Evaluation of peripheral nerve lesions

Disclosures

Dr. Ly has no disclosures.

Dr. Jordan has research funding from the Department of Defense, the National Institutes of Health, and the Burke Foundation. He receives royalties from Elsevier and has received honoraria from the American Academy of Neurology. He performs paid consultation for CereXis Pharmaceuticals, Navio Theragnostics, Health2047 Inc., and the Neurofibromatosis Network.

Introduction

Peripheral nerve lesions encompass a broad differential diagnosis and may be manifestations of an underlying autoimmune, infectious, benign, or malignant neoplastic process. Benign neoplasms include neurofibromas or schwannomas, which frequently arise sporadically but may also occur in the context of tumor predisposition syndromes such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN). These diseases are autosomal dominant genetic syndromes that, among other manifestations, predispose to benign and malignant tumors of the central and peripheral nervous system (also see Chapter 16 for further discussion of approach to NF1, NF2, and SWN). Malignant peripheral nerve sheath tumor is the most common primary malignancy associated with the nerve sheaths and often arises in preexisting plexiform neurofibromas. Other malignant etiologies include direct extension or metastatic disease from various cancers such as lymphoma and leukemia.

In this chapter, we discuss typical presentations of peripheral nerve sheath tumors that arise sporadically and in the context of genetic syndromes. We first provide an overview of NF1, NF2, and SWN, followed by case presentations and a discussion of characteristic imaging features that can be used to guide the evaluation of patients presenting with peripheral nerve sheath lesions.

Neurofibromatosis type 1

NF1 is the most common nerve sheath tumor predisposition syndrome, with an estimated birth incidence of 1:2600 to 1:3000. ^, It is caused by a germline mutation in the NF1 gene on chromosome 17q11.2. ^, The hallmark tumor type in NF1 are neurofibromas. In addition, NF1 is characterized by numerous cutaneous manifestations, such as hyperpigmented patches known as café-au-lait macules, abnormal freckling in the axillary, inguinal, and inframammary regions, and cutaneous neurofibromas. Other distinct features include certain ophthalmologic and skeletal abnormalities. In addition to nerve sheath tumors, NF1 patients carry a higher risk for other tumor types, including gliomas, pheochromocytomas, gastrointestinal stromal tumors (GISTs), and breast cancer. The diagnosis of NF1 is based on the National Institutes of Health clinical criteria ^, ( Table 9.1 ), which are highly sensitive and specific in the majority of patients.

Table 9.1

Clinical diagnostic criteria for neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis ^a

Neurofibromatosis type 1 ¹	Neurofibromatosis type 2 ²	Schwannomatosis ³
Presence of ≥2 of the following: 1. ≥6 café-au-lait macules >5 mm in diameter in prepubertal individuals and >15 mm in postpubertal individuals 2. ≥2 neurofibromas of any type or 1 plexiform neurofibroma 3. Freckling in the axillary or inguinal regions 4. ≥2 Lisch nodules 5. Optic glioma 6. A distinctive osseous lesion such as sphenoid wing dysplasia or thinning of long bone cortex, with or without pseudarthrosis 7. First-degree relative (parents, sibling, or offspring) with NF1 based on above criteria	Any 1 of the following: 1. Bilateral vestibular schwannomas (VS) before age 70 ⁴ 2. Unilateral VS before age 70 AND first-degree relative with NF2 3 Any 2 of the following: meningioma, non-vestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract AND First-degree relative with NF2 OR Unilateral VS AND negative LZTR1 testing ^b 4 Multiple meningiomas AND Unilateral VS OR Any 2 of the following: non-vestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract 5. Constitutional or mosaic pathogenic NF2 mutation from blood or by identification of an identical mutation from 2 separate tumors in the same individual	Definite Age >30 years and ALL of the following: ≥2 non-intradermal schwannomas (at least one with histologic confirmation) Diagnostic criteria for NF2 not fulfilled No evidence of vestibular tumor on high-quality MRI scan No first-degree relative with NF2 No known constitutional NF2 mutation OR Age >30 years AND one pathologically confirmed non-vestibular schwannoma AND a first-degree relative who meets above criteria Possible Age <30 years and ALL the following: ≥2 non-intradermal schwannomas (at least one with histologic confirmation) Diagnostic criteria for NF2 not fulfilled No evidence of vestibular tumor on high-quality MRI scan No first-degree relative with NF2 No known constitutional NF2 mutation OR Age >45 years and ALL of the following: ≥2 non-intradermal schwannomas (at least one with histologic confirmation) No symptoms of 8th cranial nerve dysfunction No first-degree relative with NF2 No known constitutional NF2 mutation OR Radiographic evidence of a non-vestibular schwannoma AND first-degree relative meeting criteria for definite schwannomatosis

Neurofibromatosis type 1 ¹

Neurofibromatosis type 2 ²

Schwannomatosis ³

Presence of ≥2 of the following:

1.
≥6 café-au-lait macules >5 mm in diameter in prepubertal individuals and >15 mm in postpubertal individuals
2.
≥2 neurofibromas of any type or 1 plexiform neurofibroma
3.
Freckling in the axillary or inguinal regions
4.
≥2 Lisch nodules
5.
Optic glioma
6.
A distinctive osseous lesion such as sphenoid wing dysplasia or thinning of long bone cortex, with or without pseudarthrosis
7.
First-degree relative (parents, sibling, or offspring) with NF1 based on above criteria

Any 1 of the following:

1.
Bilateral vestibular schwannomas (VS) before age 70 ⁴
2.
Unilateral VS before age 70 AND first-degree relative with NF2
3
Any 2 of the following: meningioma, non-vestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract AND
First-degree relative with NF2 OR
Unilateral VS AND negative LZTR1 testing ^b
4
Multiple meningiomas AND
Unilateral VS OR
Any 2 of the following: non-vestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract
5.
Constitutional or mosaic pathogenic NF2 mutation from blood or by identification of an identical mutation from 2 separate tumors in the same individual

Definite
Age >30 years and ALL of the following:

≥2 non-intradermal schwannomas (at least one with histologic confirmation)
Diagnostic criteria for NF2 not fulfilled
No evidence of vestibular tumor on high-quality MRI scan
No first-degree relative with NF2
No known constitutional NF2 mutation

OR
Age >30 years AND one pathologically confirmed non-vestibular schwannoma AND a first-degree relative who meets above criteria
Possible
Age <30 years and ALL the following:

≥2 non-intradermal schwannomas (at least one with histologic confirmation)
Diagnostic criteria for NF2 not fulfilled
No evidence of vestibular tumor on high-quality MRI scan
No first-degree relative with NF2
No known constitutional NF2 mutation

OR
Age >45 years and ALL of the following:

≥2 non-intradermal schwannomas (at least one with histologic confirmation)
No symptoms of 8th cranial nerve dysfunction
No first-degree relative with NF2
No known constitutional NF2 mutation

OR
Radiographic evidence of a non-vestibular schwannoma AND first-degree relative meeting criteria for definite schwannomatosis

a See also Chapter 16 for clinical review of neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

b If qualifying tumors include ≥2 non-intradermal schwannomas.

1 From Gutmann DH, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA . 1997, 278:51–57; National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, MD, July 13–15, 1987. Neurofibromatosis . 1988;1(3):172–178.

2 From National Institutes of Health Consensus Development Conference (1988). Neurofibromatosis. Consensus Statement . Arch Neurol . 1988;45(5): 575–578; Evans DG, et al. A clinical study of type 2 neurofibromatosis. Q J Med . 1992;84:603–618; Gutmann DH, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA . 1997, 278:51–57; Smith MJ, Bowers NL, Bulman M, et al. Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology . 2017;88(1):87–92.

3 From MacCollin M, Chiocca EA, Evans DG, et al. Diagnostic criteria for schwannomatosis. Neurology . 2005;64(11):1838–1845; Baser ME, Friedman JM, Evans DG. Increasing the specificity of diagnostic criteria for schwannomatosis. Neurology . 2006;66(5):730–732; Plotkin SR, Blakeley JO, Evans DG, et al. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am J Med Genet A . 2013;161A(3):405–416.

4 Some clinicians will use an age cutoff of 30 years as bilateral vestibular schwannomas will be present by the age of 30 years in the vast majority of people with NF2 (See Chapter 16 ).

Neurofibromatosis type 2

NF2 is an autosomal dominant tumor predisposition syndrome caused by a germline loss-of-function mutation of the NF2 gene on chromosome 22q11.2. The estimated incidence is 1:25,000 to 1:33,000. ^, More than 95% of patients with NF2 have bilateral vestibular schwannomas. These frequently cause bilateral sensorineural hearing loss, tinnitus, and imbalance, and may progress to deafness, brainstem compression, and other cranial nerve deficits. Other tumors frequently seen in NF2 include meningiomas, spinal ependymomas, and schwannomas of the non-vestibular cranial, spinal, and peripheral nerves ( Table 9.1 ). Unlike plexiform neurofibromas in NF1, NF2-associated schwannomas rarely undergo malignant transformation, although it has been reported after radiation.

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