Search Results (220)

Thermal ablation (TA) is an increasingly adopted minimally invasive treatment for benign thyroid nodules. However, TA induces marked histological alterations that may simulate thyroid malignancy, creating significant diagnostic pitfalls for pathologists. The present study expands our previous institutional series and further characterizes the morphologic, immunohistochemical, and molecular features of thermally ablated thyroid nodules in order to refine the differential diagnosis with thyroid carcinoma. Fourteen surgically excised thyroid nodules previously treated with laser thermal ablation were retrospectively analyzed. Histopathological evaluation focused on architectural changes, nuclear atypia, capsule alterations, degenerative phenomena, and evidence of invasion. Immunohistochemical analysis included galectin-3 (Gal-3), HBME-1, BRAF V600E, p53, and Ki-67. In addition, molecular profiling for the principal thyroid cancer-related alterations, including BRAF, RAS family genes, TERT promoter mutations, PIK3CA alterations, and RET rearrangements, was performed using targeted next-generation sequencing. All nodules showed treatment-related reactive and degenerative changes, including fibrosis/sclerosis, subcapsular hemorrhage, focal oncocytic metaplasia, and architectural distortion. No true capsular or vascular invasion was identified. Immunohistochemically, all cases were negative for Gal-3 and BRAF V600E, while HBME-1 expression was absent or only focally weak. Ki-67 proliferative activity remained consistently low (<3%) in all cases. Molecular analyses did not identify pathogenic alterations involving BRAF, RAS, TERT promoter, PIK3CA, or RET genes in any case. Thermal ablation induces reproducible reactive and degenerative histologic alterations that may closely mimic follicular or papillary thyroid neoplasms. The absence of malignancy-associated immunohistochemical and molecular alterations strongly supports the benign nature of these lesions and highlights the importance of an integrated morphologic, immunohistochemical, and molecular diagnostic approach in challenging post-ablation specimens. Thermally ablated thyroid nodules may display significant pseudo-neoplastic changes that can lead to overdiagnosis of carcinoma. Awareness of these treatment-related alterations, combined with immunohistochemical and molecular profiling, represents a reliable strategy to distinguish reactive post-ablation changes from true thyroid malignancy and to avoid inappropriate clinical management. Full article

Background/Objectives: Preoperative differentiation among benign thyroid nodules, follicular variant papillary thyroid carcinoma (FV-PTC), and classical papillary thyroid carcinoma (C-PTC) remains clinically challenging. FV-PTC is particularly difficult to identify due to its substantial sonographic and cytological overlap with both benign nodules and other malignant subtypes, frequently resulting in overtreatment or delayed diagnosis. This study aimed to develop and validate an interpretable multimodal model for accurate three-class discrimination using routine ultrasound images, with a specific focus on improving the preoperative identification of FV-PTC. Methods: This retrospective study included 479 pathologically confirmed thyroid nodules from 462 patients. Conventional ultrasound features and radiomics features extracted from grayscale ultrasound and color Doppler flow imaging were used to construct three predictive models: a Conventional Ultrasound model (conventional ultrasound features only), a Radiomics model (radiomics features only), and an Integrated model (combined features). Each model was trained using four machine learning classifiers. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score. Model interpretability was assessed using SHapley Additive exPlanations (SHAP) analysis, and clinical usefulness was evaluated using decision curve analysis (DCA). Results: The support vector machine (SVM)-based Integrated Model achieved the best overall performance. In the independent testing cohort, the AUCs were 0.853 for FV-PTC, 0.882 for C-PTC and 0.928 for benign nodules. The Integrated Model showed the greatest improvement for FV-PTC, with a ΔAUC of 0.141 compared with the Conventional Ultrasound Model. SHAP (SHapley Additive exPlanations) analysis identified wavelet-HL_gldm_Dependence and wavelet-HH_glcm_InverseVariance as the two most important radiomics predictors in both the Radiomics Model and the Integrated Model, demonstrating robust cross-model stability and high discriminative power. Conclusions: The SVM-based Integrated Model demonstrated promising performance for three-class classification of thyroid nodules and enhanced the preoperative identification of FV-PTC. This approach may provide an interpretable and noninvasive decision-support tool for refining subtype-specific risk stratification and supporting individualized clinical management. Full article

Immune remodeling within the tumor microenvironment (TME) influences the progression and clinical outcome of uterine corpus endometrial carcinoma (UCEC), but the contribution of chemokine-related regulatory genes remains incompletely characterized. This study aimed to evaluate the prognostic relevance of CXCL13 and its association with immune microenvironmental features in UCEC using publicly available transcriptomic and single-cell datasets. RNA-sequencing profiles and clinical annotations from 589 UCEC cases in The Cancer Genome Atlas (TCGA) were analyzed to assess TME composition using ESTIMATE (Estimation of Stromal and Immune cells in MAlignant Tumours using Expression data) and CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts), followed by survival analysis, differential gene expression analysis, protein–protein interaction network construction, Cox regression, and gene set enrichment analysis. A public single-cell RNA-sequencing dataset from the Gene Expression Omnibus (GEO; GSE173682) was further used to infer the cellular sources of CXCL13. Elevated CXCL13 expression was associated with favorable overall survival and enrichment of immune-activation pathways. CIBERSORT-based analysis indicated that high CXCL13 expression correlated with increased estimated fractions of CD8⁺ T cells and plasma cells, together with transcriptional features related to tertiary lymphoid structure-associated immune activation, whereas several immunosuppressive cell populations showed lower estimated abundance. Single-cell analysis suggested that CXCL13 was mainly expressed by follicular helper T cells and exhausted CD8⁺ T cells. These findings indicate that CXCL13 may serve as a prognostic biomarker associated with an immune-active TME in UCEC. Further histological, spatial, and functional validation is warranted to confirm its mechanistic role and translational potential. Full article

Background: Preoperative diagnosis of medullary thyroid carcinoma (MTC) is clinically challenging due to sonographic overlap with other thyroid tumors. To address this, we aimed to develop a multi-vendor, multimodal radiomic framework for accurate MTC identification, comparing its diagnostic performance with that of experienced radiologists. Methods: This retrospective study included 467 pathologically confirmed thyroid nodules (94 MTCs, 373 non-MTCs) acquired across multiple ultrasound platforms. The dataset was randomly partitioned into training (80%) and internal testing (20%) sets. In total, 2250 radiomic features were extracted from grayscale and color Doppler images, followed by Z-score normalization to mitigate batch effects. A robust feature selection strategy (LASSO and recursive feature elimination) identified optimal signatures for developing machine learning classifiers (SVM, LR, RF). The optimal model was further validated on an independent, balanced cohort (n = 60; comprising 12 cases each of MTC, papillary carcinoma, follicular carcinoma, follicular adenoma, and nodular goiter) and compared with experienced radiologists across seven classification tasks. Results: The RF model achieved an AUC of 0.993 in distinguishing MTC from papillary carcinoma. The LR model showed an AUC of 0.991 for identifying MTC from all other nodules. In the independent validation cohort, the models maintained superior discriminatory ability, showing better diagnostic performance compared to the image interpretation by radiologists (AUC 0.993 vs. 0.488, p < 0.001). Conclusions: The proposed multi-vendor, multimodal radiomic system demonstrated good discriminative ability in the diagnosis and stratification of MTC. By integrating grayscale and Doppler ultrasound features while overcoming scanner variability, this model shows potential as a non-invasive adjunctive tool. Full article

Background/Objectives: Trichoblastoma is a benign follicular adnexal tumor that typically arises on the head and neck. Large variants at atypical locations pose considerable diagnostic challenges because their clinical presentation can be indistinguishable from malignant soft tissue neoplasms. Herein, we describe a case of trichoblastoma presenting as a large subcutaneous thigh mass that was correctly diagnosed by fine-needle aspiration cytology. Case Presentation: A 49-year-old male presented with a 7 cm, slowly enlarging, subcutaneous mass in the left thigh of 20 years’ duration. Magnetic resonance imaging raised the possibility of a low-grade sarcoma. Fine-needle aspiration cytology yielded cohesive clusters of basaloid cells with peripheral palisading, delicate spindle-shaped follicular stromal cells intimately admixed with the epithelial component, and orangeophilic keratinous material in the background. The absence of nuclear atypia, mitotic figures, and mucinous stroma supported a preoperative cytological diagnosis of a benign follicular germinative tumor consistent with trichoblastoma, thereby guiding conservative surgical excision. Histopathological examination confirmed the diagnosis. Immunohistochemistry revealed focally positive BerEP4, CD34-positive stroma, negative androgen receptor, and positive bcl-2, consistent with trichoblastoma and distinguishing the tumor from basal cell carcinoma. The patient remained recurrence-free 12 months after surgery. Conclusions: Careful assessment of characteristic cytomorphological features, particularly a dual population of basaloid epithelial cells with peripheral palisading and specialized follicular stromal cells, is vital for the accurate preoperative cytological characterization of trichoblastoma, even at atypical anatomical sites. Full article

Background: Thyroid cancer (TC) represents the most common endocrine malignancy worldwide, with incidence increasing rapidly across diverse geographic regions. However, population-based evidence from North Africa remains limited, and comprehensive longitudinal analyses examining sex-specific incidence patterns, histological subtypes, and trends in tumor extension are lacking in Tunisia. Aim: This study aimed to (i) quantify TC incidence trends by sex and age group, (ii) characterize histological subtype-specific temporal patterns and tumor extension at diagnosis in northern Tunisia between 2000 and 2018, and (iii) to address projections in incidence by sex until 2040. Methods: A retrospective, population-based registry study was conducted using data from the Northern Tunisia Cancer Registry (NTCR), covering 11 governorates with a population of 5,233,700 in 2018. All primary invasive TC cases diagnosed between 2000 and 2018 were included (n = 3639). Age-standardized incidence rates (ASIRs) were calculated using the WHO standard population. Temporal trends were assessed using Joinpoint regression to estimate average annual percentage change (AAPC) with 95% confidence intervals. Projections of TC incidence to 2040 were generated using Bayesian autoregressive age–period–cohort models. Results: TC incidence increased significantly between 2000 and 2018, with overall ASIR rising from 2.8 to 5.0 per 100,000 person-years (AAPC = 3.8%, p < 0.001). In males, ASIR increased from 0.9 to 2.4 (AAPC = 3.0%, p < 0.001), while in females it rose from 3.7 to 7.8 (AAPC = 4.3%, 95% CI: 3.0–5.7; p < 0.001). The increase was predominantly driven by papillary thyroid carcinoma (PTC) (AAPC = 6.4% in males; 5.8% in females; both p < 0.001), whereas follicular thyroid carcinoma (FTC) remained stable. Notably, the proportion of metastatic cases decreased significantly in females (AAPC = −7.2%, p = 0.033), and the proportion of regionally advanced disease decreased in males (AAPC = −5.0%, p = 0.034). Conclusions: This population-based study demonstrates a sustained rise in TC incidence in northern Tunisia, disproportionately affecting women and largely driven by papillary histology. The concurrent increase in TC incidence alongside a reduction in regional and metastatic extension at diagnosis occurred. These findings have important implications for cancer prevention and control, highlighting the need for risk-adapted screening strategies and rationalized diagnostic practices. Full article

Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignancy arising in the thyroid or neck, with an uncertain cellular origin that complicates both diagnosis and treatment. To better understand its molecular underpinnings and identify potential therapeutic avenues, we conducted integrated whole-exome and transcriptome sequencing on six CASTLE and six thymic carcinoma samples. Whole-exome sequencing (WES) was performed on all 12 samples, while RNA sequencing was successful for 1 CASTLE and 6 thymic carcinoma samples. Our analysis included somatic mutation profiling, mutational signature deconvolution, differential gene expression, and characterization of tumor microenvironment for the cases with available data, with comparisons to genomic data from other thyroid cancers. CASTLE tumors demonstrated a higher median tumor mutational burden than thymic carcinoma and lacked the common BRAF and RAS mutations typically found in thyroid cancers. They harbored alterations in genes such as TRHDE, cilia-associated genes (ANKS6, CFAP46, DNAH6), and Wnt signaling components (TRRAP, BCL9L), as well as mutational signatures suggestive of mismatch repair deficiency and oxidative damage. MSIsensor-pro analysis of the WES data provided support for the potential for mismatch repair deficiency in a subset of CASTLE samples. Exploratory transcriptomic analysis from a single CASTLE case showed downregulation of thyroid follicular markers and an “immune-hot”, lymphocyte-rich microenvironment, closely resembling that of thymic carcinoma. While these findings require validation in larger cohorts, they support a thymic origin for CASTLE and establish its molecular distinction from follicular-derived thyroid cancers. The immunogenic tumor landscape suggests that immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, may be a promising therapeutic strategy, alongside emerging targets for precision oncology. Full article

High-grade serous ovarian carcinoma (HGSC) is predominantly diagnosed at advanced stages with extensive peritoneal metastasis. A pivotal early event in HGSC development is the peritoneal seeding of tumor cells originating from the fallopian tube epithelial (FTE) precursor lesions. Ovulation releases follicular fluid (FF), which is known to contain oncogenic factors that promote FTE cell transformation. However, the specific mechanisms and factors within FF that drive the early metastatic seeding of precancerous FTE cells remain poorly defined. We investigated the role of FF in the peritoneal dissemination of FTE-derived cells, and the abundance of fibronectin (FN) as a potential key mediator. Functional assays were performed using FN-depleted FF to assess its impact on migration, invasion, anchorage-independent growth, and peritoneal attachment. The role of the fibronectin receptor, integrin β1 (ITGB1), and the signaling pathways were evaluated via knockdown studies. In vivo xenograft models were used to quantify peritoneal seeding, and mechanistic studies elucidated the involved signaling pathways. We identified FN as a critical component of FF, present at high concentrations (~210 µg/mL), that potently drives FTE cell migration, invasion, and peritoneal seeding. Depletion of FN from FF abrogated the majority of these pro-metastatic activities in vitro and led to a dramatic 82% reduction in peritoneal tumor seeding in vivo. Knockdown of ITGB1 similarly impaired seeding. Mechanistically, FF-derived FN activates the ITGB1/FAK-SRC signaling pathway to promote tumor cell motility and colonization. Our study establishes FF-fibronectin as an important regulator of the early peritoneal seeding of HGSC precursor cells. These findings reveal a direct link between ovulation and HGSC development, suggesting that targeting the FN-ITGB1 signaling axis may offer a novel preventive strategy for high-risk individuals. Full article

A 14-year-old spayed female Jindo dog presented with a firm, non-painful right-sided cervical mass. Computed tomography identified three distinct, separate masses thought to be arising from the right thyroid lobe; the largest measured 66.6 mm × 42.0 mm × 37.6 mm with an estimated volume of 56 cm³ and showed invasion into the right internal jugular vein. Multiple hepatic nodules were detected without evidence of pulmonary metastasis and regional lymph node involvement. Right thyroidectomy with resection of the invaded vein and partial liver lobectomy were performed. The histologic results confirmed all three masses as follicular-compact thyroid carcinomas, and the hepatic lesion as metastatic thyroid carcinoma. The dog recovered uneventfully, remained euthyroid, and showed no local recurrence over a 5-month follow-up. In human medicine, multifocality is common in papillary thyroid carcinoma and is associated with a high rate of recurrence. This report documents the first canine case of multifocal thyroid carcinoma, featuring macroscopic vascular invasion and an uncommon metastatic pattern in which the liver was affected in the absence of detectable pulmonary lesion. The presence of multifocal disease within a single canine thyroid lobe necessitates comprehensive cross-sectional imaging, meticulous surgical planning with vascular considerations, and long-term monitoring to optimize the prognosis of this carcinoma. Full article

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as predictors of therapeutic response. Papillary, follicular, oncocytic, medullary, and anaplastic thyroid carcinomas harbor distinct early driver mutations, such as BRAFV600E, RAS, and fusion events (RET, NTRK, and ALK), that cooperate with secondary alterations (TERT promoter, TP53, PIK3CA, and CDKN2A/B loss) to drive dedifferentiation, metastasis, and therapeutic resistance. Insights from The Cancer Genome Atlas (TCGA) and transcriptomic scoring systems (e.g., BRAF–RAS score) now link genotype to tumor morphology, metastatic tropism, and radioactive iodine refractoriness. These molecular insights have been incorporated into updated risk stratification frameworks, preoperative surgical planning, and treatment algorithms, informing the selection of kinase inhibitors, redifferentiation strategies, and enrollment in genotype-directed clinical trials for radioiodine-refractory disease. This review synthesizes recent evidence connecting genomic alterations to clinical behavior and highlights their translation into evolving approaches for thyroid cancer management. Full article

Objective(s): To delineate the somatic mutational landscape of follicular thyroid carcinoma (FTC) from a large, real-world cohort to identify molecular subtypes and actionable targets for personalized therapeutic interventions. Methods: Genomic and clinical data for 168 FTC samples were retrieved from the AACR Project GENIE^® registry via cBioPortal. This study assessed mutation frequencies, copy number alterations, and subgroup differences (primary vs. metastatic; adult vs. pediatric) using statistical tests. Results: NRAS was the most common mutation (33.9%), followed by TERT (22.6%), DICER1 (15.5%), HRAS (11.9%), and PTEN (10.7%). DICER1 mutations were significantly enriched in pediatric cases (44.4% vs. 4.6% in adults, p < 0.001), while TERT mutations were exclusive to adults (42%). NRAS mutations were more frequent in metastatic tumors (42.4%) than primary tumors (29.2%). Conclusions: FTC tumorigenesis is driven by distinct molecular pathways, with significant heterogeneity between pediatric and adult patients as well as primary and metastatic disease. These findings underscore the necessity of molecular profiling for patient stratification and provide a strong rationale for developing personalized treatment strategies to improve clinical outcomes. Full article

Follicular-cell-derived thyroid carcinoma, while typically associated with a favorable prognosis, can undergo dedifferentiation into poorly differentiated (PDTC) or anaplastic thyroid carcinoma (ATC), leading to enhanced aggressiveness and radioiodine resistance. This review systematically examines the genetic and molecular mechanisms driving this pathological progression, highlighting the roles of key mutations—such as BRAF, RAS, TERT, and TP53—and the disregulation of signaling pathways, including MAPK and PI3K/AKT. These alterations promote the loss of thyroid-specific functions, including iodide metabolism, and correlate with poor clinical outcomes. In recent years, therapeutic strategies aimed at tumor redifferentiation have emerged as a promising approach for radioiodine-refractory disease. We summarize recent advances in the use of targeted agents, particularly BRAF and MEK inhibitors, to restore radioiodine avidity and improve treatment response. While early clinical studies show encouraging results, including tumor shrinkage and restored RAI uptake in selected patients, challenges such as treatment resistance and patient selection remain. Future efforts should focus on refining molecular stratification, developing rational combination therapies, and integrating novel modalities such as immunotherapy to overcome resistance. A deeper understanding of redifferentiation mechanisms not only provides insights into thyroid cancer progression but also supports the development of personalized treatment strategies for high-risk patients. Full article

The 2022 WHO classification gives more importance to the integration of morphological and molecular characteristics of tumors, introducing new diagnostic criteria for papillary thyroid carcinoma (PTC). The invasive encapsulated follicular variant of PTC (IEFVPTC) is now considered a separate entity and no longer a subtype of PTC, while the infiltrative follicular variant (IFVPTC) is still considered a PTC subtype. The separation of invasive encapsulated follicular variants from PTCs implies that differential diagnosis between IEFVPTC and IFVPTC can be difficult. We performed a gene expression analysis by NanoString technology on 23 PTCs, divided into 11 IEFVPTCs and 12 IFVPTCs. We focused our attention on the possible role of the tumor microenvironment (TME) and, in particular, the role of the extracellular matrix (ECM). IFVPTC, compared to IEFVPTC, showed a statistically significant downregulation of 2 genes and an upregulation of 45. Among these genes, we focused our attention on TIMP2 and COL1A2, whose high upregulation was statistically significant in IFVPTC. TIMP2 and COL1A2 are involved in ECM degradation and synthesis and in collagen biosynthesis and modification. The ECM and collagen alterations in IFVPTC could reflect the different tumor behavior of FVPTCs, allowing the identification of new biomarkers to distinguish IEFVPTC from IFVPTC. Full article

Hashimoto’s thyroiditis (HT) is the most common autoimmune thyroid disorder, characterized by progressive lymphocytic infiltration, follicular destruction, tissue fibrosis, and an elevated risk of thyroid carcinoma. While the precise mechanisms underlying HT remain incompletely defined, emerging evidence implicates dysregulated sphingolipid (SPL) metabolism, particularly the sphingosine-1-phosphate (S1P) signaling axis, as a central contributor to disease pathogenesis. S1P, a bioactive lipid mediator, integrates metabolic and immunological cues to regulate immune cell trafficking, cytokine production, apoptosis, and fibroblast activation. Aberrant activation of the sphingosine kinase (SPHK)/sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) pathway has been linked to persistent T helper 1 (Th1) cell recruitment, signal transducer and activator of transcription 3 (STAT3)-mediated immune polarization, epithelial–mesenchymal transition, extracellular matrix remodeling, and the establishment of a chronic inflammatory and fibrotic microenvironment. Moreover, S1P signaling may foster a pro-tumorigenic niche, providing a mechanistic explanation for the strong epidemiological association between HT and papillary thyroid carcinoma. This review summarizes current insights into the role of SPL metabolism in HT, highlighting its potential as a mechanistic link between autoimmunity, fibrosis, and carcinogenesis. Full article

Medullary thyroid carcinoma (MTC) is a thyroid tumor with neuroendocrine properties purportedly derived from C-cells. The biochemical activity of medullary thyroid carcinoma includes the production of calcitonin and carcinoembryonic antigen, which are sensitive tumor markers, facilitating diagnosis, follow-up, and prognostication. Calcitonin-negative medullary thyroid carcinoma is a rare, poorly understood primary neuroendocrine carcinoma of the thyroid characterized by classic medullary thyroid carcinoma morphology without raised serum calcitonin and with or without the expression of calcitonin detected by immunohistochemistry. Previous studies reported that C-cells were derived from the neural crest; however, more recently, C-cells have been indisputably shown to be derived from the pharyngeal endoderm and ultimobranchial bodies. Ultimobranchial body (UBB) remnants can persist in the thyroid and express p63, but their function is poorly understood. Some have postulated that ultimobranchial bodies may be the “stem” cell of the thyroid and may be precursors for thyroid tumors, particularly mixed tumors with follicular and medullary components. We present a unique case of calcitonin-negative MTC in a 58-year-old male arising in an inflamed and fibrotic thyroid with numerous scattered ultimobranchial body remnants and concomitant C-cell hyperplasia/medullary microcarcinoma (CCH/MMC). The ultimobranchial body remnants, C-cell hyperplasia, and medullary thyroid carcinoma were MTC classifier positive according to ThyroSeq^®. The areas representing CCH/MMC expressed calcitonin by IHC while the main MTC tumor was negative. An additional unique feature was an area demonstrating a “mixed” C-cell/thyroid follicular epithelial phenotype. In this review we review the possible etiologies of calcitonin-negative MTC, the possibility of a neoplastic sequential progression from ultimobranchial bodies to CCH/MMC to medullary thyroid carcinoma with the individual elements (UBB, CCH/MMC, MTC) demonstrated in this thyroid, and previous postulations that ultimobranchial bodies may be the source of some follicular thyroid cancers, medullary thyroid cancers, and mixed tumors of medullary and follicular epithelial types. Full article