Background: Bethesda category IV includes oncocytic (OFN) and non-oncocytic follicular neoplasms (FN). We evaluated whether a 7-gene mutation panel performs differently across these cytomorphologic phenotypes. Methods: We retrospectively reviewed 319 Bethesda IV fine-needle aspirations (2020–2025); cytomorphologic features were assessed in the 285 cases with evaluable 7-gene testing results. Risk of malignancy (ROM) and other diagnostic metrics, including mutation rates and mutation–malignancy association were calculated for FN and OFN. Results: In both FN and OFN we observed RAS-like alterations only. Mutation prevalence was higher in FN (32/112, 28.6%) than in OFN (27/173, 15.6%; OR 2.16, 95% CI 1.21–3.86; p=0.011). In FN, mutation-positive nodules showed a ROM of 50.0% (7/14) vs 14.7% (5/34) in mutation-negative cases (OR 5.80, 95% CI 1.41–23.8; p=0.024). In OFN, ROM was 42.9% (3/7) vs 34.2% (13/38) in mutation-negative cases (OR 1.44, 95% CI 0.28–7.44; p=0.686). Conclusions: A positive 7-gene result was associated with significant risk enrichment in FN, while the association in OFN did not reach significance. The lower mutation prevalence in OFN, together with available evidence that oncocytic tumors are associated with chromosome instability, supports the incorporation of copy number variation analysis as a part of broader panel testing strategy.
Thyroid cancer is the most common endocrine malignancy, and the detection of thyroid nodules has increased with the widespread use of ultrasound. In this context, the BRAF V600E mutation has emerged as an important molecular marker in papillary thyroid carcinoma; however, its prevalence varies geographically and local data remain limited. This study aimed to determine the prevalence of the BRAF V600E mutation in a Uruguayan population and to evaluate its potential role as a complementary diagnostic tool. A cross-sectional analytical study was conducted including 155 patients who underwent fine-needle aspiration (FNA) for thyroid nodules at Maciel Hospital between October 2020 and September 2022). Archived formalin-fixed paraffin-embedded (FFPE) tumor samples were also analyzed to increase the number of histologically confirmed cases. Detection of the BRAF V600E mutation was performed using allele-specific PCR. Clinical, ultrasonographic, cytological (Bethesda classification), and histopathological data were collected from medical records. The prevalence of the BRAF V600E mutation was 75.9% among 29 papillary thyroid carcinomas and only 4/151 benign lesions (2.6%). The assay showed a sensitivity of 73.3% (CI 55.6% – 85.8) and a specificity of 95.4% (IC 90.7% – 97.7%), with a positive predictive value of 75.9% (CI 57.9% – 87.8%) and a negative predictive value of 94.7 (CI 90.0% – 97.3%) Significant associations were observed between the mutation and Bethesda categories V–VI (p < 0.001), hypoechogenicity (p = 0.01) and malignant histopathology (p < 0.001). These findings support the use of BRAF mutation testing may serve as a complementary tool in the diagnostic assessment of thyroid nodules.
Introduction: Involvement of the pleural and peritoneal cavities by hematolymphoid malignancies is relatively infrequent compared to epithelial malignancies, though reported rates vary widely depending on institutional and demographic factors. When present, they may or may not be the first manifestation of disease; however, they usually indicate an advanced stage. Cytological recognition is often challenging due to morphological overlap with reactive processes, yet it remains a valuable, minimally invasive diagnostic tool. This study describes the cytomorphological spectrum, diagnostic contribution, and clinical outcomes of hematolymphoid malignancies detected in effusion cytology and contextualizes findings with published literature. Case Presentations: A retrospective review was conducted of all effusion cytology samples reported between August 2024 and August 2025 at a tertiary care center. Cases demonstrating atypical hematolymphoid cells were analyzed for clinical presentation, cytomorphology, and follow-up. A review of published English literature was also undertaken. Four hematolymphoid malignancies were identified, comprising 12.9% (4/31) of malignant effusions and 0.22% (4/1,807) of all effusion samples. Cytology was the initial diagnostic clue in 2 patients: a 16-year-old male with gastric myeloid sarcoma (alive and stable post-chemotherapy) and a 41-year-old male with ileocecal diffuse large B-cell lymphoma (died before treatment). Two additional cases represented follow-up effusions: a 60-year-old female with acute myeloid leukemia and a 62-year-old male with chronic myeloid leukemia on imatinib therapy, both of whom died shortly after effusion development. Morphological hallmarks included blasts, atypical lymphoid cells, hand-mirror forms, and immature myeloid elements. Conclusion: Though infrequently positive in hematolymphoid malignancies, effusion cytology can provide pivotal early diagnostic information and guide clinical management. Recognition of subtle cytomorphological features is essential as effusion involvement typically reflects aggressive disease and adverse outcomes.
IL-6 signalling in the bone marrow (BM) is compartmentalised. Different cell populations within the BM niche contribute distinct components of the IL-6 signalling network, yet how their roles change during myeloma progression has remained unclear. We examined how the respective contributions of mesenchymal stromal cells (MSCs) and primary multiple myeloma (MM) cells to the IL-6 signalling machinery change during disease progression. MSCs were identified as the principal source of IL-6, whereas MM cells secreted minimal IL-6 but were the primary source of soluble IL-6 receptor (sIL-6R). This functional interplay, with MSCs supplying the ligand and MM cells providing the soluble receptor, establishes a paracrine IL-6 trans-signalling axis. The contribution of MM cells to this axis increases significantly with disease stage: cells from patients with active MM secreted substantially greater quantities of sIL-6R than those from patients with smouldering disease, identifying sIL-6R as a marker of biologically active disease. This increase is mirrored by higher basal IL-6 secretion from MSCs in advanced disease, demonstrating augmentation of the IL-6 signalling pathway as disease progresses. Using Hyper-IL-6 and sgp130, we demonstrated that trans-signalling through gp130 is the dominant mechanism by which stromal-derived IL-6 protects MM cells from treatment-induced apoptosis, independent of membrane-bound IL-6R expression. Therefore, targeted inhibition of IL-6 trans-signalling with sgp130 could be used to suppress pathogenic effects in MM while preserving beneficial classical IL-6 signalling, offering a more precise and potentially safer alternative to total IL-6/IL-6R blockade. As disease progression increases trans-signalling through higher sIL-6R expression, early intervention in smouldering myeloma, before pathway amplification, may represent a more effective therapeutic strategy.
Respiratory viral infections during pregnancy can disrupt maternal immune homeostasis, thereby altering placental function and fetal neurodevelopment through cytokine-mediated immune communication. Accumulating evidence suggests that the placenta functions as an active immunological interface, integrating maternal inflammatory signals and shaping fetal neuroimmune development, supporting the concept of the "placenta-brain axis". This review synthesizes current evidence on the cytokine, chemokine, interferon, and complement networks that mediate maternal-fetal immune communication and examines how these pathways are engaged during infections. It addresses four prevalent RNA respiratory viruses for which evidence is available at one or more biological levels of the placenta-brain axis, namely influenza virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human respiratory syncytial virus (hRSV), and human metapneumovirus (hMPV). We highlight substantial differences in the depth of mechanistic evidence across these pathogens, with influenza virus and SARS-CoV-2 supported by comparatively robust experimental evidence, whereas hRSV and hMPV remain biologically plausible but mechanistically underexplored models of maternal-fetal immune communication. Hence, we propose a framework that grades mechanistic evidence across the placenta-brain axis against four explicit criteria and identify gestational timing, fetal sex, and maternal background inflammation as variables that modulate the transmission of inflammatory signals between levels. This structured approach identifies knowledge gaps and guides future mechanistic and translational research.
