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Dx: Neurofibromatosis Type 1

KEY FACTS

Terminology Abbreviation: Neurofibromatosis type 1 (NF1) Definition: Autosomal dominant neurocutaneous disorder characterized by plexiform neurofibromas (PNF) Imaging Panoramic: Enlarged mandibular foramen ("blunderbuss" foramen) and alveolar canal Increased vertical or horizontal width of coronoid notch CECT: Tissue with density of fat may be seen adjacent to enlarged mandibular foramen Bone CT & CBCT: Bowing and deformities of ramus Hyperintense T2 signal "Target" = signal center, signal periphery PNF Post-contrast CT or MR: Heterogeneously enhancing, lobulated mass along course of peripheral nerve Most conspicuous on STIR and FS T2WI Other extracranial H&N manifestations of NF1 Sphenoid dysplasia, PNF infiltration of cranial nerves, optic pathway glioma (OPG), large foramina Central giant cell granuloma (CGCG) associated Top Differential Diagnoses
Schwannoma Hemangioma Lymphatic malformation Venous malformation Rhabdomyosarcoma

Diagnostic Checklist If patient has plexiform or multiple localized NFs, consider NF1 Look for additional findings of CGCG, brain lesions, OPG, sphenoid wing dysplasia
TERMINOLOGY

Abbreviations Neurofibromatosis type 1 (NF1) Synonyms von Recklinghausen disease, autosomal dominant neurofibromatosis Definitions Autosomal dominant neurocutaneous disorder (phakomatosis) Diagnostic NF1 criteria: If 2 of following present > 6 caf au lait spots measuring 5 mm in prepubertal and 15 mm in postpubertal patients 2 neurofibromas (NF) of any type or 1 plexiform NF (PNF) Axillary/inguinal freckling (Crowe sign) Visual pathway glioma 2 Lisch nodules (optic hamartomas) Distinctive bony lesion Sphenoid wing dysplasia Thinning of long bones pseudoarthrosis 1st-degree relative with NF1

Peripheral nerve sheath tumor (PNST) = schwannoma, neurofibroma Neurofibromas: Localized, plexiform, and diffuse Malignant peripheral nerve sheath tumor (MPNST) more common in patients with NF1; most commonly arising in preexisting PNF
IMAGING

General Features Best diagnostic clue


Plexiform neurofibroma (PNF): Characteristic & diagnostic feature of NF1 Multiple localized NFs In mandible: Enlarged mandibular foramen

Location Neurofibromas may involve any space in H&N; most common = carotid space, brachial plexus, oral cavity, cheek, retropharyngeal space, posterior cervical space CN5, CN7, and CN10 most commonly involved Tongue most often involved in oral cavity Intraosseous neurofibromas rare: < 1% of all bone lesions Mandible > maxilla; usually associated with inferior alveolar nerve Size Localized NF: Millimeters to multiple centimeters PNF may reach large size Morphology Localized neurofibroma Multiple, well-circumscribed, smooth, fusiform, variably enhancing masses along course of nerves Paraspinal NF may be dumbbell-shaped smooth enlargement of bony neural foramina Schwannoma may be indistinguishable from NF Diffuse neurofibroma Plaque-like or infiltrative, poorly defined, reticulated lesion in skin & subcutaneous fat PNF: Trans-spatial, lobulated, tortuous, rope-like expansion within a major nerve distribution Resembles "tangle of worms" Radiographic Findings Extraoral plain film Enlarged mandibular foramen ("blunderbuss" foramen) and alveolar canal Increased vertical or horizontal width of coronoid notch: Considered pathognomonic feature by some Decreased mandibular angle Impacted teeth on affected side CT Findings CECT Neurofibromas frequently have low attenuation (525 HU) on pre- & post-contrast images, mimic lymphatic malformation Tissue with density of fat may be seen adjacent to enlarged mandibular foramen CBCT and bone CT Bowing and deformities of ramus may be seen MR Findings T2WI Hyperintense "Target" sign: signal center, signal periphery PNF "Fascicular" sign: Multiple small, irregular, hypointense foci ( fascicular bundles) T1WI C+ Localized NF: Homogeneous or patchy heterogeneous enhancement, well-circumscribed fusiform mass PNF: Heterogeneously enhancing, lobulated mass along course of peripheral nerve

Malignant PNST Differentiation of benign from malignant PNST difficult on imaging alone If large size (> 5 cm), heterogeneous with central necrosis, infiltrative margins & rapid growth, consider malignant PNST Diffuse NF: Plaque-like or infiltrative intense enhancement in skin and subcutaneous fat Imaging Recommendations Best imaging tool MR best to characterize & define total extent; most conspicuous on STIR and FS T2WI Bone CT delineates associated bone changes; sphenoid wing dysplasia and V3 PNF in ramus
DIFFERENTIAL DIAGNOSIS

Schwannoma

Localized neurofibroma in mandibular canal may be indistinguishable from schwannoma Associated stigmata of NF1 differentiates
Hemangioma

Expansion within mandibular canal usually serpiginous


Lymphatic Malformation

Low attenuation Unilocular or multilocular; focal or infiltrative No enhancement unless infected or mixed venolymphatic malformation
Venous Malformation

Phleboliths common
Rhabdomyosarcoma

Invasive trans-spatial mass Frequently with aggressive bone destruction


PATHOLOGY

General Features Etiology NF gene (tumor suppressor gene) normally encodes for production of "neurofibromin" that influences cell growth regulation NF gene "turned off" in NF1 Results in cell proliferation & tumor development Genetics
Autosomal dominant; 50% new mutations Gene locus = chromosome 17q11.2

"Nonsense mutation" of this gene leads to NF1 Phenotypic overlap with Noonan syndrome (short stature, hypertelorism, pulmonic stenosis) Central giant cell granuloma (CGCG) associated with NF1, giant cell lesions in Noonan CGCG in NF1 more aggressive and recurrence Associated abnormalities Other extracranial H&N manifestations of NF1 Orbit: Optic pathway glioma (OPG), optic nerve sheath ectasia, Lisch nodules, buphthalmos, large foramina Skull: Lambdoid suture defect Skull base findings Sphenoid dysplasia, probably sequelae of PNF interaction with developing underlying bone Smooth, corticated enlargement of skull base bony foramina with PNF infiltration of cranial nerves Vascular dysplasia: ICA stenosis/occlusion and moyamoya; aneurysms and AV fistula rare Neural crest tumors

Pheochromocytoma 10x in NF1 patients Parathyroid adenomas incidence

Other malignancies: Leukemia, rhabdomyosarcoma, Wilms tumor Other imaging manifestations of NF1 CNS findings Cerebral gliomas, hydrocephalus, cranial nerve schwannomas Dynamic reactive lesions; white matter, dentate nucleus, globus pallidus (GP), brainstem, thalamus, hippocampus Spinal cord astrocytomas Spine: Kyphoscoliosis, lateral thoracic meningocele, enlargement of spinal foramina Skeletal: Pseudarthrosis, thinning of long bone cortex, bowing of long bones Staging, Grading, & Classification Neurofibromas are WHO grade I Malignant PNST are WHO grade III/IV Gross Pathologic & Surgical Features
Localized neurofibroma

Fusiform, firm, gray-white mass intermixed with nerve of origin


Plexiform neurofibroma

Diffuse, tortuous, rope-like expansion of nerves resembling "tangle of worms" Involves adjacent skin, fascia, & deeper tissues
Malignant PNST

Fusiform, fleshy, tan-white mass with areas of necrosis & hemorrhage Nerve proximally & distally thickened due to spread of tumor along epineurium & perineurium Microscopic Features
Localized neurofibroma

Schwann cells, fibroblasts, mast cells in matrix of collagen fibers & mucoid substance Axons usually embedded within tumor
Plexiform neurofibroma

Schwann cells, perineural fibroblasts, grow along nerve fascicles


Malignant PNST

Fibrosarcoma-like growth of spindle cells Considered high-grade sarcomas: 5-year survival rate (15%)
CLINICAL ISSUES

Presentation Most common signs/symptoms Majority of PNF asymptomatic Cutaneous stigmata of NF1 Other signs/symptoms Swelling of cheek or intraoral soft tissue: Gingival enlargement reported Reduced translation of condyle on affected side Deviation of mandible to affected side Short stature Decreased vision with OPG Pulsatile buphthalmos with sphenoid wing dysplasia Demographics Age Any age, most common late childhood to early adult presentation New lesions may develop throughout life Malignant PNST: Usually adults, rare in children

Average lifespan of patient with NF1 15 years less than general population Epidemiology NF1 Most common autosomal dominant disorder 1 in 3,000
Most common neurocutaneous syndrome

Most common inherited tumor syndrome Localized NF 90% are solitary & not associated with NF1 10% associated with NF1 more frequently large, multiple, & involve large deep nerves (e.g., brachial plexus) Malignant PNST
50% associated with NF1 5% ofpatients with NF1 develop malignant PNST

Diffuse NF Majority are in patients without NF1 Natural History & Prognosis Usually slow growing unless malignant transformation: 2-16% risk for PNF Sudden, painful size of stable NF suggests malignant transformation Occasionally massive enlargement in young children Number of neurofibromas tends to increase with age Treatment Resection of NFs that press on vital structures Solitary NF resectable; PNF generally unresectable Radiofrequency treatment in PNF may offer new hope
DIAGNOSTIC CHECKLIST

Consider If patient has plexiform or multiple localized NFs, consider NF1 Look for additional findings of CGCG, brain lesions, OPG, sphenoid wing dysplasia Image Interpretation Pearls Beware: Trans-spatial NF may be hypodense on CT and mimic lymphatic malformation