Classification of schwannomas and the new naming convention for "neurofibromatosis-2": Genetic updates and international consensus recommendation

Abstract

Despite their similar nomenclature, Neurofibromatosis type 1 (NF1) and "Neurofibromatosis type 2" are discrete and clinically distinguishable entities. The name of "neurofibromatosis type 2" has been changed to NF2-related schwannomatosis, to reflect the fact that neurofibromas do not occur in this syndrome and therefore the name "Neurofibromatosis" is factually incorrect. Furthermore, multiple schwannomas, a hallmark feature of NF2, can also occur in patients with mutations in genes including SMARCB1 and LZTR1, all exhibiting overlapping clinical features. Current understanding suggests that schwannomatosis (SWN) encompasses a range of clinical presentations consisting of clearly defined, separate subtypes which share a common phenotype of schwannomas. Recognizing these newly emerging subtypes, the International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC) proposed a revised nomenclature for NF2 and related disorders in 2022. This review article focuses on this critical update in diagnostic terminology, highlighting the key gene-related SWN subtypes relevant to neuroradiologists. By emphasizing molecular testing alongside clinical features, the revised system facilitates a more precise diagnosis, potentially paving the way for personalized treatment strategies. Additionally, the flexible structure accommodates future discoveries of genes associated with SWN.

Keywords: LZTR1; NF2-related schwannomatosis; SMARCB1; neurofibromatosis type 2; schwannomatosis.

Figure 1.

Classic intracranial tumors of NF2-related schwannomatosis in a 17-year-old girl. Multiple schwannomas are noted on the axial post-contrast T1-weighted image (a), including large left vestibular schwannoma, small right vestibular schwannoma (white arrows), and small schwannomas within bilateral Meckel’s cave (black arrows). Sagittal post-contrast image (b) reveals multiple, enhancing, convexity, parasagittal, and posterior cranial fossa meningiomas. DOTATATE scan (c, d) reveals multiple variable-size meningiomas in the supra- and infratentorial region including a left intraventricular meningioma (white arrow).

Figure 2.

Classic spinal tumors of NF2-related schwannomatosis in a 14-year-old girl. Contrast-enhanced T1-weighted and sagittal T2-weighted MR images of the cervical spine (a, b) reveal multiple intramedullary enhancing tumors (arrows) in the medulla and cervical spinal cord (presumed ependymomas). The dominant lesion centered at the cervicomedullary junction shows prominent intratumoral cystic components (b, arrow). Surgical resection of the dominant lesion revealed grade 2 ependymoma on histopathology. Sagittal post-contrast T1-weighted image (c) of the thoracic spine reveals a dural-based enhancing mass along the dorsal cord (arrow) with increased uptake on DOTATATE scan (d, arrow) suggesting meningioma. Multiple schwannomas (presumed) are noted along the cauda equina nerve roots on the sagittal post-contrast image (e) of the lumbar spine.

Figure 3.

Meningioangiomatosis in a 12-year-old girl with NF2-related schwannomatosis. FLAIR axial (a), contrast-enhanced T1-weighted axial (b), and sagittal images (c) reveal multiple nodular cortical enhancing lesions (white arrows) with pathology revealing meningioangiomatosis. Vestibular and trigeminal nerve schwannomas noted on the axial post-contrast image (b, arrowhead). A meningioma along the upper ventral cord was noted on the sagittal post-contrast image (c, black arrow).

Figure 4.

Visual representation of the spectrum of NF2-related schwannomatosis, ranging from the mildest to the most severe phenotype, with their associated genotypic correlate.

Figure 5.

Malignant transformation of left thigh schwannoma in a 38 -year-old man with known SMARCB1 schwannomatosis. The patient also had multiple spinal schwannomas (not shown). Initial coronal contrast-enhanced T1-weighted MRI (a) reveals a bilobed mass (schwannoma) in the left thigh with mild uptake on FDG-PET exam (b). The patient experienced worsening radicular left thigh pain. Follow-up FDG-PET (c) and contrast-enhanced T1-weighted coronal MRI (d) reveal a marked increase in metabolic uptake with an increase in size and central necrosis. Histopathology revealed a malignant peripheral nerve sheath tumor (at least intermediate grade) arising from pre-existing schwannoma. H&E (40 x 10) shows highly atypical spindle cells with prominent nucleoli (e, blue arrow), mitotic activity (up to 7 mitoses per 10 high-power fields) (e, black arrows), and intersecting fascicles (f).

Figure 6.

Multiple pelvic soft tissue and orbital schwannomas in a 19-year-old man constitutional pathogenic variant in the LZTR1 gene and known schwannomatosis in a paternal cousin. Multiple T2-weighted (a, c) and contrast-enhanced T1-weighted (b, d, e) MR images of the pelvis and orbits are depicted. Numerous variable-sized schwannomas are noted through the pelvic soft tissue (a, b, d, arrows). Small orbital intraconal schwannomas are also noted (c, e, arrows) bilaterally.

Figure 7.

Spinal axial and soft tissue schwannomatosis in a 34-year-old man with a family history of schwannomatosis and constitutional pathogenic variant in the LZTR1 gene. Sagittal (a, b) and axial contrast-enhanced T1-weighted MR images along with axial T2-weighted images (c, d) reveal numerous variable-sized schwannomas along the spinal axial in the extramedullary intradural compartment with heterogenous enhancement and T2 hyperintensity (arrows). A large schwannoma was also noted along the left lower neck (c, d). Another discrete lesion is seen completely filling up the thecal sac in the lumbar region (e, f).