Peripheral nerve sheath tumors
2023-02-14 Paola Dal Cin, PhD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
Classification
Definition
Peripheral nerve sheath tumors (PNSTs) are neuroectodermal in origin, occurring anywhere that there are nerves. More than 90% of PNSTs are benign lesions. Both benign and malignant PNSTs can be sporadic or arising in relation to neurocutaneous syndromes. Tumor syndromes of nerve usually develop secondary to germline mutations in several key tumor suppressor genes: NF1, NF2, SMARCB1, or LZTR1 and PRKAR1A. Well-defined morphological criteria still allow for classification in most cases, but methylation profiling and next generation sequencing (NGS) may provide additional diagnostic and prognostic information. 1-3
| Peripheral nerve sheath tumors | Genetic event(s) |
|---|---|
| Schwannoma | Mutations of NF2 gene (22q12.2) with concurrent loss 22/22q, in 50-75% sporadic lesions,4 or, as a part of neurofibromatosis type 2 (NF2) syndrome OMIM:101000. However, both LZTR1 and SMARCB1 genes, located on chromosome 22q closed to NF2, were recurrently deleted and /or mutated in sporadic lesion. 5 Other common mutations LATS1, LATS2, ARID1A,ARID1B and DDR1. 6 |
| Several gene fusions more frequent in Schwannomatosis type 2 (SWNTS2) OMIM:615670 lesions harbored LZTR1 germline mutations, with in-frame SH3PXD2A::HTRA1 fusion been the most frequent. Addtional recurrent novel non-22q deletions in chrs. 4, 16, 19, and 21, were specifically prevalent in LZTR1-mutant samples. 5 Germline mutations in SMARCB1 occur in SWNTS1 OMIM:162091, however, the multiple lesions harbor genomic features distinct to the sporadic ones. 5 | |
| Neurofibroma (NF) | Genetic event for all neurofibroma subtypes is biallelic inactivation of the NF1 gene (17q11.2), by point mutations, microdeletion or pathogenic intronic mutations.7 Such lesions are nearly ubiquitous symptom of NF1 syndrome OMIM:162200. |
| Atypical neurofibroma (ANF) represents an intermediate step in malignant transformation, in NF1-associated neoplasms. Deletion of CDKN2A and CDKN2B are the primarily driven event associated with this malignant tranformation, but not SUZ12,EED, and TP53, which are frequently inactivated in MPNST. 8,9 | |
| Perineurioma | Deletions of chr. 22q12, including NF2 or chr.17q11.2 , including NF1 gene, are frequent and mutually exclusive events in soft tissue lesions by WES and OncoScan analyses. 10 Recurrent losses of chr.10q and chr.22q in sclerosing perineurioma.11 Intraneural perineuriomas frequently contain TRAF7 (16p13) mutations, and rarely, chr.22q12 deletions. 12 |
| Only a limited number of perineuriomas have been studied genetically.13 Complex translocations t(2;9;4) and t(1;9;4) involving 4q31 and 9q34 bands resulting in GAB1::ABL1 fusion gene in pediatric soft tissue lesions.13,14 | |
| Granular cell tumor | Loss of function mutation affecting the V-ATPase accessory genes ATP6API and ATP6AP2. 15,16 |
| Multiple lesions associated with various syndromes as NF1 OMIM:613113, Noonan OMIM:163950 and LEOPARD -1 OMIM:151100 | |
| Dermal nerve sheath myxoma | Nerve sheath myxomas and schwannomas are related neoplasms, since they have in comon loss 22q 17 and gene expression profile.18 |
| Solitary circumscribed neuroma | No specific genetic findings so far |
| Ectopic meningioma and meningothelial hamartoma | No specific genetic findings so far |
| Benign triton tumor/neuromuscular choristoma (NMC) | Neuromuscular choristoma, often associated with a fibromatosis, frequently contains CTNNB1 p.S45F mutation, which has been associated with a more aggressive clinical behavior. 19-21 |
| Hybrid nerve sheath tumor (HNST) | Monosomy 22 22 and recurrent ERBB2 mutations 23 in a subset of hybrid neurofibroma/schwannomas developing in the context of schwannomatosis. |
| Malignant peripheral nerve sheath tumor (MPNST) | Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). Germline or acquired NF1, inactivation is considered an important initiating event in MPNST. A cascade of other mutations contributes to the malignant phenotype. Loss of CDKN2A and/or CDKN2B are important early events in ANF, 9 but further progression to MPNST required a broad of additional chromosomal rearrangements 24 and frequent inactivations, including the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes. 3,25 |
| Mutations in other genes such as TP53, EED, SUZ12, and CDKN2A are required for malignant transformation to MPNST regardless of their etiology.25-27 8q gain is associated with ith high-grade transformation in MPNST. 28 | |
| Surgical resection of the tumor is the only curative therapy available, is not always possible due to the location/and or size of the tumo, and adjuvant radiotherapy is recommended. 3 | |
| Epithelioid malignant peripheral nerve sheath tumors (EMPNST) is a distinctive MPNST variant, rarely associated with NF1 syndrome. SMARCB1 inactivation had been reported, with inactivation of CDKN2A and gain of chromosome 2q. 29 | |
| Malignant melanotic nerve sheath tumor | SNP-array analysis revealed copy number and allelic imbalance involving chrs 1, 2, and 17, and mutational screening showed Inactivation of both alleles of PRKAR1A (17q22-q24) by "two hits" that is, either by one mutation coupled with LOH of 17q or by two mutation on 17q24. 30 |
| Inherited mutations in PRKAR1A reported in ~70% of the patients diagnosed with Carney complex, type 1 OMIM:160980 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 31707590 | 2020 | What's new in nerve sheath tumors. | Meyer A et al |
| 2 | 33588442 | 2021 | Diagnostic Pathology of Tumors of Peripheral Nerve. | Belakhoua SM et al |
| 3 | 35393544 | 2022 | Malignant peripheral nerve sheath tumor: models, biology, and translation. | Somatilaka BN et al |
| 4 | 24450866 | 2014 | Schwannomas and their pathogenesis. | Hilton DA et al |
| 5 | 33025139 | 2021 | Epigenomic, genomic, and transcriptomic landscape of schwannomatosis. | Mansouri S et al |
| 6 | 27723760 | 2016 | The genomic landscape of schwannoma. | Agnihotri S et al |
| 7 | 29695767 | 2018 | Cutaneous neurofibromas in the genomics era: current understanding and open questions. | Allaway RJ et al |
| 8 | 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 |
| 9 | 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 |
| 10 | 30303818 | 2018 | Recurrent Genomic Alterations in Soft Tissue Perineuriomas. | Carter JM et al |
| 11 | 16096405 | 2005 | Cytogenetic aberrations in perineurioma: variation with subtype. | Brock JE et al |
| 12 | 2801965 | 1989 | Ammoniagenesis in cultured human renal cortical epithelial cells. | Cooper AJ et al |
| 13 | 32859628 | 2020 | Recurrent Fusion of the GRB2 Associated Binding Protein 1 (GAB1) Gene With ABL Proto-oncogene 1 (ABL1) in Benign Pediatric Soft Tissue Tumors. | Panagopoulos I et al |
| 14 | 2859628 | 1985 | Tardive Tourette's syndrome treated with clonidine and mesoridazine. | Munetz MR et al |
| 15 | 30166553 | 2018 | Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors. | Pareja F et al |
| 16 | 30597645 | 2019 | Frequent mutations of genes encoding vacuolar H(+) -ATPase components in granular cell tumors. | Sekimizu M et al |
| 17 | 17222254 | 2007 | Chromosomal imbalances and NF2 mutational analysis in a series of 10 spinal nerve sheath myxomas. | Rickert CH et al |
| 18 | 21297585 | 2011 | Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis. | Sheth S et al |
| 19 | 30168738 | 2019 | Recurrent desmoid-type fibromatosis associated with underlying neuromuscular choristoma. | Stone JJ et al |
| 20 | 33442732 | 2021 | Frequent CTNNB1 p.S45 Mutations and Aggressive Clinical Behavior in Neuromuscular Choristoma-Associated Fibromatosis. | Carter JM et al |
| 21 | 34718655 | 2021 | Neuromuscular Choristoma: Report of Five Cases With CTNNB1 Sequencing. | Brandao ICS et al |
| 22 | 27765635 | 2016 | Molecular Analysis of Hybrid Neurofibroma/Schwannoma Identifies Common Monosomy 22 and α-T-Catenin/CTNNA3 as a Novel Candidate Tumor Suppressor. | Stahn V et al |
| 23 | 32017710 | 2020 | Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors. | Ronellenfitsch MW et al |
| 24 | 26740486 | 2016 | The Challenge of Cancer Genomics in Rare Nervous System Neoplasms: Malignant Peripheral Nerve Sheath Tumors as a Paradigm for Cross-Species Comparative Oncogenomics. | Carroll SL et al |
| 25 | 31023785 | 2019 | Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside. | Korfhage J et al |
| 26 | 32642732 | 2020 | Genetics of human malignant peripheral nerve sheath tumors. | Pemov A et al |
| 27 | 34059954 | 2021 | Chromosomal translocations inactivating CDKN2A support a single path for malignant peripheral nerve sheath tumor initiation. | Magallón-Lorenz M et al |
| 28 | 33591953 | 2021 | Chromosome 8 gain is associated with high-grade transformation in MPNST. | Dehner C et al |
| 29 | 30864974 | 2019 | Recurrent SMARCB1 Inactivation in Epithelioid Malignant Peripheral Nerve Sheath Tumors. | Schaefer IM et al |
| 30 | 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 |
Citation
Paola Dal Cin, PhD
Peripheral nerve sheath tumors
Atlas Genet Cytogenet Oncol Haematol. 2023-02-14
Online version: http://atlasgeneticsoncology.org/solid-tumor/209006/peripheral-nerve-sheath-tumors
