Distinct clinicopathological features in metanephric adenoma harboring BRAF mutation

Abstract

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.

Molecular characterisation of metanephric adenomas beyond BRAF: genetic evidence for potential malignant evolution

“…This study examined the genetic profiles of a series of MAs, including 11 conventional MAs and one MA with malignant features. Next‐generation sequencing revealed BRAF p.V600E mutations in all 11 conventional MAs; BRAF V600E immunohistochemistry was positive in 73% of cases, a sensitivity comparable to that in previous studies 4,5,7,8 . A single‐copy somatic BRCA2 alteration was identified in one MA (case 4); the significance of this is uncertain, as this case did not show any distinguishing morphological or clinical characteristics.…”

“…The benign nature of MA has been attributed to a BRAF V600E senescence pathway, mediated by cyclin‐dependent kinase inhibitor 2A (CDKN2A)/p16, as reported in other benign BRAF ‐mutant neoplasms such as melanocytic naevi 9,10 . In support of this concept, increased immunohistochemical p16 expression has been demonstrated in MA 5,6 . Rare metanephric tumours showing adverse features, such as sarcomatous elements and nodal metastasis, have been reported 11–16 .…”

“…Immunohistochemistry can be helpful in resolving this differential diagnosis, with MAs being commonly positive for WT1 and CD57 and negative for cytokeratin (CK) 7 3,4 . Genetically, MAs harbour BRAF V600E mutations, which are rarely found in other renal tumours 5–8 . Antibodies targeting the BRAF V600E mutant protein are available and can also aid in the diagnosis of MA 4,5,7,8 …”

“…Genetically, MAs harbour BRAF V600E mutations, which are rarely found in other renal tumours 5–8 . Antibodies targeting the BRAF V600E mutant protein are available and can also aid in the diagnosis of MA 4,5,7,8 …”

Outcome analysis of stage I epithelial‐predominant favorable‐histology Wilms tumors: A report from Children's Oncology Group study AREN03B2

“…Lastly, metanephric adenomas (MAs) are often difficult to distinguish from epithelial WTs, particularly when they show increased proliferation and/or partial encapsulation. In the past few years, up to 85% of MAs have been shown to have BRAFV600E mutations, which provide a potentially useful diagnostic marker of MAs . Indeed, BRAFV600E mutations have been identified in some (but not all) lesions in adults with increased proliferation and/or partial encapsulation .…”