[show abstract][hide abstract] ABSTRACT: The clinical features, pathologic changes, and immune repertoire in a remarkable case of chronic varicella-zoster virus (VZV) ganglioneuritis without rash are described.
[show abstract][hide abstract] ABSTRACT: Brainstem gangliogliomas (GGs) often cannot be resected, have a much poorer prognosis than those located in more common supratentorial sites, and may benefit from novel therapeutic approaches. Therapeutically-targetable BRAF c.1799T>A (p.V600E) (BRAF(V600E) ) mutations are harbored in roughly 50% of collective GGs taken from all anatomical sites. Large numbers of pediatric brainstem GGs, however, have not been specifically assessed and anatomic- and age-restricted assessment of genetic and biological factors are becoming increasingly important. Pediatric brainstem GGs (n=13), non-brainstem GGs (n=11), and brainstem pilocytic astrocytomas (PAs) (n=8) were screened by standard Sanger DNA sequencing of BRAF exon 15. Five of 13 (38%) pediatric GG harbored a definitive BRAF(V600E) mutation, with 2 others exhibiting an equivocal result by this method. BRAF(V600E) was also seen in 5/11 (45%) non-brainstem GGs and 1/8 (13%) brainstem PAs. VE1 immunostaining for BRAF(V600E) showed concordance with sequencing in 9/9 brainstem GGs including the two cases equivocal by Sanger. The equivocal brainstem GGs were subsequently shown to harbor BRAF(V600E) using a novel, more sensitive, RNA-sequencing approach, yielding a final BRAF(V600E) mutation frequency of 54% (7/13) in brainstem GGs. BRAF(V600E) -targeted therapeutics should be a consideration for the high percentage of pediatric brainstem GGs refractory to conventional therapies.
[show abstract][hide abstract] ABSTRACT: Astrocytic dysfunction is implicated in epilepsy through many proposed molecular mechanisms, but there is also a clinicopathologic entity of epilepsy featuring astrocytic inclusions.(1) At least 17 cases of early-onset epilepsy with eosinophilic, hyaline astrocytic inclusions have been reported since the early 1990s.(2-8) Most of these cases also involve developmental delay.(2-8) The diagnosis is made by neuropathologic analysis that demonstrates brightly eosinophilic, hyaline, refractile astrocytic inclusions seen under light microscopy with hematoxylin & eosin stain.(2-8) We review the clinicopathologic entity of pediatric epilepsy with hyaline astrocytic inclusions and report an illustrative case.
[show abstract][hide abstract] ABSTRACT: Skull and dura serve as effective barriers to penetration by most tumors, often preventing masses originating intracranially from extending into the contiguous bone and soft tissues, or those arising in head and neck regions from extending into the dura and brain tissue. We review our 15-year experience with extracranial tumors that had sufficiently invaded adjacent skull, dura, or brain from the "outside-in" to require a neurosurgeon to participate in the surgical resection and discuss our 40 cases in context with the literature. Sinonasal-origin tumors (n = 17) and cutaneous tumors (n = 10) were the most frequent skull-invaders. Most of the cutaneous tumor types were squamous cell carcinomas (n = 9); diverse sinonasal-origin types included 4 squamous cell carcinomas, 4 adenoid cystic carcinomas, 2 sinonasal undifferentiated carcinomas, 2 sinonasal adenocarcinomas, and single examples each of sinonasal-origin hemangiopericytoma, solitary fibrous tumor, melanoma, mucocele, and teratocarcinoma. There were 9 olfactory neuroblastomas, and middle ear-origin basal cell carcinoma, recurrent glomus jugulare, and orbital malignant hidradenoma were also seen. Unique tumors included a cutaneous cylindroma invasive of skull convexity occurring in familial cylindromatosis and a ganglioneuroma of the middle ear with massive bilateral skull base extension. Convexity dural spread, a seldom-reported pattern of dissemination, was seen in 1 olfactory neuroblastoma and 1 adenoid cystic carcinoma. The ability to show skull/dural invasion did not correlate with specific histopathologic features; even benign tumor types can show skull/dural penetration.
Journal of neuropathology and experimental neurology. 06/2013;
[show abstract][hide abstract] ABSTRACT: Background
Tissue invasion is a hallmark of most human cancers and remains a major source of treatment failure in patients with glioblastoma (GBM). Although EGFR amplification has been previously associated with more invasive tumor behavior, existing experimental models have not supported quantitative evaluation of interpatient differences in tumor cell migration or testing of patient-specific responses to therapies targeting invasion. To explore these questions, we optimized an ex vivo organotypic slice culture system allowing for labeling and tracking of tumor cells in human GBM slice cultures.Methods
With use of time-lapse confocal microscopy of retrovirally labeled tumor cells in slices, baseline differences in migration speed and efficiency were determined and correlated with EGFR amplification in a cohort of patients with GBM. Slices were treated with gefitinib to evaluate anti-invasive effects associated with targeting EGFR.ResultsMigration analysis identified significant patient-to-patient variation at baseline. EGFR amplification was correlated with increased migration speed and efficiency compared with nonamplified tumors. Critically, gefitinib resulted in a selective and significant reduction of tumor cell migration in EGFR-amplified tumors.Conclusions
These data provide the first identification of patient-to-patient variation in tumor cell migration in living human tumor tissue. We found that EGFR-amplified GBM are inherently more efficient in their migration and can be effectively targeted by gefitinib treatment. These data suggest that stratified clinical trails are needed to evaluate gefitinib as an anti-invasive adjuvant for patients with EGFR-amplified GBM. In addition, these results provide proof of principle that primary slice cultures may be useful for patient-specific screening of agents designed to inhibit tumor invasion.
[show abstract][hide abstract] ABSTRACT: This article reviews recent literature on sellar region masses that most closely mimic non-secretory pituitary adenomas: hypophysitis, pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis. Even today, these 4 entities often cannot be confidently distinguished from each other clinically or by preoperative neuroimaging features. Thus, they often come to biopsy/surgical resection and require tissue confirmation of diagnosis. Causes of secondary and primary hypophysitis will be discussed, including two newly-described types, IgG4 plasma cell hypophysitis and hypophysitis caused by anti-CTLA4 antibody therapy for cancer. For the neoplastic conditions, emphasis will be placed on literature that has emerged since these entities were first codified in the 2007 World Health Organization fascicle (38, 39, 119). The finding that immunohistochemical staining for thyroid transcription factor-1 (TTF-1) is shared by pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis suggests common lineage and explains why histological overlap can be encountered. We incorporate our own experiences over the last 30 years from two referral institutions with specialty practices in pituitary region masses.
[show abstract][hide abstract] ABSTRACT: Orbital invasion by pituitary tumors is rare. To the best of the authors' knowledge, adrenocorticotrophin (ACTH)-secreting pituitary tumors with orbital invasion have not been described in MEDLINE indexed literature. The authors report 2 cases of ACTH-secreting tumors with orbital invasion. One patient had a history of endoscopic transsphenoidal subtotal resection of an ACTH-secreting tumor and presented with recurrence in the orbit. The second patient had a long history of visual loss considered to be secondary to glaucoma. Neuroimaging revealed a destructive mass involving the sella turcica with extension in the right orbit. Debulking of the mass was performed via a transsphenoidal approach, and histopathology revealed an ACTH-secreting adenoma. ACTH-secreting adenoma should be considered in the differential of tumors involving the sella turcica with orbital invasion.
Ophthalmic plastic and reconstructive surgery 05/2013; · 0.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pleomorphic xanthoastrocytomas with anaplastic features (PXA-As) are rare tumors about which little is known regarding clinicopathologic and molecular features. Several studies have identified BRAF V600E mutations in PXA-As, but the percentage with mutation may differ between adult and pediatric examples, and limited information exists about immunohistochemistry for isocitrate dehydrogenase 1 (IDH1). Ten cases of adult PXA-As seen at our institution since 2000 were assessed for BRAF V600E mutation by polymerase chain reaction testing (PCR) and IDH1 by immunohistochemistry. Patients ranged in age from 18-68 years; four PXA-As affected temporal lobe and two were cystic. Four patients underwent gross total resection and 9 of 10 patients received cranial irradiation and/or adjuvant chemotherapy. Five survived less than 5 years, although 2 of 5 patients died from non-tumor causes. Four long-term survivors are alive at 7.5, 9.8, 11.4, and 11.9 years post-diagnosis. Two of four long term survivors had BRAF V600E mutation: patients were ages 18 and 28 years. A 48-year-old male without BRAF mutation survives at 9.8 years, even with thalamic location; conversely a 68-year-old female with temporal lobe tumor and BRAF mutation survived 1.9 years after diagnosis. All tumors were IDH1 immunonegative. This case series details clinicopathologic features of a subset of rare PXA-As in adults. BRAF V600E mutation was identified in 50 % of these cases.
Journal of Neuro-Oncology 10/2012; · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Congenital glioblastoma (cGBM) is an uncommon tumor of infancy with a reported variable but often poor cure rate, even with intensive therapy. Five patients with cGBMs, arising de novo and not in familial tumor predisposition kindreds, were studied for histological and biological features, using Affymetrix microarray. Tumors were large, often associated with hemorrhage, extended into the thalamus, and often bulged into the ventricles. One patient died acutely from bleeding at the time of operation. The 4 surviving patients underwent surgery (1 gross total resection, 3 subtotal resections or biopsies) and moderate intensity chemotherapy without radiation, and remain progression-free at a median time of 36 months (range, 30-110 months). Affymetrix microarrays measured gene expression on the 3 cGBMs from which frozen tissue was available. Unsupervised hierarchical clustering of cGBMs versus 168 other central nervous system tumors demonstrated that cGBMs clustered most closely with other high-grade gliomas. Gene expression profiles of cGBMs were compared with non-congenital pediatric and adult GBMs. cGBMs demonstrated marked similarity to both pediatric and adult GBMs, with only 31 differentially expressed genes identified (false discovery rate, <0.05). Unique molecular features of cGBMs included over-expression of multiple genes involved in glucose metabolism and tissue hypoxia. cGBMs show histological and biological overlap with pediatric and adult GBMs but appear to have a more favorable outcome, with good response to moderate intensity chemotherapy with only subtotal resection or biopsy. Further study may determine whether identified gene expression differences contribute to the improved survival seen in these tumors.
[show abstract][hide abstract] ABSTRACT: The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction-based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria.
Journal of Neuropathology and Experimental Neurology 06/2012; 71(7):604-17. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: The co-occurrence of gliomas and multiple sclerosis (MS) in the same patient is uncommon, but a well-reported phenomenon. Most have been high grade astrocytic tumors that developed after the diagnosis of MS, leading authors to postulate that chronic gliosis in demyelinative plaques might be the underlying substrate for secondary induction of a glial neoplasm. Until recently, however, genetic tools have not been available to test the hypothesis that high grade gliomas might arise from longstanding chronic gliosis, with transformation to low grade glioma, and eventually GBM, i.e., be secondary GBMs. We searched our surgical neuropathology and MS Brain Bank databases over the past 25 years (1987-2011) and identified eight cases of co-occurring MS and glioma. After careful review to guarantee both diagnoses, cases were studied by fluorescence in situ hybridization for genetic markers appropriate to diagnosis, as well as by direct sequencing for IDH1/2 and P53. No unusual genetic features were detected in our cohort; further, the 4 GBMs we did identify did not have clinical features of secondary glioblastomas nor did any of the four manifest IDH-1 immunohistochemical expression or IDH1/2 mutations, as might be expected in secondary GBMs. Conversely, PTEN loss and EGFR expression, features often found in primary GBMs, but seldom identified in secondary GBMs, were found in 3 of 4 GBMs. We conclude that gliomas in MS patients have genetic features paralleling counterparts in non-MS patients. There is no strong genetic evidence for GBMs to be secondary GBMs.
Journal of Neuro-Oncology 05/2012; 109(2):261-72. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Growth hormone (GH) pituitary tumors are almost always benign adenomas, yet are associated with significant morbidity and mortality. Surgical and medical responses of GH tumors are often incomplete, and therefore predictors of residual or recurrent disease are needed. Clinical features, including patient gender, age or size of adenoma, have proven to be unreliable predictors of recurrence. Differing clinical behavior between the two GH tumor subtypes, sparsely granulated (SG) versus densely granulated (DG), has been reported, but has not been used routinely in clinical management. SG tumors are more common in younger patients (<50 years), and are usually larger tumors. SG tumors have been reported to be less responsive to somatostatin analogs (SSA) than DG tumors. The mechanisms underlying these potential differences in tumor behavior, however, are poorly defined. Subsets (up to 50 %) of DG adenomas harbor a gsp mutation that can activate cAMP that provides a theoretical intracellular target for somatostatin therapy. In contrast, some SG tumors have reduced somatostatin receptor expression and mutations in the extracellular domain of the GH receptor that may contribute to SSA resistance. While DG versus SG growth hormone adenomas are readily distinguished by immunohistochemistry, other less common GH adenoma variants still require electron microscopy (EM) for confident subclassification. Whether these less common variants possess unique clinical features is unknown. Research is needed to identify clinically relevant biomarkers of GH pituitary tumors that predict risk of recurrence and response to medical therapy.
[show abstract][hide abstract] ABSTRACT: Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon, aggressive, embryonal pediatric brain tumor that almost always develops de novo and does not arise within, or evolve from, other brain tumor types. Although rhabdoid morphology can be seen in other tumor types, these are phenotypic mimics and, with only rare exceptions, do not manifest the INI-1 deletion at the 22q11.2 locus or the INI-1 nuclear protein loss that characterizes AT/RT. A few reports of AT/RT evolving from a low-grade ganglioglioma (GG) or pleomorphic xanthoastrocytoma have appeared. We present the case of a 6-year-old boy with a large right parietal mass whose tumor at initial presentation manifested 2 distinct components: GG with neoplastic neurons, low MIB-1 rate, and retention of INI-1 nuclear immunostaining (immunohistochemical) and, second, AT/RT with rhabdoid cells, polyphenotypic immunohistochemical expression, high MIB-1 rate, and loss of INI-1 nuclear expression. The 2 areas were separately assessed by fluorescence in situ hybridization for monosomy 22; monosomy 22 was identified in the AT/RT component but not in the GG areas. BRAF V600E mutation, a genetic abnormality seen in a significant percentage of pleomorphic xanthoastrocytomas and GGs, was assessed by polymerase chain reaction and identified in the tumor. Dual abnormalities of INI-1 loss and V600E BRAF mutation were identified in a cell culture line established from cerebrospinal fluid metastatic tumor cells. This cell line exhibited extremely rapid growth rate and rhabdoid morphology. Results suggest a postclonal modification in a subset of GG cells, with acquisition of INI-1 loss, confirming by biological methods what was previously suspected in rare reports of AT/RT evolving from other tumor types.
The American journal of surgical pathology 11/2011; 35(12):1894-901. · 4.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM.
Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation.
We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation.
These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients.
Clinical Cancer Research 09/2011; 17(22):6992-7002. · 7.84 Impact Factor