PN Tumors

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PERIPHERAL NERVE TUMORS

Large nerves
Lymphoma
Neurofibroma
Neurofibromatosis-1
Neurofibromatosis-2
Perineurioma
Peripheral nerve tumors
Schwannoma
Tumor-like disorders

TUMOR-LIKE DISORDERS

Morton's (Plantar neuroma)

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

Amputation neuroma

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

Nerve sheath ganglion (Cyst)

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

Neuromuscular hammartoma (Benign Triton tumor)

Pathology: Mosaic tumor with striated muscle mixed within nerve fascicles

Mucosal neuroma

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

Palisaded encapsulated neuroma

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

Neurothekoma

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

Ganglion cyst

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

Lipoma

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

Perineurioma: Intraneural⁶

Perineurioma

Locations
- Nerves:
  Ulnar (17%); Median (11%); Common peroneal (9%);
  Posterior interosseus (9%); Sciatic (8%); Radial (8%); Femoral(6%);
  Posterior tibial; Brachial plexus; Facial; Tongue
- Intraneural: Fusiform swelling
- Usually single lesions: Occasionally bilateral
- Other
  - Variant: Occurs in soft tissue
  - May mimic schwannomas
Epidemiology
- Onset age: 1st to 4th decades; Range 2 to 64 years
- Males = Females
Clinical
- Males = Females
- Weakness: > 80%
- Sensory loss: ~25%
- Painless
- Slow progression: Years
- Benign: Does not recur or metastasize
MRI
- Segmental enlargement
- T2 high intensity; T1 low intensity
- Other imaging studies: Sonography
Pathology
- Fusiform, segmental enlargement of affected nerve
- Proliferation of perineurial tissue: Whorls; Multiple layers
- Perineurial cell features
  - Cytoplasmic processes: Thin & Elongated
  - Basla lamina: Incomplete
  - Tight junctions: Poorly formed
  - Pinocytotic vesicles
- Tumor cells: Well differentiated
- Cell staining
  - Positive
    - Epithelial membrane antigen (EMA)
    - Vimentin
    - Glucose transporter protein-1 (Glut1)
    - Collagen IV
    - PGP 9.5
  - Negative
    - S-100
    - Leu-7
    - Neurofillaments
- Abnormalities of long arm of chromosome 22

Localized hypertrophic mononeuropathy: Endoneurial components

Perineurial & Schwann cells¹
- Onset: Mean 26 years; Range 9 to 73 years
- Clinical
  - 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
Endoneurial fibrosis²
- Clinical: Progressive weakness in course of individual nerve
- Nerves: Sciatic; Brachial plexus
- MRI: Intrinsic abnormalities of involved nerves
- Pathology
  - Disruption of fascicular anatomy
  - Endoneurial fibrosis
  - No involvement of perineurium or Schwann cells

Giant proximal nerve hypertrophy

Associated disorders
- Noonan's syndrome
- CMT1A ³

PERIPHERAL NERVE TUMORS

Schwannoma
Neurofibroma
- Solitary
- Multiple: Neurofibromatosis
Fatty: Nerve swelling without damage
- Lipofibromatous hamartoma
- Macrodystrophica lipomatosa
Hemangioma
Malignant
- Malignant Triton tumor
- Glandular malignant Schwannoma
- Malignant epithelioid Schwannoma
Also see plexopathy & neoplasm
- Brachial
- Lumbosacral

Schwannoma

Epidemiology
- Onset age: Peak 30 to 50 years; All ages affected
- Sex: Overall Male = Female; Female predominance (2:1) with intracranial lesions
- Most common peripheral nerve tumors in adults
- Incidence
  - 8% of intracranial tumors
  - 29% of primary spinal tumors
Associated disorders
- Neurofibromatosis 1
- Neurofibromatosis 2 : Especially vestibular Schwannomas
- Chromosome 22q deletions: Distinct from NF2 mutations
Clinical
- Location
  - Flexor surfaces of limbs
  - Main nerve trunks
  - Solitary
  - Arise eccentrically from within nerve
  - Often at origins of spinal or cranial nerves
  - Sensory > Motor nerves
  - Fascicles stretched over surface of tumor
- Symptoms
  - Most of are incidentally diagnosed
  - Painful swelling
    - Shooting pain & paresthesias induced by nerve palpation
    - Spontaneous pain unusual
  - Sensory loss & Weakness: Unusual unless tumor located in confined space (e.g. 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
  - Malignant transformation
    - Not in typical tumors
    - Small risk in atypical tumors
  - Symptomatic regrowth: Rare
- Treatment: Resection with preservation of nerve function
MRI
- T2 hyperintense; T1 isointense
- Gadolinium enhancement: Most sensitive; Homogeneous
Pathology
- Tumor anatomy
  - Well-circumscribed
  - 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
  - Antoni, Type B: Loose myxoid
  - Degenerative changes
    - Cysts; Calcification; Hemorrhage; Hyalinization
    - Especially in large, deep tumors
  - No intratumoral axons
- Immunoreactivity: S-100 protein > Leu-7; 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
  - Histology: Epithelioid cells in cords or nests; Occasional features of degeneration
- Neuroblastoma-like
  - Histology: Giant rosettes; May simulate neuroblastoma
- Plexiform
  - May occur sporadically, with NF2 or with Schwannomatosis
  - Benign
  - Location: Subcutaneous tissue
  - Young adults

Neurofibromas

Number
- Solitary in 90%
- Multiple tumors: Most often neurofibromatosis
Onset
- Age: 20 to 30 years
Clinical
- Painful swelling: Palpation does not induce shooting pain
- Weakness & Sensory symptoms with non-cutaneous nerves
- Prognosis: Malignant transformation
  - Solitary tumors: Rare
  - Neurofibromatosis: 4%
MRI
- T2: Hyperintense; decreased central intensity
- T1: Isointense with muscle
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
  - Cell anatomy
    - Elongated wavy interlacing hyperchromatic cells with spindle-shaped nuclei
    - Background: Disorderly loose mucoid substance with collagenous fibrils
  - Cell types within tumor
    - Schwann cells
    - Perineurial cells
    - Fibroblasts
    - Lymphocytes
    - Mast cells
  - Myelinated & unmyelinated axons within tumor
  - Immunoreactivity of tumor cells
    - S-100: Positive but Variable
    - 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

Neurofibromatosis-1

l Neurofibromin (NF1); Chromosome 17q11.2; Dominant

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: > 240 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-progessive (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
- 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
  - Noonan syndrome (12%)
    - Genetic
      - Mutations of NF-1 found in several families
      - Other patients with PTPN11 mutations
    - Clinical: Ocular hypertelorism; Down-slanted palpebral fissures; Low-set ears; Webbed neck; Pulmonic stenosis
  - Watson syndrome
  - 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
      - Especially children: 1st 4 years
      - 15% on MRI
      - May cause blindness
      - 1/3 symptomatic
  - 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

l Chromosome 22q12.2; Dominant

Prevalence: 1 in 1,000,000
Gene: Schwannomin
- 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
Criteria: 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 neuropathy⁴
    - Frequency: Occasional; More common with more severe NF-2
    - Associated Schwannomas: Cranial nerve VIII; Spinal; Cutaneous (50%)
    - Clinical: 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
      - 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

Origin
- ? Schwann cells
- Solitary or plexiform neurofibromas, especially irradiated
Frequency
- General population (0.001%)
- Neurofibromatosis (4% to 26%): More common with NF-1 gene microdeletions
Histology
- Necrosis; Mitoses; S-100 cells (50%)
- Triton tumors: Contain rhabdomyosarcoma, Cartilage, Bone, but not mucin-secreting glands
Clinical
- Swelling: Spontaneous pain; Firm; Immovable;
- Motor & sensory loss
- Rapid change in size of neurofibroma
- Location: Sciatic nerve > Brachial & Sciatic plexus
- Prognosis
  - Highly malignant; Often metastatic
  - Median survival 3 years; 5 year survival 34% to 39%
  - Worse: Large tumor (> 5 cm); NF-1; Central location
Treatment: Wide resection or Limb amputation

Return to Neuromuscular home page

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11/13/2007