Faculty Bibliography

BACKGROUND AND IMPORTANCE: We report the first case of synchronous choroid plexus papilloma of the fourth ventricle and myxopapillary ependymoma of the filum terminale. Both are papillary World Health Organization grade I tumors known to disseminate via cerebrospinal fluid pathways. CLINICAL PRESENTATION: A 65-year-old man presented with an incidental mass in the fourth ventricle found on a computed tomography scan of the head after a motor vehicle collision and an intradural mass of the filum terminale. The patient underwent resection of the fourth ventricle mass. After pathological diagnosis of a choroid plexus papilloma, the patient underwent resection of the spinal cord tumor. CONCLUSION: This case underscores the need for separate pathological diagnosis in a patient with an intradural spine lesion in the context of a benign intracranial lesion. We detail a panel of immunohistochemical markers essential for distinguishing the 2 papillary neuroectodermal tumors recovered in this case

Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor. Conventional treatment options include surgery and radiotherapy but there is no validated medical option. Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream kinases were validated immunohistochemically in corresponding formalin-fixed, paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model. EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway

Invasion is a hallmark of malignant gliomas and is the main reason for therapeutic failure and recurrence of the tumor. CXCR4 is a key chemokine receptor implicated in glioma cell migration whose expression is regulated by hypoxia. Here, we report that hepatocyte growth factor (HGF) upregulated CXCR4 protein expression in glioma cells. HGF pre-treatment increased migration of U87MG and LN229 glioma cells towards the CXCR4 ligand, stromal cell-derived factor-1alpha (SDF-1alpha). AMD3100, a CXCR4 inhibitor, inhibited the increased migration of HGF pre-treated LN229 glioma cells towards SDF-1alpha. Following exposure to HGF and hypoxia, both cell lines showed nuclear translocation of NF-kappaB (p65). The HGF- and hypoxia-induced nuclear translocation of NF-kappaB (p65) involved phosphorylation and degradation of IkappaB-alpha. Knock-down of NF-kappaB expression inhibited the induction of CXCR4 expression in response to HGF, but not to hypoxia. However, knock-down of NF-kappaB expression inhibited the induction of CXCR4 expression in response to hypoxia in the presence of HGF. NF-kappaB mediated migration towards SDF-1alpha in response to HGF. Knock-down of NF-kappaB expression resulted in decreased migration of HGF pre-treated glioma cells towards SDF-1alpha. Therefore, HGF upregulates CXCR4 expression via NF-kappaB and leads to enhanced migration. To our knowledge, this is the first report to show that a crosstalk mediated by NF-kappaB exists between the SDF-1alpha/CXCR4 and HGF/c-Met axes relevant to glioma cell migration. These findings imply that effective inhibition of glioma invasion should be directed against several ligand/receptor signaling pathways

We present a case of synchronous involvement of the pineal and suprasellar regions by a mixed germ cell tumor comprising germinoma and yolk sac tumor components, with a predominant angiomatous component. To our knowledge, it is the first case of this nature to be reported in the literature. Usually, synchronous lesions of this kind are pure germinomas, and some clinicians will forgo a biopsy and assume a germinoma histology if the serum beta-human chorionic gonadotrophin (HCG) is <50 IU/l and the alpha-fetoprotein (AFP) is within normal limits. Secondly, if a biopsy is performed on a lesion that has a prominent angiomatous component, the diagnostic germ cell tumor may be missed at the time of the biopsy. In order to alert clinicians and pathologists to this rare entity, the case is discussed with particular reference to difficulties that were encountered in rendering an accurate diagnosis, and the associated management implications

CONTEXT: A broad spectrum of nonneoplastic conditions can mimic a brain tumor, both clinically and radiologically. In this review we consider these, taking into consideration the following etiologic categories: infection, demyelination, vascular diseases, noninfectious inflammatory disorders, and iatrogenic conditions. We give an overview of such diseases, which represent a potential pitfall for pathologists and other clinicians involved in patient care, and present selected cases from each category. OBJECTIVE: To illustrate the radiologic and pathologic features of nontumoral intracranial lesions that can clinically and radiologically mimic neoplasia. DATA SOURCES: Case-derived material and literature review. CONCLUSIONS: A variety of nonneoplastic lesions can present clinically and radiologically as primary or metastatic central nervous system tumors and result in surgical biopsy or resection of the lesion. In such situations, the pathologist has an important role to play in correctly determining the nature of these lesions. Awareness of the entities that can present in this way will assist the pathologist in the correct diagnosis of these lesions

Object Antiangiogenic agents have recently shown impressive radiological responses in high-grade glioma. However, it is not clear if the responses are related to vascular changes or due to antitumoral effects. The authors report the mature results of a clinical study of bevacizumab-based treatment of recurrent high-grade gliomas. Methods Sixty-one patients with recurrent high-grade gliomas received treatment with bevacizumab at 10 mg/kg every 2 weeks for 4 doses in an 8-week cycle along with either irinotecan or carboplatin. The choice of concomitant chemotherapeutic agent was based on the number of recurrences and prior chemotherapy. Results At a median follow-up of 7.5 months (range 1-19 months), 50 (82%) of 61 patients relapsed and 42 patients (70%) died of the disease. The median number of administered bevacizumab cycles was 2 (range 1-7 cycles). The median progression-free survival (PFS) and overall survival (OS) were 5 (95% confidence interval [CI] 2.3-7.7) and 9 (95% CI 7.6-10.4) months, respectively, as calculated from the initiation of the bevacizumab-based therapy. Radiologically demonstrated responses following therapy were noted in 73.6% of cases. Neither the choice of chemotherapeutic agent nor the performance of a resection prior to therapy had an impact on patient survival. Although the predominant pattern of relapse was local, 15 patients (30%) had diffuse disease. Conclusions Antiangiogenic therapy using bevacizumab appears to improve survival in patients with recurrent high-grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored

There is considerable evidence that the tissue microenvironment can suppress cancer and that microenvironment disruption is required for cancer growth and progression. Distortion of the microenvironment by tumor cells can promote growth, recruit nonmalignant cells that provide physiological resources, and facilitate invasion. Compared with the variable routes taken by cells to become cancers, the response of normal tissue to cancer is relatively consistent such that controlling cancer may be more readily achieved indirectly via the microenvironment. Here, we discuss 3 ideas about how the microenvironment, consisting of a vasculature, inflammatory cells, immune cells, growth factors, and extracellular matrix, might provide therapeutic targets in glioblastoma (GBM) in the context of radiotherapy (RT): (1) viable therapeutic targets exist in the GBM microenvironment, (2) RT alters the microenvironment of tissues and tumors; and (3) a potential benefit may be achieved by targeting the microenvironments induced by RT

Subependymal giant cell tumors (SGCTs) are observed in 5-20% of patients with tuberous sclerosis complex (TSC) but account for approximately 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period