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Purpose: Brain metastases are rare in patients with prostate cancer and portend poor outcome. Prostate-specific membrane antigen positron emission tomography (PSMA PET)/CT scans including the brain have identified incidental tumors. We sought to identify the incidental brain tumor detection rate of PSMA PET/CT performed at initial diagnosis or in the setting of biochemical recurrence., Methods: An institutional database was queried for patients who underwent 68 Ga-PSMA-11 or 18 F-DCFPyL ( 18 F-piflufolastat) PET/CT imaging at an NCI-designated Comprehensive Cancer Center from 1/2018 to 12/2022. Imaging reports and clinical courses were reviewed to identify brain lesions and describe clinical and pathologic features., Results: Two-thousand seven hundred and sixty-three patients underwent 3363 PSMA PET/CT scans in the absence of neurologic symptoms. Forty-four brain lesions were identified, including 33 PSMA-avid lesions: 10 intraparenchymal metastases (30%), 4 dural-based metastases (12%), 16 meningiomas (48%), 2 pituitary macroadenomas (6%), and 1 epidermal inclusion cyst (3%) (incidences of 0.36, 0.14, 0.58, 0.07, and 0.04%). The mean parenchymal metastasis diameter and mean SUVmax were 1.99 cm (95%CI:1.25-2.73) and 4.49 (95%CI:2.41-6.57), respectively. At the time of parenchymal brain metastasis detection, 57% of patients had no concurrent extracranial disease, 14% had localized prostate disease only, and 29% had extracranial metastases. Seven of 8 patients with parenchymal brain metastases remain alive at a median 8.8 months follow-up., Conclusion: Prostate cancer brain metastases are rare, especially in the absence of widespread metastatic disease. Nevertheless, incidentally detected brain foci of PSMA uptake may represent previously unknown prostate cancer metastases, even in small lesions and in the absence of systemic disease., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The efficacy of salvage resection (SR) of recurrent brain metastases (rBrM) following stereotactic radiosurgery (SRS) is undefined. We sought to describe local recurrence (LR) and radiation necrosis (RN) rates in patients undergoing SR, with or without adjuvant post-salvage radiation therapy (PSRT)., Methods: A retrospective cohort study evaluated patients undergoing SR of post-SRS rBrM between 3/2003-2/2020 at an NCI-designated cancer center. Cases with histologically-viable malignancy were stratified by receipt of adjuvant PSRT within 60 days of SR. Clinical outcomes were described using cumulative incidences in the clustered competing-risks setting, competing risks regression, and Kaplan-Meier methodology., Results: One-hundred fifty-five rBrM in 135 patients were evaluated. The overall rate of LR was 40.2% (95% CI 34.3-47.2%) at 12 months. Thirty-nine (25.2%) rBrM treated with SR + PSRT trended towards lower 12-month LR versus SR alone [28.8% (95% CI 17.0-48.8%) versus 43.9% (95% CI 36.2-53.4%), p = .07 by multivariate analysis]. SR as re-operation (p = .03) and subtotal resection (p = .01) were independently associated with higher rates of LR. On univariate analysis, tumor size (p = .48), primary malignancy (p = .35), and PSRT technique (p = .43) bore no influence on LR. SR + PSRT was associated with an increased risk of radiographic RN at 12 months versus SR alone [13.4% (95% CI 5.5-32.7%) versus 3.5% (95% CI 1.5-8.0%), p = .02], though the percentage with symptomatic RN remained low (5.1% versus 0.9%, respectively). Median overall survival from SR was 13.4 months (95% CI 10.5-17.7)., Conclusion: In this largest-known series evaluating SR outcomes in histopathologically-confirmed rBrM, we identify a significant LR risk that may be reduced with adjuvant PSRT and with minimal symptomatic RN. Prospective analysis is warranted., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Radionecrosis is a well-characterized effect of stereotactic radiosurgery (SRS) and is occasionally associated with serious neurologic sequelae. Here, we investigated the incidence of and clinical variables associated with the development of radionecrosis and related radiographic changes after SRS for brain metastases in a cohort of patients with long-term follow up. 271 brain metastases treated with single-fraction linear accelerator-based SRS were analyzed. Radionecrosis was diagnosed either pathologically or radiographically. Univariate and multivariate Cox regression was performed to determine the association between radionecrosis and clinical factors available prior to treatment planning. After median follow up of 17.2 months, radionecrosis was observed in 70 (25.8%) lesions, including 47 (17.3%) symptomatic cases. 22 of 70 cases (31.4%) were diagnosed pathologically and 48 (68.6%) were diagnosed radiographically. The actuarial incidence of radionecrosis was 5.2% at 6 months, 17.2% at 12 months and 34.0% at 24 months. On univariate analysis, radionecrosis was associated with maximum tumor diameter (HR 3.55, p < 0.001), prior whole brain radiotherapy (HR 2.21, p = 0.004), prescription dose (HR 0.56, p = 0.02) and histology other than non-small cell lung, breast or melanoma (HR 1.85, p = 0.04). On multivariate analysis, only maximum tumor diameter (HR 3.10, p < 0.001) was associated with radionecrosis risk. This data demonstrates that with close imaging follow-up, radionecrosis after single-fraction SRS for brain metastases is not uncommon. Maximum tumor diameter on pre-treatment MR imaging can provide a reliable estimate of radionecrosis risk prior to treatment planning, with the greatest risk among tumors measuring >1 cm.

Case reports and animal models suggest that chemotherapy, corticosteroids and radiotherapy (RT) may increase the risk of herpes simplex encephalitis (HSE). We retrospectively examined cases of HSE at an academic hospital devoted to cancer care. Patients were identified by positive herpes simplex virus (HSV) polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) or by brain pathology. There were seven patients with HSE over a 12 year period, four of whom had received cranial RT. During this time, a total of 997 patients were treated with cranial RT, suggesting a greater incidence than the expected risk of two to four cases per million people per year in the general population. Five patients had recently received chemotherapy and three were on dexamethasone. MRI findings were typical; four patients had bilateral anterior temporal lesions and three had unilateral-temporal lesions. Four patients had a normal CSF white blood cell count, three of whom had prior RT and dexamethasone. Four patients were positive for HSV-1, and two for HSV-2. One patient had a negative CSF PCR for HSV, but autopsy confirmed active HSE. Though still rare, the risk of HSE may be increased in patients with cancer, especially in those receiving cranial RT. MRI findings were typical, but CSF white blood cell count was normal in four patients and one had negative CSF testing, suggesting that CSF results may be misleading in this population.

Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se(473)) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children's Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 overexpression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival (p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors.

A 62-year-old man with progressive cerebellar and brainstem dysfunction had gadolinium-enhancing lesions in basal ganglia and occipital lobe on MRI suggestive of primary CNS lymphoma (PCNSL). The patient, who had been treated with high-dose steroid hormones for several months, developed respiratory failure and expired before a histological diagnosis could be obtained. The postmortem examination showed Pneumocystis cariniiwas the cause of death. Pathology of the brain showed a necrotizing vasculopathy affecting the white matter of the cerebrum and cerebellum with involvement of the basal ganglia and the periventricular gray matter. Other organs such as liver, lung, and kidneys were spared. Necrotizing vasculopathy is a novel entity that should be considered in the differential diagnosis of PCNSL.

Leptomeningeal metastases are a common complication of medulloblastomas and other primitive neuroectodermal tumors (PNETs). Much rarer are PNETs apparently arising in the leptomeninges. An 8-year-old boy presented with headache and vomiting, due to neoplastic meningitis from primary neuroectodermal tumor without an identifying mass. After craniospinal irradiation and chemotherapy (carboplatin, vincristine, cyclophosphamide and lomustine) the boy was in remission for 14 months, then suffered several relapses despite various chemotherapy regimens. After the initial presentation of 3.5 years the boy began to suffer from prolonged refractory non-convulsive status epilepticus and later expired from progression of primary leptomeningeal PNET.

We report two patients with leptomeningeal metastases from squamous cell cancer of the skin. In one patient cauda equina metastases appeared 6 years after initial presentation; the tumor from radical neck dissection demonstrated perineural invasion suggesting a possible route for subarachnoid dissemination. The other patient presented 2 years after initial diagnosis with confusion and cranial nerve seven and twelve palsies. Both patients died from complications of leptomeningeal metastases.

Chordoid gliomas are an uncommon primary brain tumor with histologic features of a chordoma and immunolabeling for glial fibrillary acid protein. We report the 32nd case with a review of the literature. The clinical, radiographic and pathologic features of the tumor are presented with new pathologic findings adding support that this lesion may be of ependymal origin. Treatment and long term outcome are limited but chordoid gliomas appear to be indolent lesions that may be cured with gross total resection.

Ewing sarcoma/'peripheral' primitive neuroectodermal tumor (ES/pPNET) is the designation given to a family of small cell neoplasms that typically arise in bone or soft tissue and are unified by their common expression of the MIC2 antigen and specific translocations involving a gene on chromosome 22q12 [the most common being t(11;22)(q24;q12)]. ES/pPNET of intracranial origin is extraordinary. We report the case of a 6-year-old boy with a large left frontal region mass that adhered to dura and was extracerebral at surgery. Histologic study revealed a high-grade, undifferentiated-appearing neoplasm of small cell type that was negative on immunostudy for glial fibrillary acidic protein, synaptophysin, desmin, leukocyte common antigen, smooth muscle actin and epithelial membrane antigen, but positive for vimentin and neuron-specific enolase and diffusely labeled by antibody O13 (which recognizes the MIC2 gene product). RNA-based polymerase chain reaction assay confirmed the diagnosis of ES/pPNET by demonstrating fusion transcripts indicative of t(11;22) translocation. Bone scan, computerized tomography of the chest and bone marrow examination revealed no systemic tumor. The limited observations published to date suggest that primary intracranial ES/pPNET is most likely to present in childhood as a circumscribed, contrast-enhancing and dural-based extracerebral mass. It must be distinguished from a variety of small cell neoplasms, particularly PNETs of central neuroepithelial origin.

High dose chemotherapy (HDCT) with autologous (bone marrow or peripheral blood) stem cell rescue (ASCR) has had success in the treatment of some malignant pediatric brain tumors. We report a series of adults enrolled in one of three HDCT and ASCR protocols for malignant primary brain tumors. Overall toxic mortality was 18%; chemotherapy regimen, tumor type, and prior treatment did not predict transplant-related mortality. Patients over the age of 30 had a higher rate of toxic mortality. Patients with recurrent medulloblastoma had a significant improvement in long-term survival (median: 34 months) as compared with historical reports; two patients with glioblastoma survive beyond four years without progression, but overall, a significant improvement in long-term survival could not be demonstrated for malignant gliomas.

Astroblastoma is a rare and controversial tumor about which little is known. We have made the diagnosis in seven patients since 1990 at Memorial Sloan-Kettering Cancer Center. Four patients had astroblastomas with anaplastic features, whereas three patients had tumors which were well-differentiated. All three patients with low grade lesions are alive and recurrence free after surgery alone (mean follow-up 29 months). All four patients with anaplastic astroblastoma were treated with surgery, radiotherapy and chemotherapy. One died of infection during induction chemotherapy. Two others died of tumor progression at 28 and 42 months. Radiographic response to chemotherapy was seen in one patient. The results of our series and other reports suggest that anaplastic histology is a prognostic factor in the setting of astroblastoma. More aggressive treatment is necessary for patients with anaplastic astroblastoma although the precise role of irradiation and chemotherapy cannot be defined at this time.

Isolated neurosarcoidosis can present with a wide range of central nervous system manifestations. We present two cases of cauda equina sarcoidosis misdiagnosed initially as leptomeningeal malignancy, and review the literature. This unusual manifestation of neurosarcoidosis is typified by an indolent, chronic process with limited response to corticosteroid therapy.

Long term survival is rare in patients with glioblastoma multiforme (GBM). To determine if the tumors of patients with long survivals constitute a subgroup of patients with identifiable molecular genetic characteristics, we studied the p53 gene and Epidermal Growth Factor Receptor (EGF-R) expression in long-term survivors of GBM. A review of the Tumor Registry of Memorial Hospital for Cancer and Allied Diseases documented that 521 patients were treated for GBM between 1954 and 1987 and that 12 patients had seven-year or longer survivals. Six additional long-term survivors were identified from other institutions. After pathological re-examination, the diagnosis of 8 of these 18 (44%) tumors was changed to other histologic tumor types. Using immunohistochemical analysis, 4 of 10 confirmed malignant gliomas had over-expression of p53. Polymerase chain reaction/single-strand conformational polymorphism (PCR/SSCP) analysis and sequence analysis of these 4 tumors showed no p53 mutations in exons 5-8, the region where most mutations have been reported in human malignancies. Immunohistochemical analysis for EGF-R was performed on the tumors of the 10 long-term survivors. EGF-R over-expression was identified in 4 (40%), which is consistent with previous reported studies for GBM in general. These findings suggest that there is a subset of GBM defined by the accumulation of wild-type p53 and that the over-expression of EGF-R does not preclude long-term survival. The seven-year survival rate for confirmed GBM in patients from the Memorial Hospital Tumor Registry was at least 1%.

We describe the neuropathologic findings at autopsy in six patients who developed a progressive encephalopathy complicating the treatment of malignant gliomas with combined intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cerebral irradiation. Four brains were free of tumor and one contained a microscopic focus of residual glioma. In only one case was there evidence of tumor progression. A disseminated process characterized by miliary foci of necrosis with mineralizing axonopathy was present in all cases, restricted to the internal carotid distribution of the perfused hemisphere and involving primarily though not exclusively the white matter, which was diffusely and severely edematous. This was combined in 3 cases with a histologically dissimilar, massive necrotizing leukoencephalopathy indistinguishable from pure radionecrosis. Much of the toxicity of this therapy is mediated by vascular injury, but the disseminated necrotizing lesion probably reflects, at least in part, direct neural damage.