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PERIPHERAL NERVE TUMORS

TUMOR-LIKE DISORDERS

• Symptoms
  • Pain between 3rd & 4th metatarsals
  • Numbness of 2 adjacent toes
• Pathology: Fibrosis of plantar digital nerve

• Symptoms: Tender to pressure
• Pathology: Disorganized growth of small fascicles of peripheral nerve from proximal stump

• Anatomy: Most common in peroneal nerve
• Pathology: Mucin filled cyst in perineurium

• Pathology: Mosaic tumor with striated muscle mixed within nerve fascicles

• Nodular thickening of lips, tongue, eyelids
• Associated with Multiple endocrine neoplasia, Type 2b

• Anatomy
  • Face
  • Solitary
  • Dome-shaped
• Onset: Middle age
• Benign
• Pathology: Composed of Schwann cells, perineural cells & small axons

• Anatomy
  • Face; Neck; Shoulder
  • Dome-shaped
• Onset: Young females
• Benign
• Pathology subtypes
  • Myxomatous: Schwann cell origin
  • Cellular

• Origin: Joint or tendon sheaths
• Anatomy
  • Locations: Around wrist, knee, elbow & hip joints
  • May produce extraneural compression
  • Rarely intraneural
• Benign
• Treatment
  • Removal of cyst from nerve and joint capsule
  • May recur

• Origin: Adipocytes & Fibro-fatty tissues
• Anatomy
  • Locations: Median nerve
    • Present with carpal tunnel syndrome & macrodactyly
  • May infiltrate adjacent nerves
• Benign
• MRI: May be diagnostic
• Treatment: Dependent on whether the lipoma is intrinsic or extrinsic to nerve
  • Intrinsic: Biopsy or Release entrapment; Avoid nerve damage

PERIPHERAL NERVE TUMORS

• Schwannoma
• Neurofibroma
  • Solitary
  • Multiple: Neurofibromatosis
• N/S HNST
• Fatty: Nerve swelling without damage
  • Lipofibromatous hamartoma
  • Macrodystrophica lipomatosa
• Hemangioma
• Malignant
  • Malignant Triton tumor
  • Glandular malignant Schwannoma
  • Malignant epithelioid Schwannoma
• Perineurioma
• Also see: Plexopathy & Neoplasm
  • Brachial
  • Lumbosacral

Perineurioma: Intraneural 6 Nosology Localized hypertrophic (mono)neuropathy Interstitial hypertrophic neuropathy Pseudo-onion bulb (mono)neuropathy Hypertrophic neurofibroma Intraneural neurofibroma Clinical Onset age: Median 14 years; Range 0.5 to 64 years Females slightly more than Males Weakness Frequency: > 80% to 94% Causes most disability Distribution Usual: Single Nerve or brachial plexus Rare (3%): Bilateral Sensory: Mild Loss: 65% "Numbness" Pain: Mild; 30% Involvement less common than motor Tendon reflexes: Reduced in distribution of affected nerve Course Weakness: Slow progression (Years) or Static Benign: Does not recur or metastasize Enlarge in width, not length Skeletal: Limb length undergrowth (25%) Tumor Locations Nerves Arms & Legs: Similar frequency Most common: Sciatic or branches (8% to 42%) Common in arms: Ulnar (17%); Median (12%); Radial (10%);   Posterior interosseus (9%); Brachial plexus (10%) Legs: Common peroneal (9%); Femoral (6%); Posterior tibial Cranial: Facial; Tongue Other: Oral cavity; Skin; Mandible Anatomy Intraneural: Fusiform swelling Usually single lesions: Occasionally bilateral Mean maximal width: 10 mm Mean maximal length: 100 mm Laboratory MRI Nerve enlargement: Segmental "Fusiform" T2: High intensity T1: Low intensity Gadolinium enhancement: Strong; Homogeneous Other imaging studies: Sonography CSF: Normal protein Genetics Somatic mutations Chromosome 22q11: Homozygous deficiency TRAF7 mutations Location: WD40 domain Frequency: 60% Also occur in: Intracranial meningiomas Possible association with NF2 10 Perineurioma DNA: Macrodeletions of NF1 & NF2 genes NF2: Possible increased perineurioma frequency Pathology Nerve: Perineurioma Gross structure Fusiform: Segmental enlargement of affected nerve Length: 2.5 to 32 cm Cell origin Perineurial cells Peripheral nerve: Post-ganglionic; Extra-dural Cranial nerve: Extra-dural Tissue Whorls: Pseudo-onion bulbs Multiple layers Proliferation Cell morphologic features Perineurial-like Cytoplasmic processes: Thin & Elongated Basal lamina: Incomplete Tight junctions: Poorly formed Pinocytotic vesicles Well differentiated: Mitoses rare Perineuriomna cell staining Positive Epithelial membrane antigen (EMA) Vimentin Glucose transporter protein-1 (Glut1) Claudin-1 Collagen IV PGP 9.5 Negative S-100 Leu-7 Neurofilaments Muscle: Chronic denervation Fiber type grouping Differential diagnosis Variant: Occurs in soft tissue May mimic: Schwannomas Perineurioma: Other locations Soft tissue Onset: Middle-aged Nodular mass lesions Locations: Superficial soft tissues, extremities, trunk or viscera Sclerosing Age: Young patients Small painless subcutaneous masses Locations: Palms & fingers Local Hypertrophic Neuropathy: Perineurioma Variant Perineurial & Schwann cells 1 Clinical Onset age: Mean 26 years; Range 9 to 73 years Localized progressive weakness (90%) Sensory loss (40%) Location: Upper extremity 57%; Lower extremity 36% Progression: Slow; Average 5 years to diagnosis MRI (Fat suppression & gadolinium): Mass Pathology Whorls of perineurial cells ± Schwann cells Cells Stain for epithelial membrane antigen Have incomplete basal lamina

Perineurioma: MRI, T2 (Sciatic nerve enlarged, Arrow) From: C Zaidman; C Garcia Perineurioma: Ultrasound (Sciatic nerve enlarged, Arrow) From: C Zaidman; C Garcia Sciatic nerve: Ultrasound (Opposite side, Normal) From: C Zaidman; C Garcia Perineurioma

• Clinical
  • Progressive weakness: Course of individual nerve
  • Nerves: Sciatic; Brachial plexus
  • MRI: Intrinsic abnormalities of involved nerves
• Pathology: Endoneurial proliferation ²
  • Disruption of fascicular anatomy
  • Endoneurial fibrosis
  • No involvement of perineurium or Schwann cells

• General
  • Etiology: May be peripheral nerve neoplasms
  • Distribution: Local or Regional
  • Course: Slow progression
• Clinical
  • Weakness
  • Sensory: Loss; Pain
  • Regions
    • Lower extremity: Sciatic
    • Upper extremity: Brachial plexus; Cervical radiculopathy
• MRI
  • T1: Low intensity
  • STIR & T2: Hyperintense
  • No enhancement
• Nerve Pathology
  • Onion bulb-like formations: Pseudo-onion bulbs
  • Endoneurial space: Increased
  • Somatic mutations
    • ERBB2
    • KRAS

• Associated disorders
  • Noonan's syndrome
  • CMT1A ³

Schwannoma Epidemiology Most common peripheral nerve tumors in adults Incidence 8% of intracranial tumors 29% of primary spinal tumors Sex Overall: Male = Female Intracranial lesions: Female predominance (2:1) Genetics Family history Usually sporadic Multiple (Schwannomatosis 1 (SWNTS1)) in NF2 NF2 mutations or 22q deletion: 77% SMARCB1 Heterozygous: Susceptibility Germline or Somntic mutations Tumors: May show loss of wild type allele Also associated with: Meningiomas Clinical: Multiple or single tumors Other related genes LZTR1 , ARID1A , ARID1B , CABIN1 , DDR1 , COQ6 , TAB3 , ALPK2 , CAST , TSC1 , TSC2 Associated disorders Neurofibromatosis 1 Neurofibromatosis 2 : Especially vestibular Schwannomas Chromosome 22q deletions: Distinct from NF2 mutations Radiation: Increased frequency Clinical Onset age: Peak 30 to 50 years; All ages affected Location Solitary Arise eccentrically from within nerve Often at origins of spinal or cranial nerves Fascicles stretched over surface of tumor Cranial nerves VIII: Vestibular division Vagus (Recurrent laryngeal) Peripheral nerves Roots Most at dorsal Cauda equina: Intradural Flexor surfaces of limbs: Near joints Main nerve trunks: Peroneal; Ulnar; Sural Brachial > Lumbar plexus Sensory > Motor nerves Digital or Cutaneous nerve: Dull pain or Tenderness Symptoms Most: Asymptomatic & incidentally diagnosed Painful swelling Shooting pain & paresthesias induced by nerve palpation Spontaneous pain: Unusual; Some radicular pain Sensory loss & Weakness Unusual: Unless tumor located in confined space (Carpal tunnel) Specific tumor locations Spinal Weakness Bladder dysfunction Cranial nerve regions Hearing loss Facial weakness Deep tumors (e.g. mediastinal) May grow large before symptoms & detection Course Slow growing Usually benign Malignant transformation Not in typical tumors Small risk in atypical tumors Symptomatic regrowth: Rare Treatment Resection: Preserve nerve function & continuity May be monitored if asymptomatic MRI T2 hyperintense T1 isointense, intermediate signal Gadolinium enhancement: Most sensitive; Homogeneous Eccentric position to nerve Cystic degeneration: Common Ultrasound: Cystic lesions with sharp borders Pathology Cell component: Differentiated Schwann cells Tumor anatomy Well-circumscribed Surface: Smooth Shape: Elliptical or spherical Extra-fasicular growth Nerves of origin apparent Fascicles displaced around tumor capsule Location: Beyond oligodendoglial-Schwann cell junction Flexor surfaces May involve any nerve Tissue components Antoni, Type A: Highly cellular, closely packed; Verocay body Antoni, Type B: Loose, myxoid Degenerative changes Cysts; Calcification; Hemorrhage; Hyalinization Especially in large, deep tumors No intratumoral axons Immunoreactivity S-100 protein (100%) > Leu-7 SOX10 Epithelial membrane antigen Schwannoma: Atypical types Ancient Pathology: Cysts; Stromal edema, Xanthomatous changes; Fibrosis Course: Benign Psammomatous melanotic Pathology: Melanin; Lamellated calcospherules May occur sporadically or with Carney syndrome Location: Nerve roots Benign Associated with cardiac myxomas Cellular Histology: Predominantly Antoni, Type A; May mimic malignant lesion Location: Paravertebral region of retroperitoneum, pelvis, mediastinum Hyperchromasia; Frequent mitoses Benign Epithelioid Clinical Location: Extremities & Trunk (85%); Visceral (15%) Metastasis: Rare Histology Epithelioid cells in cords or nests Occasional features of degeneration (Nuclear atypia) Somatic tumors Dermis/subcutis Encapsulated (Epithelial membrane antigen+ perineurial capsule) Visceral tumors: Unencapsulated Loss of SMARCB1/INI1 expression: 42% Molecular: S-100 & SOX10 positive in 100% Neuroblastoma-like Histology: Giant rosettes; May simulate neuroblastoma Plexiform Conglomerate of multiple schwannomas: Occur in large nerves or plexus May occur sporadically, with NF2 or with Schwannomatosis Benign Location: Subcutaneous tissue Young adults

From: C Zaidman; C Garcia Schwannoma: Ultrasound image From: C Zaidman; C Garcia Schwannoma: MRI T1 image From: C Zaidman; C Garcia Schwannoma: MRI T2 image

Neurofibromas Genetics Driven by: NF1 loss in Schwann cells Number & Shape Solitary in 60% to 90% Neurofibromatosis: More often Multiple tumors Plexiform: Distal branches Intraneural: Often have somatic NF1 related mutations Clinical Onset Age: Usual 20 to 30 years; Range All More often symptomatic than Schwannomas Painful Swelling: Palpation does not induce shooting pain Radicular Weakness & Sensory symptoms: With non-cutaneous nerves Locations Most common: Subcutaneous or Dermal Some in nerve trunks: More often proximal Prognosis: Malignant transformation in few Solitary tumors: Rare Neurofibromatosis: 4% MRI T2: Hyperintense periphery; Decreased central intensity (Target sign) T1: Isointense with muscle; "Split fat sign" rim Enhancement: Often Larger than Schwannomas Relation to nerve: Infiltrative Pathology Cell of origin: Schwann cell Tumor anatomy Gross: Non-encapsulated; Often plexiform Intrafascicular growth: Central position in nerve Shape: Fusiform or multinodular Location Solitary: Cutaneous nerves Multiple: Non-cutaneous nerves often involved Histology Background Disordered & Loose Mucoid substance Collagenous fibrils Cell anatomy Shape: Elongated & Wavy Interlacing Hyperchromatic Nuclei: Spindle-shaped Cell types within tumor Schwann cells Perineurial cells Fibroblasts Lymphocytes Mast cells Macrophages Myelinated & unmyelinated axons within tumor Immunoreactivity of tumor cells S-100: Positive but Variable; Less than Schwannoma Not Epithelial membrane antigen (EMA) Compared to Schwannomas Fewer Schwann cells More collagen & reticulin Subtypes Dermal: No malignant transformation Subcutaneous: No malignant transformation Plexiform May cause symptoms by pressure on adjacent structures Malignant transformation (10%) To Malignant peripheral nerve sheath tumor

From: C Zaidman; C Garcia Neurofibroma: Ultrasound

Neurofibroma/Schwannoma Hybrid Nerve Sheath Tumors (N/S HNSTs) ¹¹

• Tissue features
  • Neurofibroma-like tumor: Contains Schwannoma-like nodules
  • Somatic mutations: ERBB2 (Asp769Tyr; Val777Leu)
    • Association: N/S HNST not related to NF2
• Associations: Tumor predisposition syndromes (60%)
  • NF2 26%
  • Schwanomatosis 17%
  • NF1 9%
• Clinical
  • Weakness
  • Sensory loss
  • Pain
  • Course: Slow progression
  • May present as: Local Hypertrophic Neuropathy
• Nerve pathology

Neurofibromatosis-1

• Genetics
  • New mutations
    • NF-1 gene mutation rate higher than most human genes: 1/10,000
    • 35% to 50% of NF-1 cases
    • Small deletions often from paternal gene
    • Large mutations from maternal gene
  • Specific mutations
    • General: > 3,000 different mutations identified
      • Most are small & truncating
      • Common types: Point; Splice; Small deletion, insertion or duplication
    • Microdeletions
      • Frequency: 5%–10% of individuals with NF1
      • Deletions of entire gene: Common⁵
        • Deletion features
          • Most common size
            • Includes: NF1 gene with 3 embedded genes
            • Often also includes 15 genes/transcripts
            • Common centromeric breakpoint
          • Smaller or larger deletions also described
        • Clinical: More severe phenotype than general NF-1 population
          • More neurofibromas at younger age
          • Lower mean IQ
          • Non-familial facial features
          • Higher risk of malignant peripheral nerve sheath tumors: Lifetime risk 16% to 26%
          • Dysmorphism: Craniofacial; Large hands & feet
          • Mental retardation (36%)
          • ? Many neurofibromas at an early age
    • Germline mutations: 80% predict severe neurofibromin truncation
  • Disease mechanisms
    • Haploid insufficiency of neurofibromin
    • Additional random events in individual patients
      • Acquired "second hit" mutations: Loss of heterozygosity at NF1 locus in some neurofibromas
      • Produce variable clinical manifestations
    • Allelic heterogeneity
  • Neural crest tumors without neurofibromatosis: May have acquired somatic inactivation of NF1 genes
• Protein: Neurofibromin
  • Molecular weight: 200-250 kDa
  • Subcellular location: Cytoplasmic
  • Cell location
    • Present in neurons, oligodendrocytes, astrocytes & nonmyelinating Schwann cells
    • Absent in astrocytoma cells
  • Function: Stimulates GTPase activity of RAS
  • Tumor-suppressor function: ? Multifactorial
    • RAS GTPase activation with neurofibromin loss
    • Other systems: ? EGF receptor, p53
  • NF1 GAP-related domain (GRD): Interacts with p21^ras mediated mitogenic signaling pathway
  • Neurofibromin knockout: Lethal due to cardiac abnormality
• Clinical
  • General
    • Prevalence
      • 1 in 3,000
      • New mutations cause 50%
    • Penetrance: Complete with variable clinical manifestations
    • Marked variation in clinical features among individuals
    • Greater & more serious manifestations with increasing age
    • Life expectancy: Reduced by ~15 years
  • Skin
    • Tumors: Neurofibromas; Plexiform neuroma
    • Pigmentation: Café-au-lait spots; Axillary & Inguinal freckling
      • Present in 99% of NF-1
      • Not specific for NF-1
      • May be present at birth or appear during 1st 2 years
  • Ocular: Lisch nodules (Iris hamartomas); Glaucoma; Hypertelorism
    • Lisch nodules: 10% < 10 yrs; 50% by 29 yrs; 100% > 65 yrs
    • No posterior subcapsular lens opacities
  • Skeletal
    • Scoliosis
      • Location: Lower cervical or Upper thoracic
      • Rapidly-progressive (dysplastic) form: Onset between six and ten years of age
    • Sphenoid dysplasia: Pulsating expohthalmos (Non-pulsating rule-out optic glioma)
    • Bony cortical thinning: Congenital
    • Short stature
    • Macrocephaly
  • Limbs: Pseudoarthrosis ; Thinning of long bone cortex; Leg overgrowth
    • Pseudoarthrosis: Tibia & Radius; Congenital especially specific for NF-1
    • Height: Below average
    • Head circumference: Larger than average
    • Familial spinal neurofibromatosis
  • CNS
    • Intelligence: Most patients normal
    • Learning disabilities
      • Frequency: 50%
      • ? Caused by excessive Ras activity
      • Correlate with brain heterotopias
        • Reduced long-term potentiation due to increased GABA-mediated inhibition
    • Other: Mental retardation; Aqueductal stenosis & hydrocephalus; Megalencephaly
  • Motor ⁸
    • Weakness: Mild; 20% to 30% reduced strength; Proximal & Distal
    • Clumsiness
  • Systemic features
    • Endocrine
      • Precocious puberty: Especially with tumors of the optic chiasm
      • Other: Hypertension; Hypophosphatemic osteomalacia; Hypoglycemia
    • Vascular: Arterial occlusive disease; Renal artery stenosis; Hypertension; Pulmonic valvular stenosis
    • GU: Clitoral hypertrophy
    • Pulmonary: Papillary adenomas; Interstitial pulmonary fibrosis; Pulmonary hypertension
  • Genetic associations
    • Noonan syndrome (12%)
      • Genetic
        • Mutations of NF-1 found in several families
        • Other patients: PTPN11 mutations (NS1)
      • Clinical
        • Face: Ocular hypertelorism; Down-slanted palpebral fissures; Low-set ears; Webbed neck
        • Pulmonic stenosis
        • Giant Proximal Nerve Hypertrophy
        • Also see: Noncompaction of left ventricle
    • Watson syndrome
    • Genetics: Mutations of NF-1 found in several families
    • Clinical: Multiple café au lait spots; Pulmonic stenosis; Dull intelligence
    • Leopard
      • Genetics: Allelic with Noonan syndrome (PTPN11)
      • Clinical: Multiple lentigines; Ocular hypertelorism; Deafness; Congenital heart disease
  • Solid neoplasms
    • General
      • Most common cancer pre-disposition syndrome in humans
    • Neurofibroma
      • Location: May affect virtually any organ
      • Number of neurofibromas in adults with NF1: Varies from a few to thousands
        • Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life
        • Cutaneous & subcutaneous neurofibromas may develop at any time in life: Infrequent before puberty
        • Rate of appearance may vary greatly from year to year
        • Women may experience a rapid increase in number & size of neurofibromas during pregnancy
      • Multiple neurofibromas: May be large; May involve deep & major nerves
      • Plexiform neuromas: Deep nodular
        • General: Most are internal & asymptomatic; Usually not found on physical examination
        • Form solitary tortuous enlargements of nerves
        • Extend into surrounding tissue
        • Contain axons
      • Diffuse plexiform neurofibromas
        • Onset: Children & young adults; Face < 1 year
        • Subcutaneous plaque-like elevation of skin
    • Malignant peripheral nerve sheath tumor (neurofibrosarcomas)
      • Onset: Adolescents & Adults
      • Frequency: 8% to 13% lifetime risk
      • Clinical: Painful mass
      • NF1 microdeletion: Higher risk
    • Schwannoma
    • Intracranial tumors
      • Frequency: 5% to 10%
      • Schwannoma
      • Meningioma
      • Optic gliomas
        • Epidemiology
          • Onset age: Especially children; 1st 4 years
          • Frequency: 15% on MRI
          • Less common in Asians & African-Americans
        • Cause: 2nd spontaneous inactiviating somatic NF1 mutation
          • Cell type: Stem cells
          • Cell location: 3rd ventricle
          • Timing: Late embryonic development
          • Mutation locatioin: 5" end of NF1 gene
          • Common mutation p.1809: No neoplasms
          • NF1 locus deletion: Cancer & Mental disability
          • Normal (Non-mutated) cells in tumor (Microglia): Support neoplasm growth
        • Clinical
          • May cause visual loss
            • More common in females
            • Associated with loss of ganglion cells in retina
          • Course: Variable
            • 1/3 symptomatic
            • May be more aggressive with additional BRAF mutations
          • Some respond to chemotherapy: carbo-platin; Vincristine
    • Lisch nodules: Innocuous iris hamartomas
    • Other: Pheochromocytoma; Meningioma; Optic glioma; Acoustic neuroma;
      Hypothalamic; Neurofibrosarcoma; Rhabdomyosarcoma; Duodenal carcinoid
      Somatostatinoma; Parathyroid adenoma; Intraperitoneal mesodermal tumor
  • Hematologic malignancy
    • Juvenile chronic myelogenous leukemia
      • 200x to 500x normal risk
      • Onset: Childhood
      • More often inherited from mother
    • Myelodysplastic syndromes
• Diagnostic criteria for NF-1: 2 or more of
  • Café-au-lait spots: > 5mm in prepubescent children; > 15mm after puberty
  • Multiple axillary or inguinal freckles (2 to 3 mm)
  • 1 plexiform neuroma, or 2 neurofibromas of any type
  • Glioma: Optic nerve or chiasmatic
  • Lisch nodules: 2 or more by slit lamp
  • Long bone cortex: Thinning ± Pseudarthrosis
  • Sphenoid dysplasia
  • Family history: 1st degree relative with NF-1
• NF-1 variant: Segmental NF-1
  • Mosaic form of NF-1
  • Subtypes
    • Generalized form
      • Mosaicism occurs at cellular level
      • Milder manifestations of full NF1
    • Localized form
      • Disease features in one or several segments of the body
    • Gonadal form
      • Clinically asymptomatic parents
      • Transmission of full disease to offspring
• External links
  • Gene Clinics
  • Washington University NF clinic

Neurofibromatosis-2

• Prevalence: 1 in 1,000,000
• Genetics
  • Germline mutations in NF2 patients
  • Somatic mutations in NF2-related tumors
  • Most mutations cause synthesis of truncated schwannomin protein
  • Severe disease: Nonsense & Frameshift mutations
• Protein: Merlin
  • ? Membrane stabilizing
  • Location: Fetal brain; Kidney; Lung; Breast; Ovary
• Criteria
  • Definite
    • Bilateral vestibular schwannomas, or
    • Family history of NF2 in 1 or more first-degree relative(s), plus
      • Unilateral vestibular schwannomas at age less than 30 years, or
      • Any 2 of
        • Tumors: Meningioma, Glioma, Schwannoma
        • Juvenile: Posterior subcapsular lenticular opacities; Cortical cataract
  • Probable (1 of 2)
    • Unilateral vestibular schwannomas at age less than 30 years, plus 1 of
      • Tumors: Meningioma, Glioma, Schwannoma
      • Juvenile posterior subcapsular lenticular opacities/Juvenile cortical cataract
    • Multiple meningiomas, plus 1 of
      • Unilateral vestibular schwannomas at age less than 30 years
      • Other tumors: Glioma, Schwannoma,
      • Juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
• Clinical
  • Skin
    • < 6 cafe-au-lait spots
    • Circumscribed, raised, roughened, pigmented & hairy areas
    • Neurofibromas: Not plexiform
  • Peripheral nerves: Spherical subcutaneous tumors; Neuropathy
  • Ocular
    • Visual loss: Macular hamartoma
    • Lacrimal secretion: Reduced
    • Corneal hypesthesia
    • Posterior subcapsular lens opacities
    • No Lisch nodules
  • PNS
    • Peripheral neuropathy ⁴
      • Frequency
        • Clinical
        • Occasional
        • More common with more severe NF-2
        • Subclinical
          • Common
          • Onset: May begin in childhood
          • Dorsal root ganglia: Hypertrophy
      • Associated Schwannomas: Cranial nerve VIII; Spinal; Cutaneous (50%)
      • Clinical polyneuropathy: May be Mild or Severe
        • Cramps
        • Sensory loss
        • Paresthesias
        • Weakness (50%): Distal; Legs
        • Tendon reflexes: Reduced
        • Rare mononeuritis multiplex
        • Course: Increasing weakness with time
      • Electrophysiology
        • Axonal neuropathy more common
        • Some patients with demyelination
        • May detect subclinical neuropathy
      • Pathology
        • Multiple tumorlets originating along peripheral nerves
        • Perineurium: May be focally increased in thickness
        • Endoneurial edema
        • Axonal loss
        • Schwann cells
          • Arranged in interdigiating (tumor cell) complexes without associated axons
          • Increased numbers of S-100 positive Schwann cells
        • Endo- and perineurial vessels: Perivascular fibrous thickening
    • Focal amyotrophy: Quadriceps; Anterior tibial; Hand
  • CNS
    • Bilateral acoustic neuromas: Deafness
    • Schwannomas on Cranial nerve 5, 9, 10, 12
    • Cauda equina tumors
    • Astrocytoma
    • Not optic gliomas
    • Syringomyelia: Increased frequency

Neurofibromatosis 3A, Mixed Central & Peripheral

• Skin: Cafe-au-lait spots (Pale, Large); Freckling
• Cutaneous neurofibromas
• CNS Tumors
  • Bilateral acoustic neuromas
  • Meningiomas: Posterior fossa and upper cervical
  • Neurofibromas: Spinal/paraspinal
• Onset: 2nd or early 3rd decade
• Prognosis: Rapid & fatal course from multiple CNS tumors

Neurofibromatosis 4, Atypical

Malignant Peripheral Nerve Sheath Tumors (MPNST) Origin ? Schwann cells Solitary or plexiform neurofibromas, especially irradiated Frequency & Associations General population (0.001%) Females slightly > Males Neurofibromatosis Frequency in NF1: 2% to 5% More common with NF-1 gene microdeletions Up to 50% of MPNST MPNST may arise from previoly present neurofibroma Radiation 10% of MPNST MPNST may develop 10 to 20 years later Clinical Onset age: Adults; 3rd to 6th decade Swelling: Spontaneous pain; Firm; Immovable Motor & sensory loss Rapid change in size of neurofibroma Locations Sciatic nerve > Brachial & Sciatic plexus Medium & Large size nerves Neurofibroma related New pain, weakness or neurological deficit Course: Rapid progression of symptoms Treatment: Wide resection or Limb amputation Prognosis Highly malignant; Often metastatic Median survival 3 years; 5 year survival 34% to 64% Worse: Large tumor (> 5 cm); NF-1; Central location Tumor features Size: Often large, > 5 cm Margin: May be poorly defined Histology Necrosis Mitoses S-100 cells (50%) Triton tumors: Contents Rhabdomyosarcoma Cartilage Bone Not mucin-secreting glands Genetics: Mutations Polycomb repressive complex 2 (PRC2) components Somatic mutations: 70% to 92% of MPNST SUZ12 somatic mutations 7 Present in MPNST but not in neurofibromas EED EZH2 : Upregulated in MPNST PRC2 functions Histone methyltransferase complex Represses gene expression Tumor suppressor NF1 loss: Biallelic CDKN2A : Deletions Somatic mutations causing p53 deactivation

Malignant Peripheral Nerve Sheath Tumors Features of malignancy   Size: Large (> 5 cm)   Enhancement patterns: Inhomogenous     Central decreased enhancement     Focal regions of non enhancement   Margins: Ill defined   Invasion of fat planes   Perilesional edema From: C Zaidman; C Garcia MPNST: Ultrasound From: C Zaidman; C Garcia MPNST: MRI T1 From: C Zaidman; C Garcia MPNST: MRI Contrast From: C Zaidman; C Garcia MPNST: MRI Contrast From: C Zaidman; C Garcia MPNST: MRI Contrast

Erdheim–Chester Disease ⁹

• General
  • Histiocytic neoplasm
  • Cells
    • Inflammatory foamy macrophages
    • Phenotype: CD1a–, CD68+, CD163+, Factor XIIIa+, S100±
• Clinical
  • Course
    • Onset: Middle aged adults
    • Progressive
  • Tissues involved by ECD cells
    • Bone
    • Retroperitoneum
    • Kidneys
    • Brain
    • Heart
    • Skin
    • Lungs
  • Neurologic Features
    • Cognitive impairment (52%)
    • Peripheral neuropathy (56%): Axon loss
    • Pyramidal tract signs (30%)
    • Cranial nerve involvement (61%)
    • Cerebellar ataxia (46%): Dysmetria, Dysdiodochokinesis; Oculomotor
    • Seizures (8%)
  • Treatment: BRAF & MEK inhibitors; Vemurafenib with BRAF (V600E)-mutated ECD
• Laboratory
  • Brain imaging
    • Atrophy & Demyelination
    • CNS: Focal lesions; Periventricular, Pons, Midbrain
    • Dura & Extra-axial structures, Orbital, Pituitary
    • Lesion type: Tumor-like; Multifocal; No edema
  • BRAF V600E: More atrophy
  • Brain pathology
    • Lipid-laden, phagocytic histiocytes
    • Touton giant cells
    • Demyelination
    • Axon degeneration