[Show abstract][Hide abstract] ABSTRACT: Introduction
Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75–95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP.
Using mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib – LCK, EPHA2 and SRC; EGFR pathway targets – AREG, EGFR and ERBB3; and other potentially actionable cancer targets – SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples.
We report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.
[Show abstract][Hide abstract] ABSTRACT: Context .- Most sellar region masses (85%-90%) are pituitary adenomas; however, other neoplasms or even inflammatory or cystic nonneoplastic lesions may occasionally be encountered in this location. A practical, non-electron-microscopically based approach is essential for the daily practice of diagnosing and subclassifying adenomatous and nonadenomatous sellar region lesions. Objective .- To provide an algorithmic approach to sellar region masses for the pathologist and to formulate a cost-effective, limited panel of stains and immunostains that can be used in daily practice at most small to medium-sized centers. Design .- Pool collective experience of 3 neuropathologists practicing at academic medical centers with expertise in diagnosis and treatment of sellar region masses to craft a single-page algorithmic diagram and to liberally illustrate the range of lesions present in the sellar region. Results .- After formulating a differential diagnosis, the general pathologist can generate a confident final diagnosis of adenoma using 1 histochemical (reticulin) and 1 immunohistochemical (synaptophysin) stain, supplemented by 5 immunohistochemical stains (CAM5.2, follicle-stimulating hormone, growth hormone, prolactin, and adrenocorticotropic hormone), which provide subtyping of the adenoma in the overwhelming majority of examples. CAM5.2 and clinical information further help identify clinically aggressive variants such as sparsely granulated growth hormone adenomas and silent adrenocorticotropic hormone adenomas, respectively. MIB-1, thyroid transcription factor 1, and S-100 protein can be of further assistance in select cases where increased mitotic activity or possible nonadenomatous spindle cell lesions are suspected. Conclusions .- Adenomas, normal anterior or posterior gland, and nonadenomatous masses can be easily diagnosed in a nontertiary pathology laboratory setting.
Archives of pathology & laboratory medicine 03/2015; 139(3):356-372. DOI:10.5858/arpa.2014-0020-OA · 2.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bevacizumab blocks the effects of VEGF and may allow for more aggressive radiotherapy schedules. We evaluated the efficacy and toxicity of hypofractionated intensity-modulated radiation therapy with concurrent and adjuvant temozolomide and bevacizumab in patients with newly diagnosed glioblastoma. Patients with newly diagnosed glioblastoma were treated with hypofractionated intensity modulated radiation therapy to the surgical cavity and residual tumor with a 1 cm margin (PTV1) to 60 Gy and to the T2 abnormality with a 1 cm margin (PTV2) to 30 Gy in 10 daily fractions over 2 weeks. Concurrent temozolomide (75 mg/m(2) daily) and bevacizumab (10 mg/kg) was administered followed by adjuvant temozolomide (200 mg/m(2)) on a standard 5/28 day cycle and bevacizumab (10 mg/kg) every 2 weeks for 6 months. Thirty newly diagnosed patients were treated on study. Median PTV1 volume was 131.1 cm(3) and the median PTV2 volume was 342.6 cm(3). Six-month progression-free survival (PFS) was 90 %, with median follow-up of 15.9 months. The median PFS was 14.3 months, with a median overall survival (OS) of 16.3 months. Grade 4 hematologic toxicity included neutropenia (10 %) and thrombocytopenia (17 %). Grades 3/4 non-hematologic toxicity included fatigue (13 %), wound dehiscence (7 %) and stroke, pulmonary embolism and nausea each in 1 patient. Presumed radiation necrosis with clinical decline was seen in 50 % of patients, two with autopsy documentation. The study was closed early to accrual due to this finding. This study demonstrated 90 % 6-month PFS and OS comparable to historic data in patients receiving standard treatment. Bevacizumab did not prevent radiation necrosis associated with this hypofractionated radiation regimen and large PTV volumes may have contributed to high rates of presumed radiation necrosis.
Journal of Neuro-Oncology 12/2014; 122(1). DOI:10.1007/s11060-014-1691-z · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Growth hormone (GH) pituitary tumors are associated with significant morbidity and mortality. Current treatments, including surgery and medical therapy with somatostatin analogs (SSA), dopamine agonists and/or a GH receptor antagonist, result in disease remission in approximately half of patients. Predictors of GH tumor response to different therapies have been incompletely defined based on histologic subtype, particularly densely (DG) versus sparsely (SG) granulated adenomas. The aim of this study was to examine our own institutional experience with GH adenomas and correlate how subtype related to clinical parameters as well as response to surgery and medical therapies. A retrospective chart review of 101 acromegalic patients operated by a single neurosurgeon was performed. Clinical data were correlated with histologic subtype and disease control, as defined by IGF-1 levels, and random growth hormone levels in response to surgery and/or medical therapies. SG tumors, compared to DG, occurred in younger patients (p = 0.0010), were 3-fold larger (p = 0.0030) but showed no differences in tumor-invasion characteristics (p = 0.12). DG tumors had a higher rate of remission in response to surgery compared to SG, 65.7 vs. 14.3 % (p < 0.0001), as well as to medical therapy with SSAs (68.8 % for DG vs. 28.6 % for SG tumors; p = 0.028). SG tumors not controlled with SSAs consistently responded to a switch to, or addition of, a GH receptor antagonist. Histological GH tumor subtyping implicates a different clinical phenotype and biologic behavior, and provides prognostic significance for surgical success and response to medical therapies.
[Show abstract][Hide abstract] ABSTRACT: Objectives: Metastatic leptomeningeal spread from spinal cord gangliogliomas (GGs) is exceedingly rare. Methods: Two adult women, aged 27 and 51 years, died of massive disseminations of cervicothoracic GGs 4 and 6 years, respectively, after initial diagnoses; full autopsies were performed. BRAF status was assessed by VE1 immunohistochemistry (IHC), Sanger sequencing, and a single-nucleotide base extension assay (SNaPshot, Applied Biosystems, Princeton, NJ). Results: The 27-year-old underwent two biopsies, chemotherapy, radiation, and ventriculoperitoneal shunt placement; she developed craniospinal and peritoneal dissemination. Autopsy confirmed shunt-mediated peritoneal metastases, microscopic bone marrow involvement, and profuse spinal and supratentorial leptomeningeal and parenchymal spread. The 51-year-old underwent two resections, radiation, and chemotherapy and developed pancytopenia with biopsy-proven bony metastases 15 months before death. Autopsy demonstrated leptomeningeal, subpial, and subependymal metastases. The tumors in both primary and metastatic sites were BRAF negative by VE1 IHC and two different mutational analyses. This compared with negative BRAF results for an additional four nonmetastatic adult nonsupratentorial GGs and in our study. Conclusions: We document two rare cases of massively metastatic spinal cord GGs in adult patients who were negative for BRAF V600E mutations via multiple methods.
American Journal of Clinical Pathology 08/2014; 142(2):254-60. DOI:10.1309/AJCPIBSV67UVJRQV · 3.01 Impact Factor
[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.
[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: 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; DOI:10.1097/IOP.0b013e31829164cb · 0.91 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; 111(1). DOI:10.1007/s11060-012-0991-4 · 2.79 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. DOI:10.1097/NEN.0b013e31825caf2c · 4.37 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. DOI:10.1007/s11060-012-0888-2 · 2.79 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.