Neurofibromatosis type 1 (NF1)

Other names: - Von Recklinghausen disease2,1. - Autosomal dominant neurofibromatosis2. Impression: Belong to a group of lesions: Other lesions in this group: Classification: Variants: According to W&P two major classifications are: - NF1 = a generalized form1. - NF2 = a central form1. According to Lisa Koenig: - Localized, plexiform, and diffuse2. - Malignant peripheral nerve sheath tumor (MPNST) more common in patients with NF1; most commonly arising in pre-existing PNF2. NF1: ????? - plexiform neurofibroma2. o Diffuse, tortuous, rope like expansion of nerves resembling "tangled worms"2. o Involves a Jason skin, flash, and deeper tissues2. o Microscopic features: Schwann cells,. Fibroblasts, grow along the nerve fascicles2. - Malignant PNST2. o Fusiform, fleshy, tanwhite massive areas of necrosis and hemorrhage2. o Nerve proximately and distantly thickened due to spread of tumor along epineurium & perineurium2. o Microscopic features: considered high-grade sarcomas: five years survivor rate is 15%2. Note: - is a syndrome consisting of caf au lait spots on the skin, multiple peripheral nerve tumors, and a variety of other dysplastic abnormalities of the skin, nervous system, bones, endocrine organs, and blood vessels1. - Recent observations of abnormal fat tissue in close association with changes in the osseous structure of the mandible support the theory that a mesodermal dysplasia is part of the spectrum of changes that may be observed in NF 1 lesions1. - Look for additional findings of CGCG, brain lesions, OPG, sphenoid wing dysplasia2. - The peripheral nerve tumors are of two types: o Schwannomas1. o Neurofibramas1. Pathophysiology: Etiology: - NF gene is turned off in NF12 results in cell proliferation and tumor development2. o NF gene (tumor suppressor gene) normally encodes for production of neurofibromin that influences cell growth regulation2. Genetic: Neurofibromatosis type 1 Page 1

Autosomal dominant neurocutaneous disorder (phakomatosis) characterized by plexiform neurofibraoms (PNF)2. 50% new mutations2. "Nonsense mutation" of gene locus = Chromosome 17q11.2 leads to NF12.

Epidemiology: Incidence: - NF1: most common autosomal dominant disorder (1 in 3000) 1,2. o And present in about 30 people per 10,000 population1. - 5% of patients with NF1 develop malignant PNST2. - Intraosseous neurofibraoms: o Rare: < 1 % of all bone lesions2. o Mandible > maxilla; usually associated with the mandibular canal2. Age: - any age, but most common late childhood to early adulthood2. o New lesions however may develop throughout life2. - Malignant PNST: o usually adults, rare in children2. Gender: Race: Familial prevalence: - 1st-degree relative with NF12. Other: - average lifespan of patients with NF1 is 15 years less than general population2. Clinical presentation: Symptoms: - most majority are asymptomatic and patients live a normal life with few or no symptoms1. - most common signs/symptoms: o majority of PNF are asymptomatic2. o Cutaneous stigmata of NF12. - Other signs/symptoms: o swelling of cheek or intraoral soft tissue: gingival enlargement reported2. o Reduced translation of condyle on affected side2. Deviation of mandible to the affected side2. o Short stature (similar to Noonan syndrome) 2. Clinical findings: - slow-growing, unless it is malignant transformation 2. o Sudden painful increase in size of stable NF suggests malignant transformation2. o Occasionally massive enlargement is seen in young children2. - Number of neurofibromas tends to increase with age2. - NF1: - Oral lesions: o may occur as part of NF1 1. o May be solitary1. o and are called segmental or forme fruste manifestations1. - Some manifestations are congenital, but most appear gradually doing childhood and adult life1. Neurofibromatosis type 1 Page 2

Changes in mandibular morphology can continue to increase in severity through the second decade1. - Skin lesions: o Caf au lait spots become larger and more numerous with age1. Most patients eventually have more than 6 spots larger than 1.5 cm in diameter1. Freckles1. Soft pedunculated cutaneous neurofibromas1. Firm subcutaneous neurofibromas1. Common sequel: Location: - Intraosseous neurofibromas: o Rare: < 1 % of all bone lesions2. o Mandible > maxilla; usually associated with the mandibular canal2. o Distribution of lesion: Size of lesion: - PNF may reach large-size2. Expansile: Other: - Other extracranial H&N manifestations of NF12. o Sphenoid dysplasia, PNF infiltration of cranial nerves, optic pathway glioma (OPG), large foramina2. Histology: - See notes section. Tumor Grading: - neurofibromas are WHO grade I2. - malignant PNST are WHO grade III/IV2. Radiographic features: radiographic changes in the jaws with neurofibromatosis can be characteristic1. - +/- Alterations in the shape of the mandible1. - +/- Enlargement of the coronoid notch in either or both the horizontal and vertical dimensions1. - +/- An obtuse angle between the body and the ramus1. - +/- Deformity of the condylar head1. - +/- Lengthening of the condylar neck1. - +/- Lateral bowing and thinning of the ramus1. - +/- Enlargement of the mandibular canal, mental and mandibular foramina1. - +/- Increased incidence of branched mandibular canal1. - +/- Erosive changes to the outer contour of the mandible1. - +/- Interference with normal eruption of the molars1. - +/- Abnormal accumulation of fatty tissue within deformities of the mandible is seen in CT1. Locularity: Location: - Neurofibromas may involve any space in H&N2. Neurofibromatosis type 1 Page 3

Most common = carotid space2. Brachial plexus2. Oral cavity2. cheek2. Retrophayngeal space2. Posterior cervical space2. o CN5, CN7 and CN10 most commonly involved o Tongue most often involved in oral cavity2. - Intraosseous neurofibromas: usually associated with the mandibular canal2. Extension Periphery (Edge, Margin): Shape: Size: Internal: Tooth resorption: Effect on surrounding structures: Tooth displacement: Number: Description: Plain radiographs: - Enlarged mandibular foramen (blunderbuss foramen and alveolar canal)2. - Increased vertical or horizontal width of the coronoid notch2. CECT: - tissue with density of fat may be seen adjacent to enlarged mandibular foramen2. - Heterogeneously enhancing, lobulated mass along course of the peripheral nerve2. Bone CT and CBCT: - Bowing and deformities of ramus are present2. MR imaging: - T2-WI: hyperintense signal2. o Target = Signal in the center2 + signal in the periphery of plexiform neurofibromas (PNF)2. o Heterogeneously enhancing, lobulated mass along course of the peripheral nerve2. o Most conspicuous on STIR and FS T2WI 2. Best imaging clue: o Plexiform neurofibroma (PNF): Characteristic & diagnostic feature of NF12. o Multiple localized NFs2. o In mandible: Enlarged mandibular foramen2. o Preferred Imaging modality: Plain film: - Panoramic: see enlarged mandibular foramen (blunderbuss foramen, and alveolar canal) 2. CT: Ultrasonic: MRI: Imaging challenges: Correction Laboratory tests:1 Diagnostic checklist: - Diagnostic NF1 criteria: if 2 of the following are present Neurofibromatosis type 1 Page 4

6 caf au lait spots measuring 5 mm in prepurbertal and 15 mm in postpubertal patients2. o 2 neurofibraoms (NF) of any type or 1 plexiform NF (PNF) 2. o Axillary/inguinal freckling (Crowe sign) 2. o Visual pathway glioma2. o 2 Lisch nodules (optic hamartomas) 2. o Distinctive bony lesion2. Sphenoid wing dysplasia2. Thinning of long bones pseudoarthrosis2. If patient has plexiform or multiple localized NFs consider NF12. o Look for additional findings of CGCG, brain lesions, OPG, sphenoid wing dysplasia2. o

Differential dx: Radiographically: - Schwannoma2. - Hemangioma2. - Lymphatic malformation2. - Venous malformations2. - Rhabdomysarcoma2. Histologically Clinical Association with Syndromes: Association with other lesions: - Central giant cell granuloma (CGCG)2. o CGCG in patients with NF1 is more aggressive and has higher recurrence2. - Malignant peripheral nerve sheath tumor (MPNST) more common in patients with NF1; most commonly arising in pre-existing PNF2. Mimicking of other lesions: Malignant transformation: - has occurred but in rare cases1. Management: Biopsy: Surgical management: - small cutaneous and subcutaneous neurofibromas can be removed if they are painful 1. Solitary NF is resectable2. - PNF is generally unresectable2. Large plexiform neurofibromas should be left alone1. - Radiofrequency treatment in PNF may offer new hope2. Radiographic management: Medication: Prognosis: Recurrence Rate: Metastasis to: Neurofibromatosis type 1 Page 5

Complication:

Modality: Axial bone CT Shows a massive peripheral plexiform neurofibroma (open white arrows) affecting the left maxilla in a 32 yr old man with NF1. There is remodeling of the anterior maxilla (arrow), and patchy destruction of the zygomatic arch (curved white arrow). Note displacement of the molar tooth (open black arrow)2

Modality: Coronal bone CT Shows widening of the pterygomaxillary fissure compared to the normal contralateral side (curved white arrow), and extension of the neurofibroma through the pterygomaxillary fissure (straight white arrow) into the sphenoid sinus (white open arrow)2

Neurofibromatosis type 1

Modality: Lateral radiograph in a child with NF1 Shows a skull base plexiform neurofibroma (PNF) shows a typical but rare large lambdoid defect (white arrow). Note asymmetry in the orbital roofs (white open), secondary to unilateral orbital enlargement, typical of patients with sphenoid wing Page 6 dysplasia and adjacent PNF2.

Modality: Axial bone CT Shows an expansile mass (white arrow) and bowing of the ramus (white open) typical of neurofibroma associated with the inferior alveolar nerve in a 31 year old Female with NF1. Note enlargement of the mandibular foramen compared to the contralateral side (white curved)2.

Modality: Axial CECT in the patient above Shows that the neurofibroma (white arrow) is hypodense compared to the adjacent medial pterygoid muscle (white curved)2.

Neurofibromatosis type 1

Dx: Neurofibromas: Modality: cropped panoramic radiographs (A) Shows a neurofibromas in the mandibular body along the path of the mandibular canal. (B) Note the fusiform shape as the tumor expands the canal1.

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Dx: Segmental neurofibromatosis (A) Modality: panoramic radiographs Shows enlargement of the left coronoid notch, enlargement of the mandibular foramen and interference of the eruption of the 1st & 2nd molars1. (B) Modality: Basal skull view (same patient) Showing thinning of the ramus in a lateral direction1. (C) Modality: CT axial image with soft tissue algorithm. Showing fatty tissue adjacent to the abnormal ramus1.

Neurofibromatosis type 1

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References:
1. 2.

White S, Pharoah M. Oral Radiology Principles and Interpretation. 6th ed2006. Koenig L, Tamimi D, Petrikowski G, et al. Diagnostic Imaging Oral & Maxillofacial 2011.

Neurofibromatosis type 1

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