State-of-the-art pathology: new WHO classification, implications, and new developments.

To keep up with advances in central nervous system (CNS) tumor diagnosis and discovery of new entities, the classification of these tumors requires periodic review and revision. Since the initial 1979 publication from the World Health Organization (WHO) of Histological Typing of Tumours of the Central Nervous System, 3 further editions have been published, cataloging the advances in CNS tumor classification and diagnosis over the past 3 decades. In this article, we discuss select new additions to the current classification, including new diagnostic tools, differential diagnoses, and management implications.

ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma.

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.

Intracranial lesions mimicking neoplasms.

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.

Synchronous mixed germ cell tumor of the pineal gland and suprasellar region with a predominant angiomatous component: a diagnostic challenge.

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.

High-grade glioma before and after treatment with radiation and Avastin: initial observations.

We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor-A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent "normalization" after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following antiangiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers.

A fatal complication of a vena caval filter associated with pulmonary thromboembolism.

Vena caval filters are increasingly used for the prevention of pulmonary thromboembolism in patients with deep vein thrombosis ever since the introduction of the stainless steel Greenfield filter in the 1970s. Although complications associated with their use are rare, they can be fatal, and therefore it is important for forensic pathologists to be aware of their occurrence. Because of the ramifications of a medical device failure, a thorough documentation of the autopsy findings is essential. We describe an unusual case of a 75-year-old woman who developed a fatal pulmonary thromboembolism with concurrent migration of a lesser known type of vena caval filter to the right ventricle occurring 19 days after filter placement. A review of the types of vena caval filters in current use, and their complications, are discussed.

An atypical gunshot wound from a home-made zip gun--the value of a thorough scene investigation.

Zip guns and the atypical gunshot wounds they produce are rare in forensic pathology. Because of this, investigators and forensic pathologists may be unfamiliar with their construction, appearance, and the wounds associated with them. A 43-year-old mechanic, with a history of depression was found dead in a washroom stall at work with an atypical gunshot wound of the head. Upon initial investigation, no weapon was found at the scene. Due to the nature of the scene, and the unusual characteristics of the wound, the manner of death was at first thought to be a homicide. Subsequently, a simple zip gun, which had been overlooked during the scene investigation, was discovered by a co-worker while he was cleaning the stall. Examination of the wound revealed evidence of contact range firing. A markedly deformed bullet was recovered from the head, consistent with the use of the home-made gun. These findings, along with further police investigation and review of the past medical history, indicated that the manner of death was a suicide.