Abstract
von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer disorder caused by a germline mutation in the VHL tumor suppressor gene. Loss of the wild-type allele results in ...VHL deficiency and the potential formation of cerebellar hemangioblastomas, which resemble embryonic hemangioblast proliferation and differentiation processes. Multiple, microscopic, VHL-deficient precursors, termed developmentally arrested structural elements (DASEs), consistently involve the cerebellar molecular layer in VHL patients, indicating the tumor site of origin. Unlike hemangioblastomas, however, cerebellar DASEs do not express brachyury, a mesodermal marker for hemangioblasts. In this study, neuronal progenitors occupying the molecular layer were investigated as tumor cells of origin. By immunohistochemistry, cerebellar DASEs and hemangioblastomas lacked immunoreactivity with antibody ZIC1 (Zic family member 1), a granule cell progenitor marker with concordance from oligonucleotide RNA expression array analyses. Rather, cerebellar DASEs and hemangioblastomas were immunoreactive with antibody PAX2 (paired box 2), a marker of basket/stellate cell progenitors. VHL cerebellar cortices also revealed PAX2-positive cells in Purkinje and molecular layers, resembling the histological and molecular development of basket/stellate cells in postnatal non-VHL mouse and human cerebella. These data suggest that VHL deficiency can result in the developmental arrest of basket/stellate cells in the human cerebellum and that these PAX2-positive, initiated cells await another insult or signal to form DASEs and eventually, tumors.
The role of immunotherapy in treatment of brain metastases is unknown because most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many ...malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here, we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells, and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression are essential.
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been ...linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.
To determine the origin of the neoplastic cell in central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL) and its role in tumor formation and distribution, we characterized ...and differentiated neoplastic cells from hemangioblastomas removed from VHL patients.
A total of 31 CNS hemangioblastomas from 25 VHL patients were resected and analyzed. Tumor cells from the hemangioblastomas were characterized, grown, and differentiated into multiple lineages. Resected hemangioblastomas were located in the cerebellum (11 tumors), brainstem (five tumors), and spinal cord (15 tumors). Consistent with an embryologically derived hemangioblast, the neoplastic cells demonstrated coexpression of the mesodermal markers brachyury, Flk-1 (vascular endothelial growth factor-2), and stem cell leukemia (Scl). The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin, and erythropoietin receptor. Under specific microenvironments, neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic, and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin.
The neoplastic cell of origin for CNS hemangioblastomas in VHL patients is the mesoderm-derived, embryologically arrested hemangioblast. The hematopoietic and endothelial differentiation potential of these cells can be reactivated under suitable conditions. These findings may also explain the unique tissue distribution of tumor involvement.
Spasmodic dysphonia is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although the clinical symptoms are well characterized, the ...pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in these patients as determined by a combined approach of diffusion tensor imaging (DTI) and postmortem histopathology. We used DTI to identify brain changes and to target those brain regions for neuropathological examination. DTI showed right-sided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/corticospinal tract in 20 spasmodic dysphonia patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus and cerebellar white and grey matter in the patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions, containing calcium, phosphorus and iron, in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus and cerebellum in the postmortem brain tissue from one patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization, limited only to the corticobulbar/corticospinal tract and its main input/output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of spasmodic dysphonia (r = 0.509, P = 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of this disorder.
Classically, histologic grading of gliomas has been used to predict seizure association, with low-grade gliomas associated with an increased incidence of seizures compared to high-grade gliomas. In ...2016, WHO reclassified gliomas based on histology and molecular characteristics. We sought to determine whether molecular classification of gliomas is associated with preoperative seizure presentation and/or post-operative seizure control across multiple glioma subtypes. All gliomas operated at our institution from 2007 to 2017 were identified based on ICD 9 and 10 billing codes and were retrospectively assessed for molecular classification of the
IDH1
mutation, and
1p/19q
codeletion. Logistic regression models were performed to assess associations of seizures at presentation as well as post-operative seizures with IDH status and the new WHO integrated classification. Our study included 376 patients: 82 IDH mutant and 294 IDH wildtype. The presence of
IDH
mutation was associated with seizures at presentation OR 3.135 (1.818–5.404),
p
< 0.001.
IDH
-
mutant
glioblastomas presented with seizures less often than other
IDH
-
mutant
glioma subtypes grade II and III OR 0.104 (0.032–0.340),
p
< 0.001.
IDH
-
mutant
tumors were associated with worse post-operative seizure outcomes, demonstrated by Engel Class OR 2.666 (1.592–4.464),
p
< 0.001.
IDH
mutation in gliomas is associated with an increased risk of seizure development and worse post-operative seizure control, in all grades except for GBM.
Context:
McCune-Albright syndrome (MAS) is caused by sporadic mutations of the GNAS. Patients exhibit features of acromegaly. In most patients, GH-secreting pituitary adenomas have been held ...responsible for this presentation. However, surgical adenomectomy rarely eliminates excess GH production.
Objective:
The aim of this study was to elucidate pituitary pathology in patients with MAS and to explain the basis of failure of adenomectomy to eliminate GH hypersecretion.
Design and Setting:
We conducted a case series at the National Institutes of Health.
Intervention(s):
Interventions included medical therapy and transsphenoidal surgery.
Patients and Main Outcome Measures:
We studied clinical and imaging features and the histology and molecular features of the pituitary of four acromegalic MAS patients.
Results:
We identified widespread and diffuse pituitary gland disease. The primary pathological changes were characterized by hyperplastic and neoplastic change, associated with overrepresentation of somatotroph cells in structurally intact tissue areas. Genetic analysis of multiple microdissected samples of any type of histological area consistently revealed identical GNAS mutations in individual patients. The only patient with remission after surgery received complete hypophysectomy in addition to removal of multiple GH-secreting tumors.
Conclusions:
These findings indicate developmental effects of GNAS mutation on the entire anterior pituitary gland. The pituitary of individual cases contains a spectrum of changes with regions of normal appearing gland, hyperplasia, and areas of fully developed adenoma formation, as well as transitional stages between these entities. The primary change underlying acromegaly in MAS patients is somatotroph hyperplasia involving the entire pituitary gland, with or without development of somatotroph adenoma. Thus, successful clinical management, whether it is medical, surgical, or via irradiation, must target the entire pituitary, not just the adenomas evident on imaging.
Progressively enlarging encephalopathic changes are now well-documented effects of gamma knife radiosurgery (GKRS) occurring ~3–30 months after treatment of both benign and malignant brain lesions. ...These changes can be variably associated with inflammatory demyelination and necrosis and/or recurrent tumor. While radiographic differentiation between encephalopathic changes and recurrent tumor is of high clinical relevance, confident interpretation of post-radiosurgery imaging changes can be challenging or even impossible in some cases. Gadolinium-enhanced MRI of these lesions reveals variable amounts of enhancing and non-enhancing components within these lesions that have not been clearly correlated with structural-pathologic change. The goal of this study is to characterize the histopathological changes associated with enhancing versus non-enhancing regions of GKRS-treated lesions. MRI images of patients with progressive, etiologically ambiguous brain lesions following GKRS were reviewed prior to explorative neurosurgery. Chosen for this study were lesions in which distinct areas of enhancement and non-enhancement of at least 5 mm in size could be identified (
n
= 16). Distinctly enhancing and non-enhancing areas were separately biopsied and histologically evaluated. Only cases with uniform histological results are presented in this study. Enhancing and non-enhancing areas in post GKRS lesions represent separate pathological changes. Radiographically enhancing areas correlate either with recurrent tumor growth or inflammatory demyelinating changes. Lack of radiographic enhancement correlates with coagulative necrosis if the sample is taken from the center of the lesion, or with reactive astrocytosis if the sample is taken from the periphery. Separate biopsy of enhancing and non-enhancing regions of post-GKRS encephalopathy was able to confirm that the pathologies in these areas are distinct. These findings allow for better-informed correlation of histological and radiological changes and a better understanding of post-treatment tissue pathology.
Rhabdomyosarcoma (RMS) is a pediatric malignancy with a variable prognosis depending on tumor stage and genotype. There has been a significant improvement in survival rates over the past decades. ...However, aggressive variants can metastasize to locations that are difficult to treat. We report a case of prostatic alveolar rhabdomyosarcoma with metastases to the bone marrow and thoracic spine in a child. The patient was treated with a multimodal approach that included surgical resection of the epidural mass; the administration of vincristine, dactinomycin, and cyclophosphamide; and radiotherapy. Unfortunately, after six months, the patient showed disease progression and was started on secondary-line treatment. This case illustrates the difficulties in managing end-stage metastatic rhabdomyosarcoma and is the first report of prostatic rhabdomyosarcoma presenting with spinal cord compression in a child.
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