C. ChristoferChristofer Juhlin

Radioiodine therapy of differentiated thyroid cancer is effective and possibly curative in patients with metastatic lesions that retain iodine avidity. However, in clinical practice, iodine avidity in any metastatic site is usually unknown at the point of initial treatment. Avidity prediction could enable more tailored initial radioiodine treatment. This work aimed to establish the best predictive factors for iodine avidity and subsequent treatment response. Thirty-one patients with metastatic or recurrent thyroid cancer sites in which iodine avidity could be assessed by image-based analysis were included. In tissue specimens from primary surgery, immunohistochemical expression of thyroglobulin (Tg), thyroid peroxidase (TPO), sodium-iodide symporter (NIS), and Ki67 and mutational status of BRAF, RAS, and the TERT promoter were analyzed. Biochemical and structural responses were assessed by serum Tg response and radiological evaluation. High-risk histology (widely invasive follicular, tall cell subtype papillary, differentiated high-grade, or poorly differentiated thyroid carcinoma) combined with the expression of TPO, Tg, and cytoplasmic NIS performed well in predicting treatment response and iodine avidity. Approximately half of the variation between patients was explained by those variables, outperforming pT stage and mutational status. TPO and Tg expression were the largest contributors to prediction modeling. Radioiodine treatment response and iodine avidity in thyroid cancer can be predicted from histopathological analysis of the primary tumor. High-risk histology and the expression of TPO, Tg, and NIS were robust and informative predictors. This may be used to adapt treatment strategy in adjuvant and metastatic therapy settings.

Background: In primary aldosteronism (PA), the HISTALDO framework classifies aldosterone‐producing lesions as ‘classical’ (solitary nodule) or ‘non‐classical’ (multinodular or diffuse) based on CYP11B2 immunohistochemistry, but interpretation is complicated by frequent micronodules, even in patients without PA. The CYP11B2 size ratio (B2R), a quantitative measure of size disproportion between CYP11B2‐positive nodules, offers an objective way to assess lesion architecture and has shown value in predicting cure versus relapse. In this study, diagnostic classification was intentionally B2R‐guided, generating a modified HISTALDO B2R system in clinical routine. Objective: Prospective evaluation of the prognostic value of B2R‐guided classification in routine pathology and assessment of postoperative outcomes across B2R‐defined subgroups. Methods: Specimens of 70 adrenalectomies underwent multisection CYP11B2 staining; 61 patients had at least 6 months of follow‐up (mean age 53 years, 54% were females). All had adrenal vein sampling and confirmatory testing before unilateral laparoscopic adrenalectomy. Imaging showed unilateral findings in 51%, bilateral in 8% and no detectable nodules in 41%. A B2R ≥8.1 defined classical lesions; B2R < 8.1 non‐classical. Outcomes at 6–12 months were assessed using PASO criteria, which classify biochemical and clinical success as absent, partial or complete. Results: Biochemical cure was achieved in 95% of patients with classical B2R morphology, compared with 40% of those with non‐classical B2R morphology ( p < 0.001). Complete clinical success was also significantly more frequent in the classical B2R group than in the non‐classical group (57% versus 25%, p = 0.0235). Medication‐based measures supported these findings: patients with classic histology showed a trend towards reductions in antihypertensive medication expressed as defined daily doses (DDD) (median ΔDDD 2.83 versus 2.00, p = 0.1254), and a significantly greater reduction in potassium supplementation (median ΔDDD 1.25 versus 0.00, p < 0.001) compared to those with non‐classical histology. Conclusions: B2R‐guided HISTALDO yields biologically distinct subgroups with clear prognostic separation. Earlier work using the original HISTALDO definition reported ~40%–45% persistent biochemical aldosteronism in non‐classical cases. Our findings reproduce this poor non‐classical outcome profile in a larger and more consistently defined B2R‐classified cohort. Importantly, incorporating B2R reduces misclassification of tumours as non‐classical when background nodularity is present despite a dominant CYP11B2‐positive lesion.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from thyroid parafollicular C‐cells, accounting for 1–2% of all thyroid cancers. An exceedingly rare manifestation of MTC is ectopic adrenocorticotropic hormone (ACTH) production, causing Cushing’s syndrome and complicating management. This report presents two cases of MTC with ectopic ACTH production, highlighting diagnostic challenges, therapeutic strategies, and clinical outcomes. A comprehensive literature review on this rare paraneoplastic syndrome is included and supplements the case findings. Case 1 involves a 49‐year‐old man presenting with abdominal pain, weight loss, and pulmonary nodules, diagnosed with MTC and ectopic ACTH‐related Cushing’s syndrome. Surgical resection and targeted therapy with selpercatinib improved cortisol levels but were complicated by adverse drug reactions. Case 2 details a 65‐year‐old woman with severe hypercortisolism and locally advanced MTC. Selpercatinib successfully reduced hormone levels and achieved partial tumor regression. Both cases underscore the critical role of tyrosine kinase inhibitors (TKIs) in controlling tumor progression, and paraneoplastic hormone production is exemplified in both cases, as treatment initiation was followed by a biochemical response with declining levels of ACTH, cortisol, and calcitonin. Ectopic ACTH production in MTC is a rare but clinically significant entity associated with aggressive disease. Early recognition, comprehensive biochemical and imaging evaluations, and a multidisciplinary approach are pivotal for optimal management. The advent of targeted therapies, such as selpercatinib, has transformed the therapeutic landscape, offering improved control of both tumor burden and hormone excess. This report highlights the importance of integrating genomic insights and precision medicine in addressing these complex cases.

Iodine metabolism has a central role in thyroid physiology and thyroid cancer biology, shaping both tumour behaviour and therapeutic strategies. Within the past 20 years, advancements in molecular research and targeted therapies have transformed the understanding of iodine metabolism in thyroid cancer and subsequently changed clinical management. In differentiated thyroid carcinomas, the ability of tumour cells to concentrate iodide provides the biological foundation of radioactive iodine treatment. However, loss of iodide-handling machinery function drives refractoriness in advanced disease, posing a major clinical challenge. Molecular genetics has now been integrated into routine clinical practice and genetically guided strategies to restore iodine uptake in previously non-avid lesions have emerged. This Review synthesizes these breakthroughs across molecular science, pathology, physics and clinical practice. We describe emerging predictive markers of radioiodine-refractory disease and summarize the current state of knowledge on iodide-handling mechanisms, their dysregulation in thyroid tumourigenesis and therapeutic advances made in the past 15 years aimed at redifferentiation. By bridging molecular insights with translational and clinical perspectives, we aim to highlight evolving paradigms that promise to refine patient stratification and improve outcomes in differentiated thyroid carcinoma.

Supplemental Table 1: Patient data from ATC IHC samples

Supplemental Figure 2: Representative HPLC-SEC chromatograms of UU-40 and DOTA-UU-40 and SPR sensorgrams of CD44v6-binding. A. HPLC evaluation of samples UU-40 and DOTA-UU-40 stored at -20C or -80C for 23 days. B. SPR sensorgrams of UU-40 (top row) and DOTA-UU-40 (bottom row) to CD44iso4-Fc (naturally occurring v6-positive CD44, Fc-fused) and human v6-peptide after storage at either 4C, -20C or 80C for 23 days. Affinity to the Fc-fused CD44v6 iso4-protein should be regarded as apparent affinity due to influence from avidity during measurements.

Supplemental Figure 3: CD44v6 antigen expression levels of BHT-101 and ACT-1. A. In vitro specificity of 125I- and 177Lu-UU-40 with/without 100-fold molar excess (block) of unlabeled UU-40 on BHT-101 cells. B. In vitro specificity of 125I- and 177Lu-UU-40 with/without 100-fold molar excess (block) of unlabeled UU-40 on ACT-1 cells. C. IHC staining of CD44v6 in BHT-101 xenografts. D. IHC staining of CD44v6 in ACT-1 xenografts. Unpaired t-tests assessed the level of significance between blocked and unblocked wells of both radioconjugates on both cell lines. P < 0.0001 (****), p < 0.001 (***).

Supplemental Figure 1: Representative images of IHC-stainings for CD44v6 from tumors from ATC patients. Images were obtained by high resolution microscope using 400x magnification. No image-adjustments have been made. Case no T1-T39 are cross-linked with data found in Supplemental Table 1.