Background: Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. Methods: This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan–Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. Results: A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV). BRAF mutation was present in 41%, TERT in 30%, RAS in 19%, TP53 in 10%, and RET in 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p < 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity. TP53 mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%, p = 0.03), and RAS mutation was negatively associated with PD-L1 expression (8.1% vs. 24.2% p = 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p = 0.002). Conclusions: PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC.

Background: The incidence of thyroid cancer in women is 3–4-fold higher than in men. To characterize sex-specific molecular alterations in thyroid cancer, we examined the expression of sex-biased genes in normal thyroids and thyroid tumors. Methods: Ingenuity pathways analysis was used to define sex-biased gene networks using data from the Cancer Genome Atlas (TCGA). Confirmatory studies were performed through the analysis of histone lysine demethylases (KDMs) expression by real-time PCR and immunostaining. Results: In normal thyroids, 44 sex-biased genes were comparatively upregulated in male and 28 in female patients. The expressions of 37/72 (51%) sex-biased genes were affected in cancer tissues compared with normal thyroids. Gene network analyses revealed sex-specific patterns in the expressions of KDM5C, KDM5D, and KDM6A. In confirmatory studies, KDM5D mRNA and protein were detected only in males, whereas KDM5C and KDM6A were detected in samples from male and female patients. Nuclear staining with anti-KDMs was found in normal thyroids, but a loss of nuclear expression with a concomitant gain of cytoplasmic staining was observed in cancer tissues. Conclusions: Normal thyroids have a sex-specific molecular signature, and the development of thyroid cancer is associated with a differential expression of sex-biased genes. The sex-specific expression of KDMs, coupled with cancer-related alterations in their intracellular localization, may contribute to mechanisms underlying sex differences in thyroid tumorigenesis.

Background: Thyroid cancer (TC) exhibits sex-based disparities in incidence, progression, and outcomes, with women of reproductive age exhibiting more favorable prognoses than men. This study investigates sex differences in immune cell dynamics within peripheral blood and the tumor microenvironment (TME) in TC. Methods: We performed a prospective study of 27 patients (16 females/11 males) undergoing thyroidectomy for TC or high-risk thyroid nodules. Tissue and blood were collected for immune cell analysis using flow cytometry and spatial transcriptomics. Differential-expression of immune-related genes was assessed with DESeq2, and immune cell frequencies were compared between sexes. Results: Males showed higher frequencies of dividing natural killer (NK) cells (9.67 vs 1.29, P < .001) and T-cell immunoreceptor with Ig and ITIM domains (Tigit) + CD8 T cells (2.34 vs 0.87, P = .04) in the TME. In contrast, females tended to have higher frequencies of mature NK (2.5 vs 1.08, P = .07) and CD8 T-cells (0.95 vs 0.68, P = .09). Spatial transcriptomics revealed that men had reduced expression of HLA-DRB (P = .001, antigen presentation) in both surrounding normal tissue and the tumor border and a trend for increased LAG3 (P = .09) in normal tissue compared to women. In the core of the tumor, we observed increased IFNAR1 (P = .04), CD68 (P = .04), and B2M (P = .02) in men vs women. Conclusion: Our study reveals significant sex-based differences in immune cell composition and gene expression within the TME of TC. Males exhibit a more immunosuppressive profile, with higher levels of inhibitory immune markers and lower frequencies of functional NK cells. Our findings highlight the importance of incorporating sex-specific immune profiles into development of targeted therapies for advanced TC.

Context: Supraphysiologic T4 doses are used in intermediate- and high-risk patients with differentiated thyroid cancer (IR/HR-DTC) to suppress tumor progression by TSH. However, preclinical data suggest that T4 can also act as a growth stimulus for cancer, but there is no clinical evidence supporting this claim. Objective: We analyzed the association between free T4 (FT4) and progression-free survival (PFS) in patients with IR/HR-DTC. Methods: This longitudinal cohort study, approved by multi-institutional review board, included patients with IR/HR-DTC treated uniformly with total thyroidectomy, radioiodine, and TSH suppression therapy, with at least 3 TSH and FT4 values available. Association between FT4 and PFS at landmarks 6, 12, and 18 months was assessed by Kaplan-Meier survival curves, whereas competing risks were assessed through Cox proportional hazards model. Results: From 739 screened patients, 382 met the inclusion criteria and were characterized by a median age of 46 (34-59) years, 64.1% women, and treated with a median radioiodine dosage of 159 (110-410) mCi. During follow up of 7.1 (3.4-12.7) years, 34.6% experienced disease progression. Elevated FT4, observed in 29.3% of patients, was not associated with worse PFS (hazard ratio [HR], 0.9; CI, 0.54-1.5; P = .69), whereas age (HR, 1.02; CI, 1.004-1.04; P = .01), tumor size (HR, 1.15; CI, 1.04-1.28; P = .01) and metastases to the lateral neck lymph nodes (HR, 2.9; CI, 1.7-4.74; P < .001), bones (HR, 4.87; CI, 1.79-13.3; P = .002), and brain (HR, 5.56; CI; 2.54-12.2; P < .001) were associated with shorter PFS. Conclusion: Contrary to preclinical evidence, elevated FT4 levels do not affect PFS in patients with IR/HR-DTC.

22q11.2 deletion syndrome (22.q11.2 DS) is a genetic syndrome resulting from a microdeletion on chromosome 22. It has a diverse array of manifestations, and most cases are diagnosed early in childhood. We present the case of a 38-year-old female born in a developing country who presented to our clinic to establish care for a history of primary hypothyroidism. She was clinically and biochemically euthyroid on thyroid supplementation. She was also noted to have hypocalcemia in the setting of low PTH, for which the patient was previously prescribed calcitriol. Given a history of cleft palate, abnormal facial features, mild recurrent sinopulmonary infections, and her endocrine history (including short stature with height in the 6th percentile), genetic testing was obtained. She was diagnosed with a heterozygous whole gene deletion of the TBX1 gene. Additional genetic evaluation demonstrated a 2.6-Mb microdeleted segment of the 22a11.2 region encompassing 62 genes. The patient was referred to cardiology for evaluation of cardiac involvement given a history of tachyarrhythmia. This case highlights challenges in diagnosis and the implications of a delayed diagnosis of 22.q11.2 DS.