BRAF Exon 15 Mutations in the Evaluation of Well-Differentiated Epithelial Nephroblastic Neoplasms in Children: A Report From the Children's Oncology Group Study AREN03B2

Abstract

Context.—: The distinction between well-differentiated epithelial favorable-histology Wilms tumor (EFHWT) and metanephric adenoma (MA) in children has historically been determined by the required absence of both a fibrous pseudocapsule and mitotic activity in MA. More recently these features have been allowed in adult MA. Mutations in exon 15 of the BRAF gene are reported in up to 88% of MAs but have not been reported in EFHWTs in children lacking MA features.

Objective.—: To clarify the pathologic and molecular features used to distinguish between pediatric MA and EFHWT.

Design.—: Stage I epithelial tumors classified as EFHWT on central review (36 patients) were identified from the Children's Oncology Group AREN03B2 study. Thirteen tumors had morphologic features overlapping those of MA and 23 lacked such features; 35 of 36 had tissue available for sequencing of BRAF.

Results.—: Patients with EFHWTs with MA features (13) were older (mean, 8.4 versus 1.9 years; P < .001), had smaller tumor diameters (mean, 6.0 versus 9.7 cm; P < .001), and had fewer mitoses (mean, 1 versus 48 mitoses per 10 high-power fields; P < .001) than patients with EFHWT lacking MA features (23). All EFHWTs with MA features contained at least a partial fibrous pseudocapsule; 7 of 12 (58%) had a BRAF exon 15 mutation. No BRAF exon 15 mutations were identified in 23 EFHWTs lacking MA features. None of the 13 EFHWT patients with MA features have experienced relapse (median follow-up 5.9 years).

Conclusions.—: Pediatric epithelial neoplasms with features of MA that show partial encapsulation and/or modest mitotic activity may be classified as MAs. Although BRAF mutation supports the diagnosis of MA, it is not required for the diagnosis.

Pathologic features of epithelial favorable-histology Wilms tumor (EFHWT) with and without metanephric adenoma (MA) features. All EFHWTs with MA features demonstrated closely packed epithelial structures that in areas directly interfaced with the adjacent normal renal parenchyma, as illustrated in this BRAF mutation–positive tumor (A). In all EFHWTs with MA features, areas were also seen showing an incomplete and variable fibrous pseudocapsule, as illustrated in these BRAF mutation–negative (B) and BRAF mutation–positive (C) tumors. In contrast, sections of EFHWTs lacking MA features had a wider range of epithelial patterns, from more primitive to more well differentiated, and were surrounded by a thick fibrous capsule, as seen in this BRAF mutation–negative tumor (D) (hematoxylin and eosin, original magnifications X 100 [A] and X40 [B through D]).