NHERF1/EBP50 is an organizer of polarity structures and a diagnostic marker in ependymoma

Abstract

NHERF1/EBP50, an adaptor protein required for epithelial morphogenesis, has been implicated in the progression of various human malignancies. NHERF1-deficient mice have intestinal brush border structural defects and we report here that they also have disorganized ependymal cilia with development of non-obstructive hydrocephalus. Examination of mouse and human brain tissues revealed highest NHERF1 expression at the apical plasma membrane of ependymal cells. In ependymal tumors, NHERF1 expression was retained in polarized membrane structures, such as microlumens, rosettes and canals, where it co-localized with some of its ligands, such as moesin and PTEN. Analysis of a comprehensive panel of 113 tumors showed robust NHERF1 labeling of microlumens in 100% of ependymomas, subependymomas, and pediatric anaplastic ependymomas, and in 67% of adult anaplastic ependymomas. NHERF1 staining was present in 35% of ependymoma cases that lacked reactivity for EMA, the routine immunohistochemical marker used for ependymoma diagnosis. NHERF1 labeling of microlumens was either absent or rarely seen in other types of brain tumors analyzed, denoting NHERF1 as a reliable diagnostic marker of ependymal tumors. Anaplastic foci and a subset of adult anaplastic ependymomas showed complete absence of NHERF1-labeled polarity structures, consistent with a loss of differentiation in these aggressive tumors. These data highlight a role for NHERF1 in ependymal morphogenesis with direct application to the diagnosis of ependymal tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0197-z) contains supplementary material, which is available to authorized users.

C11orf95‐RELA fusion present in a primary intracranial extra‐axial ependymoma: Report of a case with literature review

“…However, the latter are rare histological findings and in most instances, specific immunohistochemistry is required to confirm diagnosis as in our case. In addition to perivascular cytoplasmic immunoreactivity for GFAP, EMA and EBP50 are useful diagnostic markers that characteristically produce “dot‐like” and “ring‐like” patterns highlighting the intra‐cytoplasmic lumens or microlumens, the pathognomonic ultrastructural feature of ependymomas . These lumens contain microvilli with or without cilia, as was demonstrated on electron microscopy in our case.…”

Mutation Status and Epithelial Differentiation Stratify Recurrence Risk in Chordoid Meningioma—A Multicenter Study with High Prognostic Relevance

“…In this approach, NHERF1 IHC may be sent for outside testing to confirm the very rare fibroblastic-like cases from the ED group #1. By using the clinically-validated NHERF1/EBP50 as marker for microlumens [13,16,30], chordoid meningiomas were divided into three ED tumor groups ( Figure 5). Whereas the very rare meningiomas from ED group #1 may be reclassified as WHO grade I, the tumors from the other two groups warrant a higher WHO grade.…”

“…By assembling a representative cohort of cases, we have previously shown that this variant is characterized by epithelial differentiation (ED) with microlumen formation [13]. We have also found that immunohistochemistry (IHC) for NHERF1, an adaptor protein that interacts with the ezrin-radixin-moesin (ERM)-NF2 family of proteins to structure microvilli [14,15], specifically highlights microlumens [13,16]. In the current study, we analyzed a 30-patient cohort, performing mutational profiling by next generation sequencing (NGS) and correlating the findings with ED, age, gender, location, and recurrence rate.…”

Case-based review: ependymomas in adults

“…NHERF1/EBP50, a protein required for epithelial morphogenesis, appears to be more specific than EMA for labeling ependymomas. 31 In our experience NHERF1 is superior to EMA and extremely helpful in diagnosing difficult cases.…”