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.
| Neurofibromatosis type 1 1 | Neurofibromatosis type 2 2 | Schwannomatosis 3 |
|---|---|---|
Presence of ≥2 of the following:
| Any 1 of the following:
| Definite Age >30 years and ALL of the following:
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:
Age >45 years and ALL of the following:
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.
Schwannomatosis
SWN is the least common nerve sheath tumor predisposition syndrome, with an estimated incidence of 1:40,000 to 1:100,000. It is also autosomal dominant in inheritance but the median age of symptom onset is 30 years and diagnosis is often delayed by up to 10 years. To date, two genes— SMARCB1 and LZTR1 —have been linked to SWN, although these do not account for all cases and there is ongoing research to identify other associated genes. SMARCB1 mutations are found in approximately 40–50% of familial and 10% of sporadic cases, and LZTR1 mutations have been reported in 38% of familial and 22% of sporadic cases. There is substantial phenotypic overlap between NF2 and SWN and, unless a SMARCB1 or LZTR1 mutation is identified, the diagnosis of SWN is typically made after NF2 has been excluded ( Table 9.1 ). As opposed to NF2, SWN is characterized by multiple non-vestibular and non-intradermal schwannomas (although a small proportion of LZTR1-mutant schwannomatosis patients have been reported to have unilateral vestibular schwannomas). Meningiomas are found in approximately 5% of SWN patients, compared to about 50% of NF2 patients. Schwannomas most commonly involve the spinal (74%) and peripheral nerves (89%); cranial nerve schwannomas (8%) and meningiomas (5%) are rare. Patients with SWN may also develop subcutaneous schwannomas. , Malignant transformation of schwannomas has been reported but is exceedingly rare.
Clinical cases
Case . A 27-year-old otherwise healthy woman presented for evaluation of a left neck mass that she discovered when palpating her neck. She did not have any associated pain or neurologic symptoms. Her clinical examination was unremarkable except for the presence of one café-au-lait macule. An MRI of the neck demonstrated a mass involving the left brachial plexus ( Fig. 9.1 ). An initial needle biopsy was non-diagnostic. Subsequent surgical resection revealed a neurofibroma. MRIs of the brain and spine did not show any additional nerve sheath tumors. Genetic testing of blood and tumor tissue was negative for mutations in the NF1, NF2, SMARCB1, or LZTR1 genes. Taken together, this case is consistent with a diagnosis of sporadic neurofibroma.
Teaching Points: Evaluation and Management of Sporadic Solitary Neurofibroma. Up to 90% of neurofibromas are sporadic (i.e., not associated with NF1). Most patients present in their third to fourth decade. Histologically, neurofibromas are composed of Schwann cells, perineural-like cells, fibroblasts, and inflammatory cells such as mast cells and lymphocytes. Morphologically, they can be classified into localized (as seen in this case), diffuse, and plexiform types ( Table 9.2 ). Nearly all plexiform neurofibromas occur in NF1 patients, although rare cases of solitary plexiform neurofibromas in patients without NF1 have been reported. Plexiform neurofibromas also have the potential for transformation into malignant peripheral nerve sheath tumors (MPNSTs). The vast majority of neurofibromas are benign, but a small proportion can display atypical histologic features, including nuclear atypia, loss of neurofibroma architecture, and increased mitotic activity. These tumors, known as “atypical neurofibromatous neoplasm of uncertain biologic potential,” may carry an increased risk of malignant transformation.
| Localized (intraneural) | Diffuse | Plexiform |
|---|---|---|
|
|
|
Imaging characteristics . MRI is the gold standard for imaging of peripheral nerve sheath tumors. On MRI, benign neurofibromas are typically clearly demarcated, un-encapsulated, fusiform or round lesions. , They are hypo- to isointense (to muscle) on T1-weighted and hyperintense on T2-weighted sequences. Enhancement is variable and can demonstrate a heterogeneous or homogeneous pattern ( Fig. 9.1 ). Short tau inversion recovery (STIR) sequences are particularly helpful to visualize peripheral nerve sheath tumors and display a hyperintense mass ( Fig. 9.1D ). A characteristic “target sign,” defined as a hyperintense rim with a central hypointense region on T2-weighted sequences ( Fig. 9.2 ), is seen with some benign neurofibromas. Histologically, the hyperintense region reflects myxoid tissue with high water content, whereas the hypointense region in the center contains dense collagenous and fibrous tissue. , Notably, the target sign is not specific to neurofibromas, as it may also be seen with schwannomas. In addition, a “split-fat” sign may be seen on T1-weighted images, which reflects a rim of fat surrounding an intramuscular tumor at the proximal and distal ends. ,
Recommendations for patient management . Evaluation of a patient with an apparently isolated neurofibroma should include a detailed history and neurologic and skin examination, with particular attention to any neurologic dysfunction (e.g., focal weakness or paresthesias) and cutaneous stigmata of NF1 (e.g., café-au-lait macules, skinfold freckling, or cutaneous neurofibromas). Patients should undergo a slit-lamp examination for evaluation of Lisch nodules and MRI of the brain and spine to assess for additional neurofibromas, since the presence of these features supports an underlying NF1 diagnosis. Surgical referral should be considered if the neurofibroma is causing neurologic or functional compromise or if imaging is concerning for a malignant lesion. In the absence of these features, clinical and radiographic monitoring is a reasonable strategy.
Clinical Pearls
- 1.
The vast majority of neurofibromas are sporadic and not associated with NF1.
- 2.
Characteristic MRI features include heterogeneous enhancement on T1-weighted post-contrast and hyperintensity on T2-weighted and STIR sequences. A target and/or split-fat sign may be seen.
- 3.
The main differential diagnosis for a neurofibroma is schwannoma, and these two entities may be difficult to distinguish based on MRI alone.
Case. A 29-year-old woman with NF1 presented to clinic for evaluation, reporting left leg weakness without pain or a growing, palpable tumor. A lumbar spine MRI revealed enhancing, T2- and STIR-hyperintense lesions of the ganglionic and post-ganglionic nerve roots at all lumbar and sacral levels, suggestive of plexiform neurofibromas. The patient also underwent a whole-body MRI ( Fig. 9.3 ), which demonstrated extensive neurofibroma bur den involving the spinal, intercostal, and sciatic nerves. She has been monitored clinically and radiographically since, without any changes in her symptoms or tumor appearance.
Teaching Points: Diagnosis and Management of Plexiform Neurofibromas in Patients With NF1. Plexiform neurofibromas (pNFs) are histologically benign tumors of the peripheral nerve sheath that involve multiple nerve fascicles or components of a nerve plexus. They are thought to be congenital lesions and can be superficial or deep. Superficial pNFs diffusely involve the cutaneous tissues and may be associated with skin overgrowth and hyperpigmentation. Deep pNFs are located internally and frequently asymptomatic. They can only be detected with imaging and affect 40–50% of NF1 patients. , , Some deep pNFs can grow together as multiple masses, giving them the appearance of a rope or “bag of worms” ( Fig. 9.3 ). pNFs tend to grow slowly if at all over a patient’s lifetime but appear to grow most rapidly during childhood and adolescence. , Despite their benign histology, they can cause significant disfigurement and morbidity due to pain, compression of adjacent anatomical structures, and loss of function of nerves, vessels, and airways. pNFs can transform into MPNSTs, which are associated with high mortality.
Imaging characteristics . Like solitary neurofibromas, pNFs are hypointense on T1-weighted and hyperintense on T2-weighted and STIR sequences. Enhancement is common and a target sign may be seen. Whole-body MRI is used at some centers to assess a patient’s baseline internal tumor burden and may gain increasing importance as a tool to monitor tumor response and progression with the emergence of effective therapeutic agents.
Clinical Pearls
- 1.
Plexiform neurofibromas (pNFs) affect 40–50 of patients with NF1.
- 2.
Although histologically benign and typically slow growing, pNFs can cause significant morbidity due to local mass effect and infiltration of vital anatomical structures. A small proportion of pNFs can transform into malignant peripheral nerve sheath tumors.
- 3.
A regional MRI with contrast-enhanced and STIR sequences of the affected region should be obtained. Whole-body MRI may be useful to assess a patient’s baseline tumor burden.
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