Abstract Myxopapillary ependymoma (MPE) is a WHO grade 2 tumor that typically arises in the lumbosacral spine of children and young adults. Surgery is often curative, though radiotherapy may be used following subtotal resection or in rare cases of metastatic disease. Radiation-induced gliomas (RIGs) are known long-term complications of CNS-directed radiotherapy, but most occur in the cerebral hemispheres and are rarely of the small cell glioblastoma (scGBM) variety. Spinal scGBM is exceedingly rare. To our knowledge, this is the first documented case of spinal scGBM following proton beam therapy for pediatric MPE. A 17-year-old male presented with neurologic decline and was diagnosed with metastatic MPE, including a primary tumor at T11-L1. He underwent near-total resection followed by craniospinal irradiation (CSI) using proton therapy. Treatment doses included: neuraxis, 36 Gy; cerebellum to S3, 50.4 Gy; and right cerebellum, C5, T6-7, and T9-S3, 52.2 Gy. Surveillance imaging was stable, though complications included chronic neuropathy. Six years post-treatment, routine imaging identified a small enhancing lesion at C4. Within two months, the patient developed progressive neck pain, right arm weakness, and gait disturbance. MRI revealed a 1.5 x 1.4 x 3.8 cm expansile intramedullary tumor from C3-C5. Partial resection showed small round blue cells with high nuclear-to-cytoplasmic ratio, apoptosis, occasional mitoses, NKX2.2 and Olig2 positivity, and Ki67 >90%. Sequencing revealed PDGFRA and CDK4 amplification and an MRE11 mutation, consistent with scGBM. Small cell glioblastoma is a rare, aggressive variant usually confined to the brain. This report satisfies the standard criteria for RIGs, namely: (1) onset more than two years after radiotherapy, (2) localization within the irradiated field, and (3) histopathology distinct from the original lesion. This case underscores the need for long-term surveillance and expands the spectrum of RIGs to include spinal scGBM, a tumor subtype not previously associated with radiation exposure.

Abstract Radiation-induced glioblastomas (RIGs) are aggressive secondary neoplasms that arise following craniospinal radiation, characterized by distinct molecular including IDH-wildtype, PDGFRA amplication, and loss of CDKN2A/B. We report the case of a 24-year old male that was initially diagnosed with disseminated myxopapillary ependymoma in 2018 with a large tumor T11-L1 with nodular foci of enhancement throughout the lumbar spinal canal and in the cerebellum. He underwent surgical resection of the T11-L1 mass and subsequent craniospinal proton radiation. The patient remained stable until February 2025, when he presented with right-sided neck pain and right arm weakness. Imaging demonstrated a new expansile intramedullary tumor at C3-C5. Surgical resection of this recurrence revealed a small-cell glioblastoma, exhibiting IDH-wildtype status and PDGFRA amplification. The tumor did not have the classic loss of CDKN2A/B, but does have CDK4 amplification, affecting the cell cycle similarly. Unfortunately, the patient’s neurological status continued to decline after surgical resection due to the aggressive nature of RIGs, resulting in wheelchair dependence. Repeat imaging demonstrated progression of the C3-5 lesion as well as a new contrast-enhancing tumor in the medulla. The patient is currently undergoing medical management with bevacizumab and temozolomide in addition to palliative radiation to the cervical spinal tumor of 3500 cGy in 10 fractions. This case presentation underscores the clinical challenge presented by RIGs, particularly spinal glioblastomas, which are exceedingly rare and aggressive. Despite extensive multimodal interventions and advancements in tumor molecular testing, the prognosis remains poor. Future research into the molecular drivers of radiation-induced gliomas, specifically targeting amplified PDGFRA and CDK4 pathways, may enhance understanding and treatment of these aggressive secondary malignancies.

Integrated genetic profiling of archival pediatric high-grade glial tumors and reassessment with 2021 WHO classification of paediatric CNS tumours

Letter to the Editor Regarding “Small Cell Glioblastoma of the Sella Turcica Region: Case Report and Review of the Literature”

Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co-occurring alterations including cyclin-dependent kinase 4 (CDK4) amplification, receptor tyrosine-protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled-coil containing protein 1 (FGFR1-TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin-protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m2) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non-radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard-of-care therapies for patients with known Gorlin syndrome-associated glioblastomas and sonic hedgehog pathway mutations.

Glioblastoma is the most common malignant central nervous system (CNS) tumor in adults. Acute common clinical symptoms include headache, seizure, behavior changes, focal neurological deficits, and signs of increased intracranial pressure. The classic MRI finding of glioblastoma is an irregularly shaped, rim-enhancing or ring-enhancing lesion with a central dark area of necrosis. This constellation of features correlates with microscopic findings of tumor necrosis and microvascular proliferation. Besides these common features, several well-recognized histological subtypes include giant cell glioblastoma, granular cell glioblastoma, gliosarcoma, glioblastoma with a primitive neuronal component, small cell glioblastoma, and epithelioid glioblastoma. While glioblastoma was historically classified as isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant groups, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and the fifth edition of the WHO Classification of Tumors of the Central Nervous System clearly updated the nomenclature to reflect glioblastoma to be compatible with wildtype IDH status only. Therefore, glioblastoma is now defined as "a diffuse, astrocytic glioma that is IDH-wildtype and H3-wildtype and has one or more of the following histological or genetic features: microvascular proliferation, necrosis, Telomerase reverse transcriptase promoter mutation, Epidermal growth factor receptor gene amplification, +7/-10 chromosome copy-number changes (CNS WHO grade 4)."

Letter to the Editor Regarding “Primary Spinal Cord Small-Cell Glioblastoma: Case Report and Literature Review”

Small cell glioblastoma (SCGBM) is a rare variant with monomorphous cells and deceptively bland nuclei and are often misdiagnosed. Here, we present a case of small cell GBM in a 39-year-old male involving bilateral basal ganglia diagnosed as primary central nervous system lymphoma on MRI. After excision, the tumor showed features of small cell glioblastoma. Clinical features, morphological characteristics and immunohistochemical features of this rare lesion is hence discussed.

Letter to the Editor Regarding “Small Cell Glioblastoma of the Sella Turcica Region: Case Report and Review of the Literature”

e16041 Background: Adjuvant carboplatin reduces relapse risk in clinical stage I (CS1) testicular seminoma, though there is a paucity of long-term safety data. While some studies report that two cycles is more effective than one, there is no randomised trial evidence or consensus on the optimal number of cycles. European guidelines recommend a risk-based approach to consider adjuvant carboplatin in those with either rete testis involvement (RTI) or tumour size > 4cm, and surveillance for other patients. We report long-term outcomes of 2 cycles of adjuvant carboplatin dosed at area under the curve (AUC) of 7 as standard management of CS1 seminoma since 2000. Methods: We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at the Waikato, Lakes and Bay of Plenty District Health Boards. We also collected information on mortality, causes of death and subsequent malignant neoplasms (SMN). Results: Of 160 patients, median age 39 (range 20-73) years, 154 received 2 cycles of carboplatin: 148 dosed at AUC7 and six at AUC6; another six patients had one cycle of carboplatin AUC7, curtailed due to toxicity in 3 patients. Two relapses occurred: one at 10 months (in hindsight stage 2a at diagnosis) and one at 22 months (died of pulmonary embolism 2 months after achieving complete response with BEP chemotherapy). Neither RTI (present in 21.3%) nor tumour size > 4cm (in 43.1%) were predictive of relapse. No patients died of seminoma. At median follow up of 109 (range 17-209) months, relapse-free survival was 98.7%, overall survival was 97.5% and disease-specific survival was 100%. A SMN occurred in 11 patients (6.9%) at median 96 months and caused 4 deaths (melanoma, myeloma, small cell lung cancer and glioblastoma); 4 patients (2.6%) had a contralateral testicular germ cell tumour (at median 69 months). One patient had persistent grade 1 thrombocytopenia at 46 months. Conclusions: This data adds to the body of evidence that two cycles of carboplatin AUC7 is safe, effective adjuvant treatment for CS1 seminoma. It did not have significant long-term adverse effects in our population.

Objective: Small cell glioblastoma is a high anaplastic variant of GBM characterized by a monomorphic proliferation of small or medium cells with oval nuclei and scanty cytoplasm. Case study: The cytologic findings of a small cell glioblastoma in 11-year-old male and histologic features of the tumor using immunocytohistochemistry are reported. Conclusion: The accurate preoperative diagnosis of a small cell glioblastoma is crucial to developing a curative surgical plan. Cytology- confirmed by histology- provides a convenient, safe and effective approach to solving a challenging differential diagnosis. (www.actabiomedica.it)

Small cell glioblastoma (SCGBM) is a variant of glioblastomas characterized by a predominant population of small and monomorphic glial cells. The aim of the present study was to investigate clinical, neuroimaging, pathologic, and genetic features of SCGBM. The clinicopathologic and genetic features were evaluated in 14 patients with SCGBM. All cases were divided into multifocal and solitary type by MRI, and extent of microvascular proliferation, intratumoral necrosis, and perivascular lymphocytic accumulation were investigated. IDH1 mutations by immunohistochemistry (IDH1 R132H) and 1p 19q codeletion by fluorescence in situ hybridization were detected. Patients ranged from 23 to 92 years of age (median: 71 years), with three females and eleven males. The overall survival time of the patients ranged from 7 to 23 months (mean: 11 months). Nine patients (64%) were the multifocal type. Pathologic study revealed that the microvascular proliferation, necrosis, and lymphocytic infiltration were limited in SCGBM. Immunohistochemically, tumor cells were negative for IDH1 R132H in all patients. FISH analysis demonstrated that no SCGBM had 1p/19q codeletion in informative patients. Our investigation suggested that an elderly onset and multifocal lesions were characteristics of SCGBM associated with degradation of the immune response, infiltrative feature of tumor cells, and an unfavorable prognosis.

Clinical Outcomes of Small Cell Glioblastoma or Glioblastoma With Oligodendroglioma Component Treated With Radiation Therapy and Temozolomide

BackgroundCentral nervous system (CNS) tumors are the most common solid tumors that occur in children, however there were few big-data follow-up analysis published in China. Overexpression of epidermal growth factor receptor (EGFR) family members was reported on glioblastoma (GBM) and medulloblastoma (MB) before. However, the correlation between EGFR family members expression with prognosis of MB, supratentorial primitive neuroectodermal tumor (PNET) and small cell GBM is unclear in Chinese children.MethodsA retrospective and survival analysis was performed on children (age ≤ 16 years) diagnosed as CNS primary small cell tumors in the Affiliated Provincial Hospital, Shandong University from 2000 to 2012, including MB (n = 44), PNET (n = 8) and small cell GBM (n = 19). The expression of EGFR, ERBB-2, ERBB-3 and ERBB-4 were detected by immunohistochemistry (IHC). The fluorescence in situ hybridization (FISH) was used to observe the amplification of EGFR and ERBB-2 gene.ResultsMedian survival times of MBs, small GBMs and PNETs were 23 ± 6.7 months, 8 ± 4.7 months and 10 ± 1.4 months. Expression and amplification of ERBB-2, ERBB-3 and ERBB-4 were not observed in all tumor samples. The multiply Cox regression suggested the overexpression and amplification of EGFR were negative prognostic factors for MB. Radiotherapy had the positive function for all pediatric patients.ConclusionOverexpression of EGFR predicts poor outcomes of MBs, small cell GBMs and PNETs, suggesting those three CNS tumor subtypes can be considered as one group for the potential common mechanism. The current individual treatment and big data analysis of pediatric CNS embryonal tumors and GBM continues to be very challenging in China.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7649640001237474

Glioblastoma (GB) is the most common type of malignant tumor of the central nervous system and, despite extensive research, its prognosis is poor. Although recent advances have been made in the treatment of GB with aggressive resection combined with radiochemotherapy, more than three-quarters of GB patients succumb to the disease within two years. The current study presents a highly aggressive case of small cell GB as diagnosed by histological features and immunohistochemistry for vimentin, glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, isocitrate dehydrogenase 1-R132H and p53. The patient was treated using a multidisciplinary treatment strategy, which included temozolomide, CyberKnife radiotherapy and autologous formalin-fixed tumor vaccination. In addition, the patient developed radiation necrosis, which was treated with bevacizumab. In conclusion, three years following the initial diagnosis, the patient continues to experience a successful clinical course, and the observations of the current study demonstrate that a multidisciplinary treatment strategy may be effective for the treatment of aggressive GB.

Small cell glioblastoma is a histological subtype of glioblastoma with characteristic features of highly proliferative, monotonous small glial cells with high nuclear cytoplasm ratio. Morphologically, malignant lymphoma or small cell metastatic carcinoma should be carefully discriminated. Some cases are difficult to differentiate from anaplastic oligodendroglioma. In this report, we present a case of small cell glioblastoma of an elderly man. The lack of IDH1/2 mutation was confirmed by immunohistochemistry and direct sequencing. Fluorescence in situ hybridization revealed the lower rates of chromosome 1p and 19q deletion. Microsatellite analysis disclosed partial 10q alteration near the PTEN locus. Not only morphological and immunohistochemical examinations, but also cytogenetical investigations for IDH1/2 mutation, 1p/19q loss, and PTEN alteration, are strongly supportive methods for the differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma.

It is often easy to distinguish between primary brain tumors and metastases based on morphology alone. However, in some cases immunohistochemistry (IHC) is necessary to obtain a diagnosis, but, as the present case report illustrates, this is not always straightforward. A 75-year old man was admitted to the hospital with left-sided loss of motor function. A MRI revealed a 6 cm tumor in the right temporoparietal area. The histology was consistent with both glioblastoma multiforme (GBM) and small cell lung carcinoma (SCLC) but IHC was suggestive of a SCLC metastasis. PET-CT revealed no enhancement in the lung, so the tumor was treated as a GBM. Eight months after the primary diagnosis a new MRI revealed metastases in the spinal cord, but there was still no enhancement in the lungs. We reviewed the literature concerning markers used to differentiate between GBM and SCLC and found that most of these markers showed limited specificity. It is further discussed whether the case illustrates an example of spontaneous regression of primary SCLC or might be an example of a GMB metastasizing to the spinal cord. Although immunohistochemical markers are of great help in many situations, the case illustrates important limitations and the need for better diagnostic markers.

Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants

The World Health Organization recently updated its classification of central nervous system tumors, adding 8 entities, as well as defining new variants and morphologic patterns of existing entities. Despite the continued refinement of brain tumor histologic classification and grading, there remain some diagnostic "gray zones" that challenge general surgical pathologists and neuropathologists alike. These include the presence of oligodendroglial features in (mixed) oligoastrocytomas and glioblastomas (GBMs), GBM variants (such as small cell GBM), meningioma classification and grading, medulloblastoma variants, ependymoma grading, the presence of "neuronal features" in otherwise morphologically classic gliomas, and low-grade gliomas with high Ki-67 labeling indices. In the current review, we discuss these issues and offer some practical guidelines for dealing with problematic cases.

Gangliogliomas usually present as benign tumors corresponding to World Health Organization (WHO) Grade I. Very rarely, gangliogliomas show histological features of malignancy and are then classified as anaplastic gangliogliomas of WHO Grade III or IV. In most cases, anaplastic gangliogliomas developed after radiation therapy or progression from a pre-existing low-grade ganglioglioma. Here, we report the case of a 77-year-old male patient who was operated on a primary ganglioglioma with a highly anaplastic glial component corresponding to a small-cell glioblastoma. To our knowledge, this is the first reported case of a primary anaplastic ganglioglioma with a small-cell glioblastoma component.