Thyroid Health: New Diagnostics for Better Treatment

This month we explore how molecular diagnostics and imaging can refine risk stratification and personalise therapeutic strategies in thyroid disease. A meta-analysis of 18 studies highlights Programmed Death-Ligand 1 (PD-L1) as a potential prognostic biomarker of reduced disease-free survival in thyroid carcinoma. Molecular imaging with radioiodine isotopes and PET/CT scans has become crucial in assessing disease aggressiveness and guiding treatment decisions. A multicentre study evaluating thyroid fine-needle aspirations using a 7-gene molecular assay has shown that BRAF V600E and BRAF-like mutations have high positive predictive values for malignancy, while RAS-like alterations show moderate predictive value in indeterminate cases.

Concerning treatment, expert groups recommend optimising biomarker testing strategies for various thyroid cancer types. A large-scale analysis of thyroid function tests has refined reference intervals for TSH, free T4 and free T3, aiming for a more evidence-based interpretation of these tests. Finally, the development of a validated ELISA test for thyroglobulin (Tg) determination on dried blood spots (DBS) from newborns offers a promising avenue for integrating iodine status monitoring into routine newborn screening programmes. In thyroid cancer treatment, precision medicine approaches help prevent overtreatment in low-risk cases while ensuring adequate intervention for high-risk disease. Selective RET inhibitors and combined BRAF/MEK inhibition have shown efficacy in specific thyroid cancer subtypes, while immunotherapeutic approaches continue to be investigated.

These therapeutic advances underscore the continued evolution in thyroid disease management, emphasising personalised approaches to optimise individual patient outcomes.

Recent key publications

1) Programmed Death-Ligand 1 (PD-L1) Is a Potential Biomarker of Disease-Free Survival in Papillary Thyroid Carcinoma: a Systematic Review and Meta-Analysis of PD-L1 Immunoexpression in Follicular Epithelial Derived Thyroid Carcinoma. Endocr Pathol 2020; 31:291-300. Girolami I, Pantanowitz L, Mete O et al.

Link to full article: http://www.ncbi.nlm.nih.gov/pubmed/?term=32468210  

A systematic review and meta-analysis of 18 studies revealed that programmed death-ligand 1 (PD-L1) expression significantly correlates with reduced disease-free survival in thyroid carcinoma (RR 1.63, CI 1.04-2.56) and shows significant associations with chronic lymphocytic thyroiditis and BRAF V600E mutations in papillary thyroid carcinomas, though no correlation was found with overall survival. The findings, particularly robust in papillary thyroid carcinoma compared to dedifferentiated variants, suggest PD-L1 immunohistochemistry could serve as a valuable prognostic biomarker for disease recurrence in papillary thyroid carcinoma patients, with evidence quality ranging from low to high across the analysed studies.

2) Theranostics of Thyroid Cancer. Semin Nucl Med 2024; 54:470-487. Giovanella L, Tuncel M, Aghaee A et al.

Link to full article: http://www.ncbi.nlm.nih.gov/pubmed/?term=38503602   

Molecular imaging techniques, encompassing radioiodine isotopes for differentiated thyroid carcinoma risk stratification, [18F]FDG PET/CT for aggressive variants and metastatic disease, and [18F]FDOPA PET/CT for medullary thyroid cancer, have become fundamental in refining pathology-based classification systems and directing individualised therapeutic approaches. The integration of these imaging modalities with emerging therapeutic strategies, including redifferentiation protocols for radioiodine-refractory disease and peptide receptor theranostics, has demonstrated significant potential in improving outcomes for patients with advanced differentiated and medullary thyroid cancers.

3) Evaluation of BRAF, RAS, RET/PTC, and PAX8/PPARG alterations in different Bethesda diagnostic categories: A multicentric prospective study on the validity of the 7-gene panel test in 1172 thyroid FNAs deriving from different hospitals in South Italy. Cancer Cytopathol 2020; 128:107-118. Bellevicine C, Migliatico I, Sgariglia R et al.

Link to full article: http://www.ncbi.nlm.nih.gov/pubmed/?term=31821746 

A multicentre prospective study evaluating 1172 thyroid fine-needle aspirations using a 7-gene molecular assay demonstrated that BRAF V600E and BRAF-like mutations had a high positive predictive value (80%) for malignancy, while RAS-like alterations showed moderate predictive value (32.4%) in cases of atypia of undetermined significance. The study revealed that mutation-positive rates correlated with malignancy risk across diagnostic categories, suggesting that molecular testing can enhance preoperative risk stratification of indeterminate thyroid nodules, particularly when considering the distinct biological implications of different mutation types.

4) Consensus Statement: Recommendations on Actionable Biomarker Testing for Thyroid Cancer Management. Mete O, Boucher A, Schrader KA et al.  Endocr Pathol 2024; 35:293-308.

Link to full article: http://www.ncbi.nlm.nih.gov/pubmed/?term=39579327

Contemporary thyroid cancer management has evolved to incorporate comprehensive biomarker testing algorithms derived from both germline and somatic analyses, which guide therapeutic decision-making through a multidisciplinary approach despite existing disparities in testing implementation. Based on extensive literature review and international guidelines, expert panels have formulated therapy-agnostic recommendations to optimise biomarker testing strategies across medullary, non-anaplastic follicular cell-derived and anaplastic thyroid cancers, while acknowledging practical constraints and jurisdictional limitations.

5) Multidisciplinary approach to redefining thyroid hormone reference intervals with big data analysis. Clin Biochem 2024; 133-134:110835. Lewis CW, Raizman JE, Higgins V et al.

Link to full article: http://www.ncbi.nlm.nih.gov/pubmed/?term=39442856

Through big data analysis of over one million thyroid function test results from Alberta, Canada, researchers established refined reference intervals for TSH (0.20-6.50 mIU/L for ≥1 year), free T4, and free T3, utilising multiple statistical models and expert review while excluding confounding factors such as specialist care, inpatient status, and thyroid-related comorbidities. The implementation of these optimised reference intervals, particularly the widened TSH upper limit of 6.50 mIU/L, along with an updated TSH reflex algorithm that triggers free T4 testing only at TSH <0.1 mIU/L, aims to enhance the clinical interpretation and utilisation of thyroid function tests through a more evidence-based approach.

6) Development of an enzyme-linked immunosorbent assay for newborns dried blood spot thyroglobulin. Eur Thyroid J. 2024; 13. Fuentes Peña C, Opazo MC, Méndez L et al.

Link to full article: http://www.ncbi.nlm.nih.gov/pubmed/?term=39485728

A validated enzyme-linked immunosorbent assay (ELISA) for thyroglobulin (Tg) determination on dried blood spots (DBS) from newborns demonstrated robust analytical performance with a detection limit of 2.4 µg/L, quantification limit of 5.8 µg/L, and good correlation with plasma Tg measurements (R = 0.88), while showing stability for 12 months at both -20ºC and 4ºC, though notably, DBS-Tg concentrations were found to decrease with increasing haematocrit values. The successful validation of this DBS-Tg assay offers an opportunity to integrate iodine status monitoring into routine newborn screening programmes for inherited metabolic diseases, with the caveat that haematocrit effects should be considered when comparing populations with different prevalence of anaemia.