Juvenile myelomonocytic leukemia (JMML) is a rare RAS/MAPK-driven pediatric myelodysplastic/myeloproliferative neoplasm. The phenotype and survival relevance of NRAS/KRAS alterations remain difficult to interpret because of co-mutations, evolving sequencing, incomplete germline confirmation, and post-diagnostic HSCT.

We retrospectively reviewed 34 children with JMML and classifiable NRAS and/or KRAS alterations diagnosed between November 2010 and September 2022. Patients were classified as NRAS-only, KRAS-only, or NRAS/KRAS co-mutated. Direct comparisons used single-subtype cases. OS was analyzed in evaluable patients, with HSCT modeled as a time-dependent covariate.

The cohort included 20 NRAS-only, 12 KRAS-only, and 2 NRAS/KRAS co-mutated cases. KRAS-only cases had higher monocyte percentage (27.2% vs. 16.7%; p = 0.023) and lymphocyte percentage (48.1% vs. 39.0%; p = 0.018), whereas absolute monocyte count was comparable (4.0 vs. 4.0 × 10⁹/L; p = 0.930). PTPN11 was the most frequent non-RAS co-mutation (7/34) and occurred in both NRAS/KRAS co-mutated cases. Methylation status was available in 11 patients and analyzed descriptively. NRAS/KRAS subtype did not significantly stratify OS (HR for KRAS-only vs. NRAS-only, 0.55; 95% CI, 0.18-1.62; p = 0.276). HbF did not significantly stratify OS, while diagnostic total hemoglobin showed only an exploratory univariable association. Exact HSCT dates were retrieved for all 11 transplanted patients; time-dependent Cox analysis showed a significant association between HSCT and better OS (HR, 0.11; 95% CI, 0.02-0.56; p = 0.007).

NRAS/KRAS status defined a limited diagnosis-time phenotype but did not independently stratify survival. JMML survival analyses should integrate co-mutations, germline and testing-era limitations, HbF/hemoglobin risk context, and time-dependent HSCT handling.

Background: The survival benefit of primary tumor resection (PTR) in patients with synchronous metastatic primary malignant bone neoplasms (PMBNs) remains controversial. We aimed to evaluate the association between PTR and survival outcomes using a large population-based cohort with rigorous confounding control. Methods: Patients diagnosed with synchronous metastatic PMBNs (osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma) between 2004 and 2022 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were stratified by receipt of PTR. Propensity score matching (PSM; 1:1 nearest-neighbor, caliper = 0.03) was applied to balance baseline covariates. Kaplan-Meier analysis with log-rank testing and multivariable Cox proportional hazards regression stratified by matched pairs were used to assess overall survival (OS) and cancer-specific survival (CSS). Subgroup analyses were performed across four histological subtypes. Results: A total of 1046 patients were included (resection: n = 658, 62.9%; no resection: n = 388, 37.1%). After PSM, 488 patients (244 per group) were retained. In the matched cohort, PTR was independently associated with significantly improved Overall survival (OS) (HR = 0.34, 95% CI: 0.21-0.54, p < 0.001) and cancer-specific survival (CSS) (HR = 0.35, 95% CI: 0.22-0.55, p < 0.001). Subgroup analyses demonstrated significant survival benefit in osteosarcoma and chondrosarcoma (both p < 0.001), but not in Ewing sarcoma or chordoma. Conclusions: PTR is associated with a significant survival benefit in selected patients with synchronous metastatic PMBNs, particularly those with osteosarcoma and chondrosarcoma. These findings support individualized, multidisciplinary decision-making regarding surgical intervention in this population.

Background/Objectives: Hypoxia-inducible factor 1-alpha (HIF-1α) is a transcription factor that escapes proteasomal degradation under hypoxic conditions, translocates to the nucleus, and activates genes involved in anaerobic glycolysis (e.g., GLUT1 and LDH-A) and vascular endothelial growth factor (VEGF) expression. Through its role in tumor progression, angiogenesis, and metabolic reprogramming, elevated HIF-1α levels have been reported in various malignancies; however, its serum concentration in malignant salivary gland neoplasms remains unexplored. This study aimed to assess serum HIF-1α levels in patients with salivary gland malignancies. Methods: Serum samples were collected from 30 patients diagnosed with malignant salivary gland neoplasms. HIF-1α concentration was determined using an enzyme-linked immunosorbent assay (ELISA). Results: The mean serum HIF-1α concentration was 89.20 ± 44.56 pg/mL. Exploratory analyses demonstrated higher HIF-1α levels in stage III tumors compared with stage II tumors and in high-grade tumors compared with lower-grade lesions. Conclusions: This is the first study to quantify serum HIF-1α levels in patients with malignant salivary gland neoplasms. The findings suggest that while HIF-1α may have potential as a biomarker, its potential as a biomarker of tumor aggressiveness or of malignant salivary gland neoplasms is limited due to high interindividual variability. Further studies with larger cohorts and standardized methodologies are necessary to establish reference values and clarify the clinical significance of HIF-1α in salivary gland malignancies.

Male hypogonadism is associated with metabolic and cardiovascular comorbidities, and emerging evidence implicates testosterone deficiency in immune dysregulation that may elevate cancer risk. To review current evidence on the relationship between male hypogonadism, immune function, and cancer risk, focusing on mechanisms linking testosterone deficiency to immune suppression and oncologic outcomes. PubMed/MEDLINE, Google Scholar, and SciSpace were systematically searched (through April 2026) using predefined search strings. After removal of duplicates (n = 1535 records screened), 156 full-text articles were assessed for eligibility; 20 studies met predefined inclusion criteria (comprising 4 experimental studies, 4 prospective/RCT studies, 7 observational studies, and 5 reviews used as secondary literature) and were included in a narrative synthesis. Testosterone deficiency was consistently associated with elevated IL-6, TNF-α, IL-1β, and CRP, impaired neutrophil maturation, and reduced NK-cell cytotoxicity. Androgen deprivation augmented thymic output and anti-tumor T cell responses in prostate cancer models, yet promoted chronic inflammation in other contexts. Epidemiologically, low testosterone correlated with increased colorectal cancer risk and poorer survival in advanced malignancies; the prostate cancer relationship followed a paradoxical saturation model. The immunological consequences of hypogonadism are context-dependent. Testosterone deficiency drives pro-inflammatory signaling that may promote carcinogenesis, while androgen-mediated immunosuppression can paradoxically impair anti-tumor surveillance. No simple linear relationship exists between hypogonadism and cancer risk via immune suppression. Prospective studies are needed to guide clinical decisions on testosterone replacement therapy in hypogonadal men.

Cancer predisposition syndromes (CPSs) account for 8.5-18% of all childhood cancer cases. Most of them are inherited in an autosomal dominant pattern; consequently, there is a 50% risk of transmission to offspring. Early detection of CPSs is crucial for choosing patient treatment strategies and for counseling in the family. This study enrolled 886 pediatric patients with hematologic and solid neoplasms from prospective and retrospective cohorts (2018-2025). Clinical exome or multigene panel sequencing was used to analyze blood DNA. Overall, 186 pathogenic/likely pathogenic (PLP) variants in cancer-associated genes were identified in 176/886 (20%) of patients, and the most frequently mutated were the NF1 (n = 35) and TP53 (n = 18) genes. Among the 186 PLP variants, 126/886 (14.2%) were causative for pediatric neoplasms, while 56/886 (6.3%) were heterozygous mutations associated with adult-onset CPSs affecting DNA repair. The highest total mutation rate was revealed in retinoblastoma (80%), peripheral nerve sheath tumors (60%), and pheochromocytoma/paraganglioma (47%), while the lowest rate was found in hematologic malignancies (4.6%) and neuroblastoma (12%). The wide range and high frequency of deleterious variants in pediatric patients, especially in those with solid tumors, highlights the importance of multigene panel sequencing for the accurate determination of CPSs.

CMTs are biologically heterogeneous neoplasms for which reliable prognostic biomarkers remain limited. This study investigated the clinical significance of serum cancer antigen 15-3 (CA 15-3) and the immunohistochemical expression of Ki-67 and cyclooxygenase-2 (COX-2) in CMTs. Fifty-four female dogs with histologically confirmed CMTs and twelve healthy controls were prospectively evaluated. Serum CA 15-3 concentrations were measured before surgery and at 21 and 90 days post-mastectomy, while Ki-67 and COX-2 expression were assessed in tumor tissues. CA 15-3 was undetectable in controls and significantly higher in malignant than benign neoplasms (p < 0.05), with moderate correlations with clinical stage (s = 0.59), histological grade (s = 0.64), and the number of nodules (s = 0.42). Levels remained elevated in advanced stages despite surgery. ROC analysis identified a CA 15-3 cutoff of 3.01 IU/mL (AUC = 0.92) for discriminating malignant from benign tumors. Ki-67 correlated with histological grade (ρ = 0.41) but showed limited prognostic accuracy (AUC = 0.63). COX-2 expression lacked significant associations and showed poor discriminatory power (AUC = 0.44). Survival analyses did not identify significant differences among groups. Principal component analysis demonstrated clustering of aggressive CMTs according to biomarker profile. These findings suggest that serum CA 15-3 may represent a useful adjunct prognostic biomarker in canine mammary oncology, while the combination of serum and tissue biomarkers may improve prognostic stratification and may guide therapeutic decision-making in veterinary oncology. These findings support the growing role of biomarker panels in the clinical management of CMTs.

Multiple endocrine neoplasia (MEN) syndromes are rare hereditary disorders characterized by the development of multiple endocrine and non-endocrine tumours with variable penetrance and age-dependent expression. Although uncommon, these syndromes are highly relevant from both biological and clinical perspectives, as they exemplify the direct link between germline genetic alterations and tumorigenesis. Early tumour detection is critical in MEN syndromes because many associated neoplasms-such as medullary thyroid carcinoma (MTC), pancreatic neuroendocrine tumours (NETs), pheochromocytomas, and parathyroid disease-may remain clinically silent for prolonged periods while retaining malignant potential. Delayed diagnosis is associated with advanced disease and worse outcomes, whereas early identification enables curative or organ-preserving interventions. This clinical challenge has driven the development of integrated diagnostic strategies combining genetic testing, biochemical markers, and imaging. Among these, genetic testing plays a pivotal role, providing definitive diagnosis, enabling family screening, and guiding risk-adapted surveillance. The aim of this review is to provide a comprehensive synthesis of genetically driven diagnostics in MEN syndromes, outlining the current state of the art and future directions in precision medicine.

Cutaneous metastases are an uncommon but clinically significant manifestation of internal malignancy, occurring in approximately 0.7-10.4% of patients with cancer. In some cases, they represent the first clinical manifestation of an otherwise occult malignancy, making accurate diagnosis critical for timely patient management. Distinguishing cutaneous metastases from primary cutaneous neoplasms, particularly malignant adnexal tumors, remains one of the most challenging problems in dermatopathology because of their substantial clinical, histopathologic, and immunophenotypic overlap. This review summarizes the epidemiology and biology of cutaneous metastasis and the clinical presentation of cutaneous metastases and emphasizes the central role of clinicopathologic correlation in diagnosis. Histologic features such as a purely dermal or subcutaneous location, intravascular tumor emboli, and a "bottom-heavy" growth pattern favor metastasis, whereas the presence of an in situ component or transition from a benign precursor lesion strongly supports a primary cutaneous neoplasm. We review the diagnostic utility of optimized immunohistochemical panels, highlighting the complementary roles of p63, cytokeratin 15, calretinin, and D2-40 (podoplanin) in establishing primary adnexal lineage, together with emerging markers including SOX10, androgen receptor, TRPS1, adipophilin, INSM1, SATB2, and BerEP4 for diagnostically challenging cases. We also discuss recent advances in molecular biology and comprehensive genomic profiling, including recurrent gene fusions (e.g., MYB::NFIB, CRTC1::MAML2, and YAP1 fusions) and characteristic mutational signatures that provide increasingly robust diagnostic evidence of tumor lineage. Finally, we provide a comprehensive, practical diagnostic algorithm for differentiating primary cutaneous adnexal carcinomas from cutaneous metastases of adenocarcinomas. By integrating traditional histopathologic techniques with modern immunohistochemical and molecular techniques, pathologists and clinicians can successfully navigate this complex differential diagnosis and thereby facilitate appropriate patient management and therapeutic intervention.

Background/Objectives: Borderline ovarian tumor (BOT) is an ovarian neoplasm of low malignant potential that lacks stromal invasion. The aim of this study was to compare intraoperative frozen section analysis (IFSA) findings with final pathology results in patients diagnosed with BOT on frozen sections and to identify risk factors associated with cancer. Methods: This study included data from patients who underwent surgery for an ovarian mass between 2020 and 2024 and were diagnosed with BOT on IFSA. Demographic, obstetric, and clinical characteristics, as well as frozen section and final pathology findings, were recorded. The CAR, NLR, and PNI scores were calculated. Patients were grouped as premenopausal or postmenopausal and compared. Based on the final pathology report, patients were also classified as having BOT or cancer and compared. Results: A total of 92 patients were included in the study, and 53 (57.6%) were postmenopausal. The prevalence of cancer was significantly higher in the postmenopausal group (p = 0.022). Final pathology revealed cancer in 11 patients (11.9%). Age group > 45 years (OR = 12.50) and serous subtype on IFSA (OR = 10.77) were significant risk factors for cancer detection. Cutoff values for distinguishing carcinoma from BOT were identified for CAR (≥1.75), NLR (≥2.64), and PNI (≤48.64). Conclusions: In this study, the rate of invasive carcinoma on final pathology among patients diagnosed with BOT on IFSA was 11.9%. Age group > 45 years and serous subtype on IFSA were independent risk factors. The cutoff values for CAR, NLR, and PNI may support risk stratification for carcinoma.

Background/Objectives: Sellar solitary fibrous tumors (SFTs) are exceptionally rare mesenchymal neoplasms that frequently mimic non-functioning pituitary adenomas (PAs) because of overlapping clinical manifestations and nonspecific radiological findings. Consequently, preoperative diagnosis remains challenging and definitive diagnosis relies on histopathological and immunohistochemical evaluation. Methods: We report a sellar SFT initially diagnosed as a PA and analyze the diagnostic features of previously reported cases to identify recurring diagnostic pitfalls. Clinical, endocrinological, radiological, intraoperative, histopathological, and immunohistochemical findings from a patient with a sellar SFT were retrospectively reviewed. A structured literature review of previously reported sellar SFTs was performed to compare presenting symptoms, endocrine abnormalities, imaging characteristics, pathological findings, and diagnostic features. Results: A 65-year-old man presented with headache, progressive visual impairment, fatigue, and anterior hypopituitarism. Magnetic resonance imaging demonstrated a heterogeneously enhancing sellar lesion with suprasellar extension and cavernous sinus involvement, leading to an initial diagnosis of non-functioning PA. Endoscopic transsphenoidal surgery revealed an unexpectedly hypervascular and firm tumor. Histopathological examination demonstrated a spindle-cell neoplasm with a hemangiopericytoma-like vascular pattern, six mitoses per 10 high-power fields, absence of necrosis, and diffuse nuclear STAT6 positivity, establishing the diagnosis of CNS WHO grade 2 solitary fibrous tumor according to the 2021 WHO classification. Review of the literature demonstrated that most sellar SFTs share similar clinical and radiological features with PAs and are diagnosed only after surgical resection. Conclusions: Sellar SFT should be considered in the differential diagnosis of atypical sellar masses despite the absence of characteristic imaging findings. Recognition of intraoperative features, together with appropriate immunohistochemical evaluation, particularly STAT6 staining, is essential for accurate diagnosis. Current evidence remains insufficient to define the optimal postoperative management of completely resected sellar SFTs, emphasizing the importance of individualized treatment decisions and long-term surveillance.