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The accurate diagnosis and classification of gliomas are essential for appropriate treatment planning and prognosis prediction. This study aimed to investigate the molecular diagnostics of IDH‐wildtype diffuse astrocytic gliomas and identify potential genetic variants that could differentiate glioblastoma (GBM) from lower‐grade gliomas when DNA methylation analysis is not feasible. In total, 479 H3‐and IDH‐wildtype diffuse astrocytic gliomas were included in this study. All the cases were diagnosed according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Panel sequencing data were collected, and clinicopathological information was retrieved from medical records. Genetic alterations and histological findings were analyzed to determine their diagnostic utility and prognostic implications. Out of 479 cases, 439 (91.6%) were diagnosed with GBM, including 28 cases that were molecularly diagnosed as GBM. However, 40 (8.4%) cases could not be classified according to the 2021 WHO classification and were diagnosed as lower‐grade diffuse astrocytic glioma, IDH‐wildtype, not elsewhere classified (LGNEC). In addition to the three genetic alterations included in the diagnostic criteria of GBM, PTEN and EGFR mutations were found to be enriched in GBM. Patients harboring mTOR pathway mutations demonstrated a more favorable prognosis and often exhibited morphology resembling subependymal giant cell astrocytoma, along with a high tumor mutational burden. Among patients with mTOR pathway mutations, those lacking molecular diagnostic features of GBM exhibited outstanding survival outcomes, even in the presence of grade 4 histology. Integration of molecular features enhanced the diagnostic accuracy of IDH‐wildtype gliomas. Some molecular alterations enriched in GBM offer valuable insights for molecular diagnosis and glioma classification. Furthermore, high‐grade diffuse astrocytic gliomas featuring mTOR pathway mutations in the absence of molecular diagnostic features of GBM could represent more favorable tumor types distinct from GBM. This study investigates molecular diagnostics in 479 cases of H3‐ and IDH‐wildtype diffuse astrocytic gliomas, aiming to distinguish genetic variants between glioblastoma (GBM) and lower‐grade gliomas when DNA methylation analysis isn't feasible. In addition to the three genetic alterations in GBM diagnostic criteria, PTEN and EGFR mutations were identified as enriched in GBM. Patients with mTOR pathway mutations exhibited a more favorable prognosis, often morphologically resembling subependymal giant cell astrocytoma and showing a high tumor mutational burden.

Background/Objectives: Brain metastasis (BM) is a common and often early manifestation in lung adenocarcinoma (LUAD), yet its tumor microenvironment remains poorly defined at the time of initial diagnosis. This study aims to characterize early immune microenvironmental alterations in synchronous BM using spatial proteomic profiling. Methods: We performed digital spatial proteomic profiling using the NanoString GeoMx platform on formalin-fixed paraffin-embedded tissues from five treatment-naïve LUAD patients in whom BM was the initial presenting lesion. Paired primary lung and brain metastatic samples were analyzed across tumor and stromal compartments using 68 immune- and tumor-related protein markers. Results: Spatial profiling revealed distinct expression patterns between primary tumors and brain metastases. Immune regulatory proteins—including IDO-1, PD-1, PD-L1, STAT3, PTEN, and CD44—were significantly reduced in brain metastases (p < 0.01), whereas pS6, a marker of activation-induced T-cell death, was significantly upregulated (p < 0.01). These alterations were observed in both tumor and stromal regions, suggesting a more immunosuppressive and apoptotic microenvironment in brain lesions. Conclusions: This study provides one of the first spatially resolved proteomic characterizations of synchronous BM at initial LUAD diagnosis. Our findings highlight early immune escape mechanisms and suggest the need for site-specific immunotherapeutic strategies in patients with brain metastasis.

Metastatic leiomyosarcoma to the thyroid is an extremely rare occurrence, and only 18 cases have been reported. Here, we report a case of a 37-year-old woman who presented with multiple masses on the scalp. Excisional biopsy was done and the mass revealed fascicles of smooth muscle fibers which showed positive staining for smooth muscle actin, thus confirming the diagnosis of leiomyosarcoma. The patient was also found to have a 0.9 cm mass within the left thyroid. Fine-needle aspiration was done and the cytological smear showed hypercellular spindle cell clusters with hyperchromatic and large nuclei. Normal thyroid follicular cells were found within or around tumor cells. In this report, we present the cytologic findings of metastatic leiomyosarcoma to the thyroid and offer differential diagnoses of the aspirated spindle cells.

Misdiagnosis of endocervical adenocarcinoma (EAC) as endometrial endometrioid carcinoma (EEC) is one of the major concerns when evaluating endometrial curettage specimens. It is difficult to differentiate EAC involving the endometrium from EEC, particularly when the specimens have only a few small tumor fragments. We report a case of endocervical adenocarcinoma in situ (AIS) with multifocal microscopic involvement of the endometrium. The endometrial curettage specimen obtained from an 82-year-old woman consisted of a large volume of blood and fibrin, with small endometrial tissue fragments showing microscopic foci of atypical glandular proliferation. Based on the presence of complex glands with stratified mucin-poor columnar epithelium and intermediate-grade nuclear atypia, a preoperative diagnosis of grade 1 EEC was made. However, the hysterectomy specimen revealed an endocervical AIS involving the endocervix and low uterine segment. Frequent mitotic figures and apoptotic bodies, characteristic of AIS, were present. The endometrium showed a few microscopic foci of atypical glandular proliferation involving the surface only. Their histological features were similar to those of the endocervical AIS. Immunohistochemically, the atypical glands exhibited block p16 positivity. The final diagnosis was a superficially spreading endocervical AIS with multifocal microscopic involvement of the endometrial surface epithelium. In summary, small tumor tissues in an endometrial curettage may lead to misdiagnosis of AIS or EAC as EEC, especially when the pathologists are unaware of the possibility of microscopic endometrial involvement of AIS or EAC. The origin of the tumor can be correctly determined based on a combination of histological features and immunostaining. Endocervical AIS involving the endometrium should be included in the differential diagnosis of neoplastic glandular lesions in endometrial curettage specimens. An accurate diagnosis in these cases is important because of its significant implications for clinical management.

Pleomorphic high-grade squamous intraepithelial lesions (PHSILs) of the uterine cervix are characterized by strikingly pleomorphic and enlarged nuclei with brisk mitotic activity. The aim of this study was to analyze the clinical outcomes of patients with PHSIL. Clinical data were collected from the electronic medical records of 44 patients with PHSIL. The patients' mean age was 52.1 years. The initial cytological diagnosis was HSIL in 43.2% of patients. High-risk human papillomavirus was detected in 89.5% of patients. The human papillomavirus type was not predominated by one specific type. The patients were treated with conization alone or with conization with subsequent hysterectomy. Two cases of squamous cell carcinoma coexisting with PHSIL, and one case of adenoid basal carcinoma were detected among the surgical specimens. Follow-up cytology revealed negative results for intraepithelial lesions in all patients, except for one patient who experienced recurrent PHSIL 41 months after hysterectomy and underwent laser ablation. The incidence rates of concurrent squamous cell carcinoma (4.5%) and recurrence (2.3%) in our PHSIL cohort were lower than those previously reported in patients with conventional HSIL. Our findings suggest that pleomorphic nuclear change alone in PHSIL was not associated with worse clinical outcomes than conventional HSIL and support the notion that PHSIL does not require more aggressive clinical management than conventional HSIL. However, close follow-up with cytological examination may be necessary to determine the potential risk of recurrence.

Background/Aim: Ovarian endometrioid carcinoma (EC) and high-grade serous carcinoma (HGSC) may exhibit various growth patterns and mimic mesonephric-like adenocarcinoma (MLA). We investigated the clinicopathological and molecular features of ovarian carcinomas with mesonephric-like differentiation (MLD). Patients and Methods: We analyzed the electronic medical records and pathology slides of two EC-MLD and three HGSC-MLD patients, and conducted immunostaining and targeted sequencing of their samples. Results: All cases showed architectural diversity, compactly aggregated small tubules and ducts, and eosinophilic intraluminal secretions, indicating the possibility of an ovarian MLA. However, the following histological and immunophenotypical features confirmed the diagnoses of EC-MLD and HGSC-MLD: squamous, tubal, and sertoliform differentiation; serous tubal intraepithelial carcinoma; solid, endometrioid, transitional (SET) feature; solid, transitional, endometrioid, mucinous-like (STEM) feature; diffuse expression of hormone receptors and Wilms tumor 1; mutant p53 immunostaining pattern; and wild-type v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog gene. Conclusion: A subset of ovarian ECs and HGSCs can display MLD and mimic an MLA. A thorough histological examination combined with ancillary tests is crucial to differentiate between these ovarian neoplastic entities.