Arteriovenous malformations (AVM) of the brain are considered congenital. Most AVMs are presumably sporadic, however rare familial cases occur and they may be observed in certain genetic disorders. We sought to determine the frequency of KRAS mutations and their association with clinicopathologic characteristics. We searched our neuropathology database from 2014-2017 for resected AVMs of the brain or dura mater. Twenty-one AVMs were tested (12 females, 9 males; average age: 32 years). KRAS mutations were found in 6/21 cases (28.5%). Five mutations were p.G12V, and one p.G12C. The KRAS-mutant group contained 4 females and 2 males, with an average age of 28 years, compared to 34 years in the non-mutant group (p=0.54). The average AVM size in the KRAS-mutant group was 3.9 cm, compared to 3.1 cm in the nonmutant group (p=0.52). There were no histologic differences between KRAS-mutant and nonmutant cases. In summary, KRAS mutations occur in almost one third of brain AVMs. KRAS p.G12V was the most common mutation identified. We also demonstrate the first reported instance of a KRAS p.G12C mutation in a brain AVM. The mean age of patients with KRASmutant AVMs was lower than the non-mutant group, and the mean size larger. Histologic characteristics were equally distributed between KRAS-mutant and non-mutant groups.

Histologically, it is nearly impossible to distinguish the dedifferentiated component of dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma (UPS) of bone when the low-grade cartilaginous component is absent. Previous studies have revealed that isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are present in a significant number of cartilaginous tumors including most conventional chondrosarcomas and dedifferentiated chondrosarcomas. These mutations have not been studied in UPSs of bone. We sought to investigate whether an IDH1 or IDH2 mutation signature could be used as a clinically diagnostic marker for the distinction of dedifferentiated component of chondrosarcoma from UPS of bone. Sixty-eight bone tumor cases, including 31 conventional chondrosarcomas, 23 dedifferentiated chondrosarcomas, and 14 UPSs of bone, were collected for IDH1/2 mutation analysis either using the Qiagen IDH1/2 RGQ PCR Kit or using whole-exome sequencing. IDH1/2 mutations were detected in 87% (20/23) of dedifferentiated chondrosarcomas and 30% (6/20) of conventional chondrosarcomas. No mutations were detected in the IDH1/2 codon 132 or codon 172 among 14 UPSs of bone. Identification of IDH1 or IDH2 mutations supports the diagnosis of dedifferentiated chondrosarcoma rather than UPS of bone while also providing some insight into the pathogenesis of these 2 lesions.

BRAF mutation recently has been reported in metanephric adenoma. We sought to determine the clinical and morphologic features of BRAF-mutated metanephric adenoma and to correlate BRAF mutation with BRAF V600E immunohistochemical staining results. A series of 48 metanephric adenomas and 15 epithelial-predominant nephroblastomas were analyzed for the occurrence of BRAF mutation (BRAF V600E/V600E complex, BRAF V600D, BRAF V600K and BRAF V600R) using the BRAF RGQ PCR kit (Qiagen). Immunohistochemistry was performed using monoclonal mouse antibodies against p16INK4 and VE1 (Spring Bioscience), recognizing the BRAF V600E mutant protein. Forty-one of 48 cases (85%) showed BRAF V600E mutation; none of the other BRAF variants was detected. Of 41 BRAF-mutated metanephric adenomas, 33 showed positive VE1 immunostaining (sensitivity 80%, specificity 100%); in all cases we detected p16INK4 expression regardless of BRAF mutation status. All epithelial-predominant nephroblastomas were BRAF-wild-type and none expressed VE1. The following features were associated with BRAF V600E mutation: older patients (p=0.01), female predominance (p=0.005) and the presence of a predominantly acinar architecture (p=0.003). In summary, BRAF-mutated metanephric adenomas were associated with older age, female predominance, and the presence of a predominant acinar component. A subset (20%) of BRAF-mutated metanephric adenomas was not detected by VE1 immunostaining.

No abstract

Determination of the isocitrate dehydrogenase (IDH) mutation status, presence or absence of mutation in IDH genes (IDH1 or IDH2), has become one of the most important molecular features taken into account in the management of patients with diffuse gliomas. Tumors that are IDH-mutant have a better prognosis than their counterparts with similar histologic grade and IDH-wildtype phenotype. IDH1-R132H is the most common IDH mutation, present in ~90% of IDH-mutant cases. This mutation yields an altered protein that can be detected by immunohistochemistry. We evaluated the IDH1-R132H antibody (clone H09) to determine IDH mutation status as the first line test and compared with the results of polymerase chain reaction (PCR) testing that can detect more types of mutations in IDH1 or IDH2. A total of 62 gliomas were evaluated: 30 glioblastomas (including 3 gliosarcomas), 11 grade III diffuse gliomas, 17 grade II diffuse gliomas, and 4 circumscribed gliomas. Twelve of 62 cases were IDH-mutant by immunohistochemistry and 15 of 62 by PCR. PCR detected the following mutations: IDH1-R132H (11 cases), IDH1-R132C (1 case), IDH2 R172, NOS (1 case), IDH1 R132, NOS (1 case), and IDH2-R172K (1 case). The R132H antibody had high specificity (100%) and sensitivity (80%) to detect IDH mutation status; the discordant results were 3 false-negatives. IDH-R132H immunostain is suitable as a first line test. Nonimmunoreactive cases could be studied by PCR following recommendations of the 2016 World Health Organization guidelines.