Cranial & Paraspinal Nerve Tumors
2023-05-02 Scott Ryall, PhD Affiliation1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)
Classification
Definition
Tumors of the cranial and paraspinal nerves are common neoplasms seen throughout the craniospinal axis and encompass a group of heterogeneous tumors with unique morphologic and biological properties. 1 They may arise sporadically or as part of a plethora of tumor predisposition syndromes. They most frequently arise from peripheral nervous system elements including Schwann and perineural cells. The previously termed “CNS paragangliomas” involve neuroendocrine cells of the sympathetic and parasympathetic nervous system and as a result, the newly termed "cauda equina neuroendocrine tumors" (WHO grade 1) are now considered a "cranial & paraspinal nerve tumor" rather than their previous consideration as a "neuronal and mixed neuronal-glial tumor." 2,3 Also included in cranial & paraspinal nerve tumors are schwannoma (WHO grade 1), neurofibroma (WHO grade 1), perineurioma (WHO grade 1), hybrid nerve sheath tumors (HNST), malignant melanotic nerve sheath tumor (MMNST), and malignant peripheral nerve sheath tumor (MPNST).
| Cranial & Paraspinal Nerve Tumors | Genetic Event(s) |
|---|---|
| Schwannoma | Loss of function events, predominantely as frameshift or nonsense mutations, in NF2 are the most common genetic feature of schwannoma, present in 50-75% of tumors with co-occurring loss of the wildtype chromosome 22 allele. 4-7 A key tumor supressor, NF2 is located at the 22q12.2 locus and encodes for merlin (also known as schwannomin), a pertinent regulatory protein that prevents growth via contact-dependent inhibition. 8 Recent efforts have also identified recurrent mutations in LATS1, LATS2 (promoter methylation of LATS1 and LATS2 is more common), ARID1A, ARID1B, and DDR1 in subsets of schwannoma. 5,6 SH3PXD2A::HTRA1 in-frame fusions, the result of a chromosome 10q inversion, have likewise been reported in approximately 10% of schwannoma. 6,9 Methylation analysis reveals distinct pattern associated with schwannoma that may form subgroups associated with their anatomical location. 6,10,11 The presence of multiple Schwannoma is an important diagnostic component of Neurofibromatosis type 2 (NF2) OMIM:101000 and schwannomatosis OMIM:162091. Germline NF2 mutations are a diagnostic requirement for NF2 syndrome while the germline alterations causing schwannomatosis are often unknown. However, germline variants in SMARCB1 and LZTR1 define subsets of schwannomatosis, but may also be present in sporadic tumors. 12-14 Schwannoma arising in this context illustrate a "four-hit" mechanism of tumorigenesis in which sequential inactivation of both copies of SMARCB1 or LZTR1 and NF2 occurs via a combination of mutations and the deletion of the other wldtype allele. 15 |
| Neurofibroma | The defining genetic event for neurofibromas is the bi-allelic inactivation of the tumor suppressor NF1 located on chromosome 17q11.2. 1,16,17 NF1 encodes neurofibromin, a GTPase-activating protein that acts as a negative regulator of RAS signalling by facilitating the conversion of RAS-bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). 18-20 In the context of NF1-related tumorigenesis, this ultimately results in upregulation of the RAS/RAF/MEK/ERK and/or PI3K/AKT/mTOR pathways, which have important roles in cell growth, survival and migration. 19,21 Multiple neurofibroma is an important diagnostic component of Neurofibromatosis type 1 (NF1) OMIM:162200. Methylation analysis segregates dermal, intraneural and plexiform neurofibromas, suggesting a unique cell of origin based on tumor location. 10 Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP) is used to denote a neurofibroma with worrisome histologic features but not clearly deserving a diangosis of malignancy. 22 This classification remains controversial. In the setting of NF1 inactivation, deletions of CDKN2A and/or CDKN2B are common in ANNUBP. 23,24 Heterozygous loss of SMARCA2 either on its own or in conjunction with CDKN2A and/or CDKN2B loss has also been shown in ANNUBP. 24 |
| Perineurioma | The majority of intraneural perineurioma have mutations in the WD40 domain of TRAF7, similar to those seen in meningiomas. 25 In the absence of a TRAF7 mutation, some perineuriomas have large chromosomal abnormalities such as deletions of chromosome 22q which includes NF2. 25 Soft tissue perineuriomas are devoid of TRAF7 mutations but do harbor deletions of chromosome 22q (including NF2) and 17q (including NF1), often mutually exclusive of one another. 26 The rarity of perineurioma has prevented current methylation-based classification of the neoplasm to be completed at this time. |
| Hybrid Nerve Sheath Tumor (HNST) | Hybrid nerve sheath tumors (HNST) are benign neoplasms consisting of features associated with multiple conventional peripheral nerve sheath tumors (neurofibroma, schwannoma, perineurioma). Hybrid schwannoma/perineurioma tend to arise sporadically 27 while hybrid neurofibroma/schwannoma is strongly associated with NF1 OMIM:162200, NF2 OMIM:101000 and schwannomatosis OMIM:162091. 28 Likewise, hybrid neurofibroma/perineurioma has been associated with NF1. 29,30 Activating mutations in the catalytic domain of the ERBB2 and heterozygous RET mutations were reported in a subset of schwannomatosis- and NF2-related hybrid neurofibroma/schwannoma tumors, respectively. 31 Methylation analysis segregates these tumors into a subgroup consisting of the majority of schwannomatosis-related hybrid neurofibroma/schwannoma tumors. 31 VGLL3 rearrangements, often as fusion events, are prominent in hybrid neurofibroma/schwannoma. 32 |
| Malignant Melanotic Nerve Sheath Tumor (MMNST) | Malignant melanotic nerve sheath tumors (MMNST, previously melanotic schwannomas) can be sporadic or arise in the context of Carney complex OMIM:160980, a multiple neoplasia syndrome. 33,34 Molecular studies of these tumors, both sproadic and syndromic, have identified frequent loss of function mutations in PRKAR1A on chromosome 17q24.2 or in the less characterized locus on chromosome 2p16. 35,36 PRKAR1A encodes for a regulatory subunit that forms protein kinase A (PKA) and these loss of function variants result in increased PKA activity and dysregulation of several downstream singaling pathways. 37 Chromosomal copy number analysis has shown recurrent whole chromosome losses of 1, 2, 17, 21, and 22q and gains of 5, 6, 7, 8, and 9 in MMNST. 36,38 Both gene expression and DNA methylation analysis classify MMNST as separate entities from both conventional schwannomas and melanomas. 11,34,38 |
| Malignant Peripheral Nerve Sheath Tumor (MPNST) | Approximately 50% of malignant peripheral nerve sheath tumors (MPNST) arise in the context of NF1 OMIM:162200 via Schwann cells harboring bi-allelic NF1 inactivation. 39,40 MPNST are further molecularly characterized by inactivation of the polycomb repressive complex 2 (PRC2) components SUZ12 or EED leading to a global loss of the repressive trimethylation mark on the histone H3 tail at position 27 (H3K27me3) in tumor cells. 41,42 Chromosomal copy number analysis of MPNST reveals numerous chromosomal gains and losses including, but not limited to, losses in 1, 10, 11, 17 and 22 and gains in 2, 5, 7, 8, and 14. 10,43 Mutations in TP53 have also been reported in MPNST, primarily in those unassociated with NF1. {28124441, 29118384) DNA methylation analysis segregates MPNST based on their retention or loss of H3K27me3. 10 Epithelioid MPNST are not associated with NF1. Rather, most are driven by inactivating alterations of SMARCB1. 44,45 Recurrent copy number alterations of epithelioid MPNST include deletions of CDKN2A and/or CDKN2B, loss of chromosome 22q, and gains of chromosome 2p. 45 |
| Cauda Equina Neuroendocrine Tumor | Nearly all cauda equina neuroendocrine tumors are sporadic. Presently, the molecular alterations that drive their tumorigenesis are largely unknown, as they lack any recurrent chromosomal abnormalities and do not harbor SARDH mutations as is seen in non-spinal paragangliomas. 46,47 DNA methylation analysis classifies cauda equina neuroendocrine tumors as a distinct entity separate from non-spinal paragangliomas, pheochromocytomas, and other neuroendocrine neoplasms. 46,47 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 33588442 | 2021 | Diagnostic Pathology of Tumors of Peripheral Nerve. | Belakhoua SM et al |
| 2 | 27157931 | 2016 | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. | Louis DN et al |
| 3 | 34185076 | 2021 | The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. | Louis DN et al |
| 4 | 8889506 | 1996 | Frequency and distribution of NF2 mutations in schwannomas. | Jacoby LB et al |
| 5 | 26360373 | 2015 | Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas. | Oh JE et al |
| 6 | 27723760 | 2016 | The genomic landscape of schwannoma. | Agnihotri S et al |
| 7 | 28409725 | 2018 | Genetic landscape of sporadic vestibular schwannoma. | Håvik AL et al |
| 8 | 22750751 | 2012 | Merlin: the wizard requires protein stability to function as a tumor suppressor. | Morrow KA et al |
| 9 | 34213706 | 2021 | The SH3PXD2A-HTRA1 fusion transcript is extremely rare in Norwegian sporadic vestibular schwannoma patients. | Taule-Sivertsen P et al |
| 10 | 26857854 | 2016 | Methylation-based classification of benign and malignant peripheral nerve sheath tumors. | Röhrich M et al |
| 11 | 29539639 | 2018 | DNA methylation-based classification of central nervous system tumours. | Capper D et al |
| 12 | 24362817 | 2014 | Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. | Piotrowski A et al |
| 13 | 25480913 | 2015 | Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. | Smith MJ et al |
| 14 | 25335493 | 2015 | Expanding the mutational spectrum of LZTR1 in schwannomatosis. | Paganini I et al |
| 15 | 18072270 | 2008 | Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. | Sestini R et al |
| 16 | 25293717 | 2015 | Somatic neurofibromatosis type 1 (NF1) inactivation events in cutaneous neurofibromas of a single NF1 patient. | Emmerich D et al |
| 17 | 28068329 | 2017 | The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas. | Pemov A et al |
| 18 | 15805275 | 2005 | Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. | Dasgupta B et al |
| 19 | 28230061 | 2017 | Neurofibromatosis type 1. | Gutmann DH et al |
| 20 | 30308447 | 2018 | Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA. | Tsipi M et al |
| 21 | 21686117 | 2010 | Ras history: The saga continues. | Cox AD et al |
| 22 | 28551330 | 2017 | Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview. | Miettinen MM et al |
| 23 | 29774626 | 2018 | Analysis of intratumor heterogeneity in Neurofibromatosis type 1 plexiform neurofibromas and neurofibromas with atypical features: Correlating histological and genomic findings. | Carrió M et al |
| 24 | 30722027 | 2019 | Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1-associated atypical neurofibromas. | Pemov A et al |
| 25 | 28019650 | 2017 | Genomic analysis reveals frequent TRAF7 mutations in intraneural perineuriomas. | Klein CJ et al |
| 26 | 30303818 | 2018 | Recurrent Genomic Alterations in Soft Tissue Perineuriomas. | Carter JM et al |
| 27 | 19623031 | 2009 | Hybrid schwannoma/perineurioma: clinicopathologic analysis of 42 distinctive benign nerve sheath tumors. | Hornick JL et al |
| 28 | 22446939 | 2012 | Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients. | Harder A et al |
| 29 | 23676318 | 2013 | Hybrid peripheral nerve sheath tumors, including a malignant variant in type 1 neurofibromatosis. | Kacerovska D et al |
| 30 | 24751814 | 2014 | Hybrid perineurioma-neurofibroma in a patient with neurofibromatosis type 1, clinically mimicking malignant peripheral nerve sheath tumor. | Inatomi Y et al |
| 31 | 32017710 | 2020 | Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors. | Ronellenfitsch MW et al |
| 32 | 33649458 | 2021 | Hybrid schwannoma-perineurioma frequently harbors VGLL3 rearrangement. | Dickson BC et al |
| 33 | 2305928 | 1990 | Psammomatous melanotic schwannoma. A distinctive, heritable tumor with special associations, including cardiac myxoma and the Cushing syndrome. | Carney JA et al |
| 34 | 24145644 | 2014 | Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of "melanotic schwannoma". | Torres-Mora J et al |
| 35 | 12676898 | 2003 | Chromosome 2 (2p16) abnormalities in Carney complex tumours. | Matyakhina L et al |
| 36 | 26031761 | 2015 | Consistent copy number changes and recurrent PRKAR1A mutations distinguish Melanotic Schwannomas from Melanomas: SNP-array and next generation sequencing analysis. | Wang L et al |
| 37 | 25592387 | 2016 | MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics. | Schernthaner-Reiter MH et al |
| 38 | 25399693 | 2015 | Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles. | Koelsche C et al |
| 39 | 23036231 | 2012 | Malignant peripheral nerve sheath tumours in inherited disease. | Evans DG et al |
| 40 | 33224354 | 2020 | Neurofibromatosis type I-associated malignant peripheral nerve sheath tumors: a case report and literature review. | Wu Y et al |
| 41 | 25240281 | 2014 | PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. | Lee W et al |
| 42 | 25305755 | 2014 | Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. | Zhang M et al |
| 43 | 16527603 | 2006 | Chromosomal aberrations and microsatellite instability of malignant peripheral nerve sheath tumors: a study of 10 tumors from nine patients. | Kobayashi C et al |
| 44 | 25602794 | 2015 | Epithelioid malignant peripheral nerve sheath tumor: clinicopathologic analysis of 63 cases. | Jo VY et al |
| 45 | 30864974 | 2019 | Recurrent SMARCB1 Inactivation in Epithelioid Malignant Peripheral Nerve Sheath Tumors. | Schaefer IM et al |
| 46 | 32892244 | 2020 | The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma. | Ramani B et al |
| 47 | 32926213 | 2020 | Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity. | Schweizer L et al |
Citation
Scott Ryall, PhD
Cranial & Paraspinal Nerve Tumors
Atlas Genet Cytogenet Oncol Haematol. 2023-05-02
Online version: http://atlasgeneticsoncology.org/solid-tumor/209123/cranial-paraspinal-nerve-tumors
