ABSTRACT
AIM: Medulloblastomas (MBs) are the most commonly observed malignant brain tumors affecting children; they can be classified into molecular subgroups based on the 2016 and 2021 WHO classifications, as WNT-activated, SHH-activated and TP53-wild type, SHH-activated and TP53-mutant, and non-WNT/non-SHH. However, the molecular methods to determine these subgroups are not easily accessible for routine testing as they are expensive. Here, we investigated the efficacy of immunohistochemical methods to determine molecular subgroups and prognostic predictions of MB. MATERIAL AND METHODS: ß-catenin, GAB1, YAP1, filamin A and p53 were immunohistochemically stained, and MYC and MYCN fluorescent in situ hybridization (FISH) procedures were applied to 218 cases in our series. RESULTS: Based on the histomorphological characteristics of the cases, 67.9% were deemed classic MB; 15.6% as desmoplastic/nodular medulloblastoma (DNMB); 12.8% as large cell/anaplastic (LC/A) MB; 3.7% as medulloblastoma with extensive nodularity (MBEN). Molecular characteristics revealed that 50.5% had non-WNT/non-SHH; 33.9% had SHH-activated and TP53-wildtype; 8.7% had WNT-activated; 6.9% had SHH-activated and TP53-mutant. According to the survival curves, LC/A MBs or non-WNT/non-SHH tumors showed the worst prognosis, whereas DNMBs and WNT-activated tumors showed the best prognosis. Classic MBs or SHH-activated tumors showed a moderate course. MYCN amplification was found to act as an independent poor prognostic factor in the study. CONCLUSION: The distribution of histological subtypes and molecular subgroups, amplification rates, and prognostic data obtained through immunohistochemical methods in our study were consistent with those reported in the literature. It was therefore hypothesized that the determination of molecular subgroups by immunohistochemical methods can be useful in daily diagnostic practice, especially in centers with limited access to molecular techniques.
ABSTRACT
According to the 2021 World Health Organization classification of brain tumors, astrocytomas containing a CDKN2A/B homozygous deletion (HD) are designated as grade 4 even when no microvascular proliferation and/or necrosis is present. In this study, we aimed to investigate the relationship between CDKN2A HD and loss of methylthioadenosine phosphorylase (MTAP) expression in adult-type IDH-mutant gliomas and to assess the sensitivity and specificity of MTAP immunohistochemistry (IHC) along with interobserver agreement as a surrogate biomarker for CDKN2A HD. Eighty-eight astrocytomas and 71 oligodendrogliomas cases that were diagnosed between 2014 and 2021 at Hacettepe University were selected and tissue microarrays were conducted to perform CDKN2A fluorescence in situ hybridization and MTAP IHC. Twenty-five (15.7%) cases harbored CDKN2A HD. MTAP loss was detected in 28 (15.7%) cases by the first observer and 27 (17%) cases by the second observer. The sensitivity and specificity of MTAP were calculated as 88% and 95.52%-96.27% for 2 observers. A very good/perfect agreement was noted between the observers (Cohen kappa coefficient = 0.938). Intratumoral heterogeneity was observed in 4 cases. MTAP IHC was found to be a reliable surrogate biomarker as a possible alternative to CDKN2A HD identification with a high sensitivity and specificity along with high interobserver agreement.
Subject(s)
Astrocytoma , Glioma , Purine-Nucleoside Phosphorylase , Adult , Humans , Immunohistochemistry , Homozygote , In Situ Hybridization, Fluorescence , Reproducibility of Results , Sequence Deletion , Glioma/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Astrocytoma/geneticsABSTRACT
Glioblastoma is one of the most devastating neoplasms of the central nervous system. This study focused on the development of serum extracellular vesicle (EV)-based glioblastoma tumor marker panels that can be used in a clinic to diagnose glioblastomas and to monitor tumor burden, progression, and regression in response to treatment. RNA sequencing studies were performed using RNA isolated from serum EVs from both patients (n = 85) and control donors (n = 31). RNA sequencing results for preoperative glioblastoma EVs compared to control EVs revealed 569 differentially expressed genes (DEGs, 2XFC, FDR < 0.05). By using these DEGs, we developed serum-EV-based biomarker panels for the following glioblastomas: wild-type IDH1 (96% sensitivity/80% specificity), MGMT promoter methylation (91% sensitivity/73% specificity), p53 gene mutation (100% sensitivity/89% specificity), and TERT promoter mutation (89% sensitivity/100% specificity). This is the first study showing that serum-EV-based biomarker panels can be used to diagnose glioblastomas with a high sensitivity and specificity.
ABSTRACT
Periventricular white matter lesions (WMLs) are common MRI findings in migraine with aura (MA). Although hemodynamic disadvantages of vascular supply to this region create vulnerability, the pathophysiological mechanisms causing WMLs are unclear. We hypothesize that prolonged oligemia, a consequence of cortical spreading depolarization (CSD) underlying migraine aura, may lead to ischemia/hypoxia at hemodynamically vulnerable watershed zones fed by long penetrating arteries (PAs). For this, we subjected mice to KCl-triggered single or multiple CSDs. We found that post-CSD oligemia was significantly deeper at medial compared to lateral cortical areas, which induced ischemic/hypoxic changes at watershed areas between the MCA/ACA, PCA/anterior choroidal and at the tip of superficial and deep PAs, as detected by histological and MRI examination of brains 2-4 weeks after CSD. BALB-C mice, in which MCA occlusion causes large infarcts due to deficient collaterals, exhibited more profound CSD-induced oligemia and were more vulnerable compared to Swiss mice such that a single CSD was sufficient to induce ischemic lesions at the tip of PAs. In conclusion, CSD-induced prolonged oligemia has potential to cause ischemic/hypoxic injury at hemodynamically vulnerable brain areas, which may be one of the mechanisms underlying WMLs located at the tip of medullary arteries seen in MA patients.
Subject(s)
Cortical Spreading Depression , Migraine with Aura , White Matter , Mice , Humans , Animals , Cortical Spreading Depression/physiology , Constriction , Mice, Inbred BALB C , Arteries , IschemiaABSTRACT
OBJECTIVE: Our understanding of IgG4-RD and pachymeningitis has grown substantially, but the optimal approach for diagnosis, management, and long-term outcomes is still an area of uncertainty. METHODS: HUVAC is a database for IgG4-RD patients, this database was retrospectively evaluated for pachymeningeal disease. Demographic, clinical, serological, imaging, histopathological data, and treatment details were re-interpreted in patients with pachymeningitis. RESULTS: Among 97 patients with IgG4-RD, 6 (6.2%) had pachymeningitis. None of these patients had extracranial features, and also, in most of the patients, serum IgG4 levels were normal. Tentorium cerebelli and transverse sinus dura were the most commonly involved in the posterior fossa. During 18 months of median follow-up on steroid+-rituximab, none of them relapsed as pachymeningitis. CONCLUSION: Our patients were mainly older males with sole neurological involvement. Non-specific headache was the most common manifestation, and serum IgG4 levels were not useful for diagnosis. Typical radiology and tentorial thickening should suggest IgG4-RD and prompt an early biopsy. Moreover, accompanying hypophysitis could also be a clue. With steroids+ rituximab treatment, no relapse related to meningeal involvement was seen in long-term follow-up.
Subject(s)
Immunoglobulin G4-Related Disease , Meningitis , Male , Humans , Immunoglobulin G , Immunoglobulin G4-Related Disease/diagnosis , Immunoglobulin G4-Related Disease/drug therapy , Immunoglobulin G4-Related Disease/pathology , Follow-Up Studies , Rituximab/therapeutic use , Retrospective Studies , Meningitis/diagnostic imaging , Meningitis/drug therapyABSTRACT
In our manuscript, we propose a common terminology in the Turkish language for the newly adopted WHO classification of the CNS tumors, also known as the WHO CNS 5th edition. We also comment on the applicability of this new scheme in low and middle income countries, and warn about further deepening disparities between the global north and the global south. This division, augmented by the recent COVID-19 pandemic, threatens our ability to coordinate efforts worldwide and may create significant disparities in the diagnosis and treatment of cancers between the "haves" and the "have nots".
Subject(s)
COVID-19 , Central Nervous System Neoplasms , Central Nervous System Neoplasms/diagnosis , Developing Countries , Humans , Language , Pandemics , World Health OrganizationABSTRACT
OBJECTIVE: To share our clinical experience of 25 years and identify prognostic factors for progression-free and overall survival in pediatric intracranial ependymomas. METHODS: In total, 61 children who were treated between 1995 and 2020 in a single institution were included in the study. Medical records of the patients were retrospectively reviewed to obtain and analyze the following data: patient age at first surgery, sex, presenting symptoms, hydrocephalus and any invasive treatment, anatomic site, extent of resection, pathologic grade, time to progression, and time to death. Progression-free and overall survival rates and affecting factors were analyzed by Kaplan-Meier method. RESULTS: Dysphagia, number of surgeries, and spinal seeding were associated with progression free and overall survival in univariate analysis. The extent of resection, World Health Organization grade, and visual problems were also associated with progression whereas sex was associated with overall survival. Cox regression identified the extent of resection and single surgery as an independent prognostic factor for progression-free survival. No independent factor was found for overall survival. CONCLUSIONS: This single center experience of 25 years confirms the beneficial effect of gross total resection on disease progression. Although spinal seeding seems to affect survival rates, greater number of cases are needed to reveal its full effect.
Subject(s)
Brain Neoplasms , Ependymoma , Brain Neoplasms/surgery , Child , Disease-Free Survival , Ependymoma/pathology , Humans , Prognosis , Retrospective Studies , Treatment OutcomeABSTRACT
PURPOSE: Hypophysitis is a heterogeneous condition that includes inflammation of the pituitary gland and infundibulum, and it can cause symptoms related to mass effects and hormonal deficiencies. We aimed to evaluate the potential role of machine learning methods in differentiating hypophysitis from non-functioning pituitary adenomas. METHODS: The radiomic parameters obtained from T1A-C images were used. Among the radiomic parameters, parameters capable of distinguishing between hypophysitis and non-functioning pituitary adenomas were selected. In order to avoid the effects of confounding factors and to improve the performance of the classifiers, parameters with high correlation with each other were eliminated. Machine learning algorithms were performed with the combination of gray-level run-length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray-level co-occurrence entropy. RESULTS: A total of 34 patients were included, 17 of whom had hypophysitis and 17 had non-functioning pituitary adenomas. Among the 38 radiomics parameters obtained from post-contrast T1-weighted images, 10 tissue features that could differentiate the lesions were selected. Machine learning algorithms were performed using three selected parameters; gray level run length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray level co-occurrence entropy. Error matrices were calculated by using the machine learning algorithm and it was seen that support vector machines showed the best performance in distinguishing the two lesion types. CONCLUSIONS: Our analysis reported that support vector machines showed the best performance in distinguishing hypophysitis from non-functioning pituitary adenomas, emphasizing the importance of machine learning in differentiating the two lesions.
Subject(s)
Hypophysitis , Pituitary Neoplasms , Humans , Machine Learning , Magnetic Resonance Imaging/methods , Pituitary Neoplasms/diagnostic imaging , Pituitary Neoplasms/pathology , Retrospective StudiesABSTRACT
BACKGROUND: The presence of metastatic disease is one of the most important factors limiting survival in patients with uveal melanoma. Studies on proteins associated with metastatic mechanisms are sparse in the literature. METHODS: Enucleation samples from 15 patients with metastatic uveal melanoma (Group 1), liver metastasectomy samples from 8 patients with metastatic uveal melanoma (Group 2), and enucleation samples from 20 patients with non-metastatic uveal melanoma as controls (Group 3) were included in the study. Antibodies against heat shock protein 27 (HSP-27), BRCA1-associated protein-1 (BAP1), C-C chemokine receptor 7 (CCR7), B-Raf proto-oncogene serine/threonine-protein kinase V600E (BRAF V600E), and programmed death-ligand 1 (PD-L1) were used to detect immunoreactivity in each sample by immunohistochemical methods. Correlations between these expressed proteins and selected histopathological and clinical features, and metastatic process were investigated. RESULTS: The frequencies of HSP-27 (median score: Group 1: 8, Group 2: 12, Group 3: 4) and BRAF V600E expressions (number of samples: Group 1: 4 (26.7%), Group 2: 1 (12.5%), Group 3: 0 (0%)), and BAP1 expression loss (number of samples : Group 1: 12 (80%), Group 2: 8 (100%), Group 3: 9 (45%)) were higher in samples from patients with metastatic uveal melanoma (Group 1 + 2) than in those from patients with non-metastatic disease (Group 3) (P = 0.001, P = 0.034, and P = 0.007, respectively). CCR7 expression (median score: Group 1: 0, Group 2: 2, Group 3: 3) was similar among these three groups (P = 0.136). No samples exhibited PD-L1 expression (P = 1.000). One-unit increases in the HSP-27 expression level and BAP1 expression loss were significantly related to 1.375- and 7.855-fold increases in the risk of metastasis, respectively (P = 0.007 and P = 0.017). CONCLUSION: HSP-27 and BAP1 are considered to be associated with metastasis, indicating these proteins as potential treatment targets in metastatic uveal melanoma.
Subject(s)
B7-H1 Antigen , Liver Neoplasms , B7-H1 Antigen/genetics , HSP27 Heat-Shock Proteins/genetics , Humans , Liver Neoplasms/genetics , Melanoma , Proto-Oncogene Proteins B-raf/genetics , Receptors, CCR7 , Tumor Suppressor Proteins , Ubiquitin Thiolesterase/genetics , Uveal NeoplasmsABSTRACT
OBJECTIVE: Epilepsy surgery has shown efficacy in children. We aimed to assess long-term seizure outcome in children who underwent epilepsy surgery and determine predictive factors for seizure freedom. METHODS: This is a retrospective study of 196 children who underwent epilepsy surgery between 1994 and 2015 and had a minimum postoperative follow-up of 5 years. RESULTS: The median age at the time of surgery was 9.5 (0.08-19.8) years; 110 (56.1%) had temporal, 62 (31.6%) had extratemporal resections, and 24 (12.2%) had hemispheric surgery. The duration of postsurgical follow-up was between 5 and 20 years (mean±SD: 7 ± 3.2). Overall, 129 of 196 (65.8%) patients had Engel class I outcome at final visit. Among patients who underwent temporal, extratemporal and hemispheric surgery; 84 of 110 (76.4%), 34 of 62 (54.8%), and 11 of 24 (45.8%) patients had complete seizure freedom, respectively (p: 0.016). Patients with tumors had the best outcome, with 83.1% seizure freedom. The number of preoperative antiseizure medications (OR 3.19, 95% CI 1.07-9.48), the absence of postoperative focal epileptiform discharges (OR 8.98, 95% CI 4.07-19.79) were independent predictors of seizure freedom. Across two decades, the age at surgery was decreased (p: 0.003), overall seizure freedom (61.8% vs 68%) did not differ. In the past decade, a higher proportion of malformations of cortical development was operated (14.7% vs 35.9%, p: 0.007). SIGNIFICANCE: Our findings showed favorable long-term seizure outcome in children who underwent epilepsy surgery. The results are encouraging for developing centers with limited resources to establish pediatric epilepsy programs.
Subject(s)
Epilepsy , Seizures , Child , Epilepsy/pathology , Epilepsy/surgery , Humans , Neurosurgical Procedures/methods , Retrospective Studies , Seizures/surgery , Treatment OutcomeABSTRACT
INTRODUCTION: Low-grade epilepsy-associated neuroepithelial tumors (LEATs) create a diagnostic challenge in daily practice and intraoperative pathological consultation (IC) in particular. Squash smears are extremely useful in IC for accurate diagnosis; however, the knowledge on cytopathologic features of LEATs is based on individual case reports. Here, we discuss the 3 most common and well-established entities of LEATs: ganglioglioma (GG), dysembryoplastic neuroepithelial tumor (DNT), and papillary glioneuronal tumor (PGNT). METHODS: Thirty patients who underwent surgery for GG, DNT, and PGNT between 2001 and 2021 were collected. Squash smears prepared during intraoperative consultation were reviewed by 1 cytopathologist and an experienced neuropathologist. RESULTS: Among the 30 tumors, 16 (53.3%) were GG, 11 (36.6%) DNT, and 3 (10%) PGNT. Cytomorphologically, all of the 3 tumor types share 2 common features such as dual cell population and vasculocentric pattern. GG smears were characteristically composed of dysplastic ganglion cells and piloid-like astrocytes on a complex architectural background of thin- to thick-walled vessels. DNT, on the other hand, showed oligodendroglial-like cells in a myxoid thin fibrillary background associated with a delicate capillary network. Common cytological features of PGNT were hyperchromatic cells with narrow cytoplasm surrounding hyalinized vessels forming a pseudopapillary pattern and bland cells with neuroendocrine nuclei dispersed in a neuropil background. CONCLUSION: A higher diagnostic accuracy can be obtained when squash smears are applied with frozen sections. However, it is important to integrate clinical and radiologic features of the patient as well as to know the cytopathologic features of the LEAT spectrum in the context of differential diagnosis to prevent misinterpretation in the IC.
Subject(s)
Brain Neoplasms , Epilepsy , Neoplasms, Neuroepithelial , Brain Neoplasms/complications , Brain Neoplasms/pathology , Brain Neoplasms/surgery , Cytodiagnosis/methods , Epilepsy/diagnosis , Epilepsy/etiology , Epilepsy/surgery , Ganglioglioma/complications , Ganglioglioma/pathology , Ganglioglioma/surgery , Humans , Intraoperative Period , Neoplasms, Neuroepithelial/complications , Neoplasms, Neuroepithelial/pathology , Neoplasms, Neuroepithelial/surgery , Referral and ConsultationABSTRACT
INTRODUCTION: Isolated spinal cord angiitis (ISCA) is very rare disease. But, it is frequently encountered in the differential diagnosis of atypical spinal cord syndromes. CASE PRESENTATION AND REVIEW OF THE LITERATURE: We present a 31-year-old male who presented with progressive paraparesis, and diagnosed with pathologically confirmed ISCA. Longitudinal cystic transverse myelitis was documented in spinal MRI. He responded well to cyclophosphamide and steroid combination, and no relapse was noted during the 4-year follow-up. A standard systematic analysis of the germane literature disclosed 15 more ISCA cases. In total 16 cases (mean age: 46.5, 10 males), ISCA was diagnosed with pathological evaluation in all (Biopsy in 11, Autopsy in 5). MRI lesion is characterized by usually multisegmental longitudinal and sometimes cystic expansile lesions. In seven cases, it was described as "(pseudo)tumoral" by the authors. Albeit absence of elevation of CSF protein/WBC or "compatible" spinal MRI lesion may aid to exclude ISCA to some extent, pathological confirmation is currently necessary for the diagnosis. In 11 cases, ISCA was treated similar to primary supratentorial vasculitis. Mortality rate is 31%. DISCUSSION: ISCA diagnosis, a typical example of which we have presented here, can only be established by tissue examination. However, noninvasive diagnostic criteria are critically needed. Our data suggest that this can only be possible with multinational multicenter prospective registry.
Subject(s)
Myelitis, Transverse , Spinal Cord Diseases , Vasculitis, Central Nervous System , Adult , Humans , Magnetic Resonance Imaging , Male , Multicenter Studies as Topic , Myelitis, Transverse/pathology , Neoplasm Recurrence, Local/pathology , Spinal Cord/diagnostic imaging , Spinal Cord/pathology , Spinal Cord Diseases/diagnostic imaging , Spinal Cord Diseases/pathology , Vasculitis, Central Nervous System/diagnostic imaging , Vasculitis, Central Nervous System/drug therapyABSTRACT
BACKGROUND: Understanding the secondary damage mechanisms of traumatic brain injury (TBI) is essential for developing new therapeutic approaches. Neuroinflammation has a pivotal role in secondary brain injury after TBI. Activation of NLRP3 inflammasome complexes results in the secretion of proinflammatory mediators and, in addition, later in the response, microglial activation and migration of the peripheral immune cells into the injured brain are observed. Therefore, these components involved in the inflammatory process are becoming a new treatment target in TBI. Dexmedetomidine (Dex) is an effective drug, widely used over the past few years in neurocritical care units and during surgical operations for sedation and analgesia, and has anti-inflammatory effects, which are shown in in vivo studies. The aim of this original research is to discuss the anti-inflammatory effects of different Dex doses over time in TBI. METHODS: Brain injury was performed by using a weight-drop model. Half an hour after the trauma, intraperitoneal saline was injected into the control groups and 40 and 200 µg/kg of Dex were given to the drug groups. Neurological evaluations were performed with the modified Neurological Severity Score before being killed. Then, the mice were killed on the first or the third day after TBI and histopathologic (hematoxylin-eosin) and immunofluorescent (Iba1, NLRP3, interleukin-1ß, and CD3) findings of the brain tissues were examined. Nonparametric data were analyzed by using the Kruskal-Wallis test for multiple comparisons, and the Mann-Whitney U-test was done for comparing two groups. The results are presented as mean ± standard error of mean. RESULTS: The results showed that low doses of Dex suppress NLRP3 and interleukin-1ß in both terms. Additionally, high doses of Dex cause a remarkable decrease in the migration and motility of microglial cells and T cells in the late phase following TBI. Interestingly, the immune cells were influenced by only high-dose Dex in the late phase of TBI and it also improves neurologic outcome in the same period. CONCLUSIONS: In the mice head trauma model, different doses of Dex attenuate neuroinflammation by suppressing distinct components of the neuroinflammatory process in a different timecourse that contributes to neurologic recovery. These results suggest that Dex may be an appropriate choice for sedation and analgesia in patients with TBI.
Subject(s)
Brain Injuries, Traumatic , Dexmedetomidine , Animals , Anti-Inflammatory Agents , Brain Injuries, Traumatic/complications , Dexmedetomidine/pharmacology , Dexmedetomidine/therapeutic use , Disease Models, Animal , Humans , Interleukin-1beta/therapeutic use , Mice , NLR Family, Pyrin Domain-Containing 3 Protein , Neuroinflammatory DiseasesABSTRACT
PURPOSE: Synthetic MRI (SyMRI) enables to quantify brain tissue and morphometry. We aimed to investigate the WM and myelin alterations in patients with unilateral hippocampal sclerosis (HS) with SyMRI. METHODS: Adult patients with isolated unilateral HS and age-matched control subjects (CSs) were included in this study. The SyMRI sequence QRAPMASTER in the coronal plane perpendicular to the hippocampi was obtained from the whole brain. Automatic segmentation of the whole brain was processed by SyMRI Diagnostic software (Version 11.2). Two neuroradiologists also performed quantitative analyses independently from symmetrical 14 ROIs placed in temporal and extratemporal WM, hippocampi, and amygdalae in both hemispheres. RESULTS: Sixteen patients (F/M = 6/10, mean age = 32.5 ± 11.3 years; right/left HS: 8/8) and 10 CSs (F/M = 5/5, mean age = 30.7 ± 7 years) were included. Left HS patients had significantly lower myelin and WM volumes than CSs (p < .05). Myelin was reduced significantly in the ipsilateral temporal lobe of patients than CSs, greater in left HS (p < .05). Histopathological examination including luxol fast blue stain also revealed myelin pallor in all of 6 patients who were operated. Ipsilateral temporal pole and sub-insular WM had significantly reduced myelin than the corresponding contralateral regions in patients (p < .05). No significant difference was found in WM values. GM values were significantly lower in hippocampi in patients than CSs (p < .05). CONCLUSION: SyMRI revealed myelin reduction in the ipsilateral temporal lobe and sub-insular WM of patients with HS. Whether this finding correlates with electrophysiological features and SyMRI could serve as lateralization of temporal lobe epilepsy need to be investigated.
Subject(s)
Epilepsy, Temporal Lobe , Myelin Sheath , Adult , Epilepsy, Temporal Lobe/diagnostic imaging , Epilepsy, Temporal Lobe/pathology , Hippocampus/diagnostic imaging , Hippocampus/pathology , Humans , Magnetic Resonance Imaging , Myelin Sheath/pathology , Sclerosis/diagnostic imaging , Sclerosis/pathology , Young AdultABSTRACT
Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response.
Subject(s)
Astrocytoma , Tuberous Sclerosis , Humans , Astrocytoma/metabolism , DNA Methylation/genetics , Sirolimus/therapeutic use , Tuberous Sclerosis/complications , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathologyABSTRACT
PURPOSE: Apocrine adenocarcinoma is a cutaneous adnexal malignancy which can rarely arise from ocular structures. In this retrospective study, we report our experience with four patients who had primary periocular apocrine adenocarcinoma initially presenting with an orbital tumor. METHODS: Data extracted included demographics, clinical, imaging, and histopathological features, and treatment outcomes. RESULTS: The definitive diagnosis was established after an incisional biopsy in all cases. Two patients were then managed with exenteration. The third patient underwent local resection followed by radiotherapy but had to be exenterated because of new tumor formation 7 years later. The fourth patient had to be managed with oral bicalutamide which kept the tumor stable for 3 years. Recurrence-free survival for the radical surgical treatment group was 10, 6, and 7 years respectively. CONCLUSION: Periocular apocrine adenocarcinoma may insidiously develop as an orbital mass without any clinically detectable primary eyelid skin or conjunctival lesions. This tumor must be in the differential diagnosis of medially located ill-defined orbital masses in patients over 50 years of age. Orbital exenteration appeared as an effective treatment of apocrine adenocarcinoma with orbital extension. Anti-androgenic treatment in an androgen receptor-positive tumor provided temporary local tumor control.
Subject(s)
Adenocarcinoma , Orbital Diseases , Orbital Neoplasms , Skin Neoplasms , Adenocarcinoma/diagnosis , Adenocarcinoma/therapy , Humans , Middle Aged , Orbit Evisceration , Orbital Diseases/surgery , Orbital Neoplasms/diagnosis , Orbital Neoplasms/therapy , Retrospective Studies , Skin Neoplasms/pathologyABSTRACT
Poorly differentiated chordoma is a newly recognized entity in the recent World Health Organization (WHO) classification of tumors of soft tissue and bone. Slightly over 60 such cases have been documented. Herein, we present a clinicopathological profile, including radiological features, of nine cases, which occurred in five males and four females, with age varying from 1 to 29 years (median = 43), in the cervical spine (n = 2), skull base (n = 2), clivus (n = 2), thoracic spine (n = 1) lumbar spine (n = 1) and coccyx (n = 1) Average tumor size was 4.8 cm. None of the 6-referral cases was diagnosed as a poorly differentiated chordoma at the referring laboratory. Histopathologically, all cases displayed a cellular tumor comprising polygonal cells (n = 9) displaying moderate to marked nuclear pleomorphism with prominent nucleoli (n = 7), eosinophilic (n = 9) to vacuolated cytoplasm (n = 7), rhabdoid morphology (n = 4), interspersed mitotic figures (n = 5), focal necrosis (n = 6) and inflammatory cells (n = 9). A single tumor displayed areas resembling classic chordoma, transitioning into poorly differentiated areas. There were multinucleate giant cells and physaliphorous cells in two tumors, each, respectively. Immunohistochemically, tumor cells were positive for AE1/AE3 (7/7), EMA (7/7), cytokeratin (CK) MNF116 (1/1), OSCAR (1/1), brachyury (9/9, diffusely), S100P (4/7, mostly focally), and glypican 3(2/4). SMARCB1/INI1 was completely lost in all nine tumors. A single case tested by FISH showed homozygous deletion of the SMARCB1 gene. Therapeutically (n = 7), all patients were treated with surgical resection (invariably incomplete) (n = 5), followed by adjuvant radiation therapy (n = 4) and chemotherapy (n = 4). While a single patient partially responded to treatment and another patient is alive with no evidence of disease after 23 years, three patients died of disease, six, eight, and 11 months post-diagnosis, despite adjuvant treatments. A single patient presented with a metastatic lung nodule, while another developed widespread metastasis. Poorly differentiated chordomas display a spectrum of features, are associated with a lower index of suspicion for a diagnosis, and display aggressive outcomes. Critical analysis of radiological and histopathological features, including necessary immunostains (brachyury and SMARCB1/INI1), is necessary for their timely diagnosis. These tumors show loss of SMARCB1/INI1 immunostaining and homozygous deletion of INI1/SMARCB1 gene.
Subject(s)
Chordoma , SMARCB1 Protein , Adolescent , Adult , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Child , Child, Preschool , Chordoma/diagnosis , Chordoma/diagnostic imaging , Chordoma/genetics , Chordoma/pathology , Female , Humans , Immunohistochemistry , Infant , Male , Neoplasm Metastasis/pathology , SMARCB1 Protein/analysis , SMARCB1 Protein/genetics , Sequence DeletionABSTRACT
Spheroidal corneal degeneration is predominantly seen in advanced age and hereditary predisposition to this disorder is very rare. This report describes the occurrence of bilateral band-shaped spheroidal corneal degeneration in two siblings.
Subject(s)
Corneal Dystrophies, Hereditary , Siblings , Cornea , HumansABSTRACT
OBJECTIVES: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. MATERIALS AND METHODS: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. RESULTS: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. CONCLUSION: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.
Subject(s)
Alopecia/genetics , CADASIL/genetics , Cerebral Infarction/genetics , High-Temperature Requirement A Serine Peptidase 1/genetics , Leukoencephalopathies/genetics , Mutation , Spinal Diseases/genetics , Adult , Age of Onset , Alopecia/diagnosis , Alopecia/physiopathology , CADASIL/diagnosis , CADASIL/physiopathology , Cerebral Infarction/diagnosis , Cerebral Infarction/physiopathology , Consanguinity , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , Heredity , Heterozygote , Homozygote , Humans , Leukoencephalopathies/diagnosis , Leukoencephalopathies/physiopathology , Male , Middle Aged , Pedigree , Phenotype , Severity of Illness Index , Spinal Diseases/diagnosis , Spinal Diseases/physiopathologyABSTRACT
Objective This study was aimed to assess the clinical aggressiveness of pituitary neoplasms that were previously defined as atypical adenomas. Methods A total of 1,042 pituitary adenomas were included in the study and 101 of them were diagnosed as atypical adenoma. Demographic characteristics, radiological evaluations, and clinical information were obtained from a computer-based patient database. Cases were categorized as atypical or typical using the criteria listed in 2004 Classification of Tumors of Endocrine Organs. Results The cure and reoperation rates did not show any statistically significant difference between the typical and atypical adenomas. However, a higher K i -67 labeling index was found to be associated with a higher rate of reoperation ( p = 0.008) in atypical adenomas. Of note, cavernous sinus invasion or parasellar extension was found to be associated with lower cure rates in patients with atypical pituitary adenomas ( p < 0.001 and p = 0.001, respectively). Conclusion Although atypical pituitary adenomas are known to be more invasive, this study demonstrated that the reoperation and cure rates are the same for typical and atypical adenomas. Our findings advocate for omitting the use of atypical adenoma terminology based solely on pathological evaluation. As stated in the 4th edition of the World Health Organization (WHO) classification, accurate tumor subtyping, evaluation of proliferation by means of mitotic count and K i -67 labeling index, and radiological and intraoperative assessments of tumor invasion should be taken into consideration in the management of such neoplasms.