Rhabdomyosarcoma Harboring NRAS or HRAS Mutation Arising in Giant Congenital Melanocytic Nevus: Report of 2 Cases.

Nonmelanoma malignancies associated with congenital melanocytic nevi (CMN) are extremely rare, with only 12 reported cases of rhabdomyosarcoma (RMS) to date. We present 2 additional cases of RMS arising in giant CMN, with immunohistochemical and molecular biologic investigations. The first case was a 32-year-old woman with a personal history of melanoma in giant CMN who, after successful treatment and long remission, presented with a new 1-cm nodule within the CMN. Microscopically, the atypical areas exhibited a round cell/alveolar morphology with immunoreactivity for desmin and myogenin, and lacked PAX3/7::FOXO1 fusions typical for alveolar RMS on a reverse transcription polymerase chain reaction analysis. An identical NRAS p.Q61R mutation with comparable variant allele frequency (32% and 44%) was identified in both the nevus and the RMS tissue by next-generation sequencing. The second patient was a 5-year-old girl with a rapidly growing, bleeding, ulcerated 3 × 4 cm interscapular mass within a giant CMN that histologically seemed as a proliferation of pleomorphic spindle, polygonal and epithelioid cells with marked pleomorphism immunoreactive for myogenin, muscle-specific actin, and smooth muscle actin. Next-generation sequencing yielded an HRAS p.Q61R mutation with limited variant allele frequency (7%) in the RMS component, while ATRX p.Q2193* variant was detected in the nevus. Our study is apparently the first report of NRAS and HRAS mutations in tumors with RMS phenotype arisen in CMN.