Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) Mutations Drive the Pathogenesis of Multifocal Neurofibroma...

Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by 2 cases of plexiform neurofibromas harboring ERBB2 hotspot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA-sequencing panel. Clinical history, radiologic findings, and follow-up information were retrieved from chart review. Pathologic features, and genomic and germline findings, were reviewed. We identified 5 patients; all except 1 were women, with a median age of 34 years (range: 24-40 years). All revealed multiple PNSTs with a segmental distribution on imaging, including the pelvis (n = 2), upper limb (n = 2), and stomach (n = 1). None of the patients had a family history or displayed clinical features of neurofibromatosis type 1, except for 1 patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n = 4), intraneural with Schwann cell micronodule (n = 2), and diffuse (n = 1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n = 3; exon 20, n = 2; exon 21, n = 1). One additional case had 2 concurrent ERBB2 mutations in exons 20 and 21. On germline testing, only 1 patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, and LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation, 1 being enrolled on an HER2 inhibitor trial for 7 years owing to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications.