once metastasis occurs; nevertheless, a dependable prognostic tool for lymph-node-positive MTC patients remains elusive.

    Machine-learning prediction of 3- and 5-year mortality in lymph-node-positive medullary thyroid carcinoma: a study based on the SEER database and external validation in a Chinese cohort · 2026 · DOI

  • CONCLUSION Anlotinib combined with albumin-bound paclitaxel, followed by anlotinib maintenance, may represent a promising salvage strategy for sorafenib-refractory RAIR-DTC, which warrants further investigation in larger prospective trials.

    Anlotinib plus albumin-bound paclitaxel induction-maintenance for sorafenib-refractory radioiodine-refractory differentiated thyroid cancer: A case report and review of literature · 2026 · DOI

  • This study has several limitations that should be considered when interpreting the findings. First, the search strategy was constrained by institutional access restrictions, which prevented searches of Scopus and Web of Science and may have reduced the overall comprehensiveness of the litera- ture search. Nevertheless, the databases that were searched were considered sufficient to provide a broad overview of the available evidence. In addition, the restriction to Eng- lish-language publications may have resulted in the exclu- sion of relevant studies from non-English-speaking regions, particularly given known geographical variation in thyroid cancer epidemiology. Several methodological limitations of the included stud- ies should also be acknowledged. Most studies were retro- spective cohort designs, which are inherently susceptible to selection bias, reliance on previously recorded and poten- tially incomplete data, and limited ability to control for con- founding variables. Furthermore, the absence of individual patient data limited the ability to perform more detailed sub- group analyses. Statistical heterogeneity was evident in several analyses, including TSH levels (I²=73%), hypoechogenicity (I²=91%), and irregular margins (I²=87%). Although subgroup or sen- sitivity analyses would have been informative in exploring potential sources of heterogeneity, these were not feasible for many variables because of the limited number of avail- able studies. This variability may partly be explained by differences in study design, patient populations, ultrasound definitions, and diagnostic thresholds across the included studies. Several pooled estimates were also derived from rela- tively small numbers of studies or participants, which may have reduced their precision. Some predictors were reported in only two or three studies, increasing the risk of unstable 1 3European Archives of Oto-Rhino-Laryngology estimates. This is reflected in the wide confidence intervals for certain associations, such as palpable lymphadenopathy (OR 7.73, 95% CI 3.03–19.75). Likewise, the large effect sizes observed for factors such as lymph node involvement and microcalcifications should be interpreted with caution, as they may partly reflect sparse data and small sample sizes pending confirmation in larger prospective studies.

    Predictors of thyroid cancer in paediatric patients with thyroid nodules: A systematic review and meta-analysis · 2026 · DOI

  • Although this case offers insightful information, it has certain drawbacks. Firstly, the results have limited generalizability because this is a retrospective single-case study. Large-scale prospective clinical trials are still needed to confirm the efficacy and safety of the sequential treatment approach (chemotherapy followed by anlotinib) outlined in the report. Secondly, due to the retrospective nature of this study, the data integrity is limited in some respects. The patient received treatment at multiple medical institutions, which prevented the acquisition of complete longitudinal data on serum Tg and TgAb levels. The quantitative characterization of the shift from remission to distant metastasis is limited by the lack of serial Tg/TgAb trends, which are crucial biomarkers for tracking recurrence in differentiated thyroid cancer. Thirdly, the clinical significance of the detected RET p.G849S variant remains classified as a VUS. Although its high abundance (46.72%) suggests a clonal event, functional validation or paired analysis with the primary tumor tissue was not performed, making it impossible to determine whether this variant represents a true driver mutation or a passen- ger event that emerged during metastasis. Lastly, even though the patient has achieved a long-lasting partial remission, the follow-up time is still relatively short. In order to evaluate the long-term viability of this therapeutic approach, longer-term observation is required to evaluate long-term progression-free survival, overall survival, and the potential emergence of acquired resistance to anlotinib. chemotherapy strategies through pharmacogenomic analysis, thereby guiding truly personalized treatment. This case also high- lights the need to constantly look for new targets in the field of precision oncology for thyroid cancer because some RAIR-DTC patients do not have operable driver mutations. Lastly, this case provided a real-world example of the 2025 ATA guidelines’ prin- ciple: TKIs should be started for progressive RAIR-DTC cases without operable mutations. New clinical evidence, the patient’s unique toxic history, and local guidelines should all be taken into consideration when modifying the treatment plan. Anlotinib was substituted for chemotherapy when treatment tolerance was low, leading to long-lasting PR.

    Papillary thyroid carcinoma with brain and lung metastases: a case report · 2026 · DOI

  • This means that the model was developed in a surgically selected population, and its predictive performance in a broader PTMC population, especially in low-risk patients under active surveillance, remains unclear, with the possibility of spectrum bias.

    A clinically practical machine learning nomogram for preoperative CLNM prediction in PTMC: tumor-capsule distance and D2–40 evidence · 2026 · DOI

  • Fourth, functional validation was limited to a single RAIR-high/ATC-like thyroid cancer cell line (CAL-62), so the current in vitro results should be viewed as proof-of-concept support rather than definitive evidence of generalisability across RAIR-like thyroid cancers.

    A RAIR–ATC transcriptional axis and multimodal drug-response modelling reveal class-level vulnerabilities in thyroid cancer · 2026 · DOI

  • should be acknowledged. All included studies were observational, precluding causal inference. Exposure misclassification was likely due to heterogeneous infertility definitions and limited information on infertility duration, etiology, and treatment history. Evidence of small-study effects was detected, although adjusted analyses sup- ported the robustness of the association. Finally, the limited number of prospective studies restricted our ability to assess temporality and dose–response relationships. While a stronger association between infertility and thyroid cancer risk was observed in men, this finding should be interpreted with caution due to the limited number of male-specific studies and the non-significant interaction test. Given the current evidence, it would be premature to draw definitive conclusions about the role of biological sex in this relationship. Additionally, male infertility may act as a marker for broader endocrine or genetic dysregulation (38), but the small number of studies and the potential for inflated precision estimates due to sparse data must be considered. Given the rising prevalence of infertility and the increasing incidence of thyroid cancer, clinicians should be aware of the possible increased thyroid cancer risk among infertile individuals, particularly among individuals with additional endocrine or auto- immune risk factors. Future research should prioritize large, well- designed prospective cohort studies with standardized infertility definitions, detailed characterization of infertility etiology, hor- monal and autoimmune profiling, and rigorous control for surveil- lance bias. Such studies are essential to clarify causality, identify high-risk subgroups, and disentangle the roles of infertility biology and fertility treatments in thyroid carcinogenesis. Both infertility and thyroid cancer have profound implications for patients’ quality of life, psychosocial well-being, and long-term survivorship (39, 40). While epidemiologic risk estimation is crucial, it is equally important to consider how these conditions affect individuals’ daily lives. Patient-reported outcomes (PROs) have emerged as essential tools in assessing the broader clinical significance of reproductive and oncologic conditions (41, 42). PROs provide valuable insights into the impact of disease and treatment on patients’ physical, emotional, and social well-being, offering a more comprehensive understanding of the burden these conditions impose. We recommend further investigation into the role of PROs in this context, as highlighted in recent studies, which underscores the importance of PROs in oncology clinical trials and healthcare decision-making (43). Future studies should consider incorporating PRO assessments to better contextualize the transla- tional relevance of infertility and thyroid cancer epidemiology.

    Association between infertility and thyroid cancer risk: a systematic review and meta-analysis · 2026 · DOI

  • terms of model generalization, computational efficiency, and applicability to diverse patient populations. Finally, Section V summarizes the this research, key suggesting paths future study and potential improvements to the methodology. insights and contributions of for in II. Materials and Methods The task of this study can be comprehensively divided into two main parts: model training and model evaluation. In the model training phase, as depicted in Fig. 1, we begin by collecting a diverse set of raw then meticulously ultrasound preprocessed to create a high-quality dataset. Each image is standardized and rescaled to a resolution of 640 × 640 pixels, with three color channels (R, G, and B). This standardization ensures uniformity across images, which are regions of the dataset, which is critical for effective model training. To increase the robustness of the dataset, we implement various data augmentation techniques. This involves systematically applying transformations such as flipping the images horizontally and vertically, rotating them by random angles, and cropping them to interest. These focus on specific augmentation strategies help to introduce variability in the training data, allowing the model to generalize better and perform accurately on unseen data. The model is then trained on this augmented dataset to minimize the loss function, which measures the difference between predicted outputs and actual labels. In the model evaluation phase, we scale the preprocessed ultrasound images appropriately before feeding them into the trained model. The model processes these images and generates multi-head detection results, which allow for the identification of multiple features or abnormalities within the images simultaneously. To further enhance the interpretability of the model's outputs, we apply various postprocessing techniques. While these techniques are pivotal for improving output clarity, a detailed discussion of these methods will not be covered in this paper. In the sections that follow, we will thoroughly discuss the essential steps of the proposed framework, highlighting techniques the methodologies and employed throughout the study. A. Patient's Data Preparation A well-balanced sample of benign and malignant nodules was collected before training the model to ensure reliable findings. The demographic and clinical characteristics of the study population are summarized in Table 1. The dataset comprises 105 benign nodules originating from 92 patients, including 60 women and 32 men, with an average age of 52.45±11.87 years. Conversely, the study also includes 105 malignant Fig. 1. Overview of the LabelMe-based data preparation pipeline and enhanced YOLOv8 object detection framework. Manuscript received 14 August 2025; Revised 2 December 2025; Accepted 20 March 2026; Available online 14 May 2026 Digital Object Identifier (DOI): https://doi.org/10.35882/jeeemi.v8i3.1137 Copyright © 2025 by the authors. This work is an open-access article and licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (CC BY-SA 4.0). 863 Journal of Electronics, Electromedical Engineering, and Medical Informatics Homepage: jeeemi.org; Vol. 8, No. 3, July 2026, pp: 861-877 e-ISSN: 2656-8632 nodules sourced from 90 patients, including 67 women and 23 men, with an average age of 49.72 ±10.95 years.

    Predicting the Severity of Thyroid Nodules with YOLOv8 and CA+LSR Architecture · 2026 · DOI

  • The molecular predictive biomarker testing consensus for advanced thyroid cancer (reference 28) suggests standardized TERT mutation testing protocols, but the paper does not establish optimal mutation detection thresholds or define whether variants in non-canonical promoter regions of TERT in papillary thyroid carcinoma should be included in clinical risk stratification.

    TERT promoter variants in risk stratification of Polish patients with papillary thyroid carcinoma · 2026 · DOI

  • The paper references frequency of TERT promoter mutations in 2,092 thyroid carcinoma patients (reference 23) but does not specify whether genotype-phenotype correlations were analyzed across different histological subtypes and TNM staging categories within papillary thyroid carcinoma.

    TERT promoter variants in risk stratification of Polish patients with papillary thyroid carcinoma · 2026 · DOI

  • Studies on TERT promoter mutations in papillary thyroid microcarcinomas (reference 25) are mentioned but their independent prognostic value and integration into risk stratification specifically for microcarcinoma subsets versus larger tumors has not been systematically compared.

    TERT promoter variants in risk stratification of Polish patients with papillary thyroid carcinoma · 2026 · DOI

  • The paper references dynamic risk stratification in thyroid cancer follow-up but does not specify prospective validation protocols integrating TERT promoter mutation testing into response-to-therapy assessment models for real-world clinical implementation.

    TERT promoter variants in risk stratification of Polish patients with papillary thyroid carcinoma · 2026 · DOI

  • While the paper discusses coexistence of TERT promoter mutations and BRAF V600E alterations in papillary thyroid carcinoma, the mechanistic relationship between these dual mutations and their synergistic effects on tumor aggressiveness and radioactive iodine refractoriness requires systematic investigation.

    TERT promoter variants in risk stratification of Polish patients with papillary thyroid carcinoma · 2026 · DOI

  • The study focuses on Polish patients with papillary thyroid carcinoma; validation of TERT promoter variant risk stratification models in ethnically diverse populations with different genetic backgrounds and TERT mutation prevalence patterns remains unexplored.

    TERT promoter variants in risk stratification of Polish patients with papillary thyroid carcinoma · 2026 · DOI

  • OBJECTIVES: Investigate the impact of daily occupational walking steps on the progression of papillary thyroid cancer (PTC), a topic hitherto underresearched.

    Occupational daily walking steps have inverse relationship with papillary thyroid cancer risk and progression: a retrospective analysis · 2024 · DOI

  • However, the etiology has not been clarified much, except for reasons such as age, a history of radiation to the neck region, and a previous history of PTC, which predispose to DTC.

    Relationship between Thyroid Stimulating Hormone Level and Aggressive Pathological Features of Papillary Thyroid Cancer · 2022 · DOI

  • The results of the multifactorial studies of the development of thyroid carcinogenesis testify the insufficient knowledge about the influence and significance of certain TC factors, which requires systematization in order to improve the oncoepidemic situation in the country.

    Modern view on the risk factors for malignant tumors of the thyroid gland: a systematic review · 2018 · DOI

  • Despite the notable increasing incidence of papillary thyroid microcarcinoma (PTMC), the optimal treatment of the patients with PTMC remains controversial.

    Surgical treatment in papillary thyroid microcarcinoma · 2018 · DOI

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65 open questions have been extracted from the limitations and future-work passages of 508 Thyroid Cancer Diagnosis and Treatment papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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