General
- Aka: von recklinghausen disease
- Neurofibromatosis type 1 is a Autosomal dominant disorder
- Caused by a mutation in the neurofibromatosis type 1 gene.
- It's a tumor suppressor gene located on chr 17
- Most children with NF1 will have only mild symptoms.
Number
- Approximately 1 in every 2,500/3000 people is born with NF1.
- In the UK, every day a child is born with NF1.
- There are about 25000 people in the UK with a diagnosis of NF1
Definition
New (two or more of the following)
- Six or more café-au-lait spots, bilaterally localized (clarification of existing criterion)
- ≥ 5 mm in prepubertal children, ≥ 15 mm in postpubertal children.
- Bilateral freckles in axilla or groin * (clarification of existing criterion)
- Axillary freckling (Crowe’s sign) is present in 20-50% of individuals with NF1 and commonly appears between 3 and 5 years of age.
- Two or more neurofibromas of any type or one plexiform neurofibroma
- Two or more iris Lisch nodules OR two or more choroidal abnormalities (CAs) (addition to existing criteria)
- Additional consideration
- If Lisch nodules are present, no advantage to obtaining optical coherence tomography (OCT) for choroidal abnormalities.
- OCT assessment for CA’s should be limited to cases of diagnostic uncertainty and where OCT can be easily obtained in the outpatient clinic (i.e. without sedation/anesthesia)
- Optic pathway glioma
- Within 20 yrs of age, peak incidence 5yrs
- 30-70% cases
- Unilateral 50% case
- Bilateral 20% case
- More at optic nerve rather chiasmal
- Prognosis is better than sporadic forms
- Some can regress
- A distinctive osseous lesion such as:
- Sphenoid wing dysplasia **;
- Lytic defect in the lambdoid suture, Absence of the orbital roof and floor, elevated lesser sphenoid wing, enlarged middle cranial fossa, enlarged cranial nerve foramina, unilateral orbital enlargement, and J-shaped sella turcica.
- Anterolateral bowing of tibia (tibial dysplasia); or
- Pseudarthrosis of a long bone (clarification of existing criterion)
- A pathogenic NF1 variant (addition to existing criteria)
- A parent with NF1 by the above criteria (clarification of existing criterion)
Old (two or more of the following)
- ≥6 café au lait spots
- Prepubertal: ≥ 5mm diameter
- Post pubertal: ≥ 15mm diameter
- ≥2 neurofibromas of any type, or one plexiform neurofibroma (neurofibromas are usually not evident until age 10–15 yrs). May be painful
- Freckling (hyperpigmentation) in the axillary or intertriginous (inguinal) areas
- Optic glioma (pilocystic astrocytoma)
- ≥2 Lisch nodules
- Pigmented iris hamartomas that appear as translucent yellow/brown elevation
- Tend to become more numerous with age
- Distinctive osseous abnormality, such as sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis (e.g. of tibia or radius)
- A first degree relative (parent, sibling, or offspring) with NF1 by above criteria
Associated findings
Proposed nomenclature for the spectrum of nerve sheath tumours associated with NF1
Diagnosis | Proposed definition |
Neurofibroma | Benign Schwann cell neoplasm with thin (often wavy) nuclei, wispy cell processes, and a myxoid to collagenous (shredded carrots) matrix; immunohistochemistry includes extensive but not diffuse S100 and SOX10 positivity and a lattice-like CD34+ fibroblastic network |
Plexiform neurofibroma | Neurofibroma diffusely enlarging and replacing a nerve, often involving multiple nerve fascicles, delineated by EMA+ perineurial cells |
Neurofibroma with atypia (ancient neurofibroma) | Neurofibroma with atypia alone, most commonly manifesting as scattered bizarre nuclei |
Cellular neurofibroma | Neurofibroma with hypercellularity but retained neurofibroma architecture and no mitoses |
ANNUBP (Atypical neurofibromatous neoplasm of uncertain biological potential. ) | Schwann cell neoplasm with at least two of the following four features: cytological atypia, loss of neurofibroma architecture, hypercellularity, and a mitotic count of > 0.2 mitoses/mm² and < 1.5 mitoses/mm² (> 1 mitosis/50 HPF and < 3 mitoses/10 HPFᵃ) |
MPNST (malignant peripheral nerve sheath tumour), low-grade | Features of ANNUBP, but with a mitotic count of 1.5–4.5 mitoses/mm² (3–9 mitoses/10 HPFᵃ) and no necrosis |
MPNST, high-grade | MPNST with a mitotic count of ≥ 5 mitoses/mm² (≥ 10 mitoses/10 HPFᵃ), or with a mitotic count of 1.5–4.5 mitoses/mm² combined with necrosis |
- ᵃ1 mm² ≈ 5 HPF of 0.51 mm in diameter and 0.20 mm² in area.
Schwann-cell tumours on any nerve
- but bilateral VSs are virtually non-existent in NF1
Spinal and/or peripheral nerve neurofibromas
- Cervical/thoracic region
- Vertebral dysplasia
Multiple skin neurofibromas
Aqueduct stenosis
Macrocephaly
- Secondary to aqueduct stenosis and hydrocephalus, increased cerebral white matter
Malignant tumours that have increased frequency in NFT
- Neuroblastoma
- Ganglioglioma
- Sarcoma
- Leukaemia
- Wilm’s tumor
- Breast cancer
Pheochromocytoma
- Occasionally present
Intracranial tumours
- Hemispheric astrocytoma are the most common
- Solitary or multicentric meningiomas (usually in adults).
- Gliomas associated with NF1 are usually pilocytic astrocytoma.
Brainstem astrocytoma
- Types
- Location (56% are multiple focal)
- Medullary: 68%
- Pontine: 52%
- Midbrain: 44%
- Has more indolent course than sporadic midline glioma
- Slow progression
- Some may even regress
Unilateral defect in superior orbit
- Leading to pulsatile exophthalmos
Neurologic or cognitive impairment:
- 30–60% have mild learning disabilities
Kyphoscoliosis
- Seen in 2–10%
- Often progressive, which then requires surgical stabilization
Visceral manifestations
- Due to involvement of autonomic nerves or ganglia within the organ.
- Up to 10% of patients have abnormal gastrointestinal motility/neuronal intestinal dysplasia related to neuronal hyperplasia within submucosal plexus
Plexiform neurofibromas
- 20%
- Tumours from multiple nerve fascicles that grow along the length of the nerve.
- Almost pathognomonic for NF1
Target sign in subcutanous tissue. Can have malignant transformation and it is the number 1 cause of death. Poor surgical treatment.
Vascular lesion
- Non CNS vascular lesion
- Renal artery stenosis
- Aortic stenosis
- CNS vascular lesion
- Moya-moya
- Arterial ectasia & aneurysm
- Children more stenotic disease
- Adults more Aneurysmal disease
“Unidentified bright objects” (UBOs)
- Aka focal areas of signal intensity (FASI)
- On brain or spinal MRI
- 53–79% of patients (bright on T2WI, isointense on T1WI)
- Might be due to
- Hamartomas
- Heterotopias
- Foci of abnormal myelination or
- Low grade tumours.
- Tend to resolve with age
- Hard to differentiate with gliomas
- Has less mass effect than gliomas
- Dysplastic glial proliferation, hamartomatous changes,
- Heterotopia, spongiform myelinopathy or vacuolar changes of myelin
- Increased risk of proliferative change in young children with a large number and volume of NBO
- Reference: Di Paolo Radiology 1995, Griffiths 1999, Varella 1997
Pathology
- Neurofibraoma
- Unencapsulated, well-circumscribed masses of spindle cells, which occur in the dermis (cutaneous), in the peripheral nerve (solitary), or in a large nerve trunk (plexiform); cutaneous neurofibromas are visible as skin nodules and may cause hyperpigmentation of overlying skin
Genetic
- Autosomal dominant
- 100% penetrance after 5 yrs old
- NF1 gene at chromosome 17q11.2 micro deleted → no Neurofibromin → no negative regulation of Ras oncogene → upregulates the cyclic adenosine monophosphate (cAMP) levels → increases cell proliferation and survival.
- 50% risk of spontaneous mutations
Clinical features
- Café-au-lait spots
- Skin fold freckling
- Neurofibromas
- Lisch nodules
- Developmental difficulties
- Plexiform neurofibromas
- Optic nerve glioma
- Bowing of long bones
Counselling
- Prenatal diagnosis by linkage analysis if there are 2 or more affected family members
- 70% of NF1 gene mutations can be detected using protein truncation analysis
Neurofibromas
- Dermal and plexiform neurofibromas are characteristic of NF1.
- Deep-seated intraneural variants
- Less common
- May produce neurologic symptoms.
- The lifetime risk of malignant transformation of plexiform neurofibromas to MPNST is ≈ 10%.
- Neurofibromas largely prevail in NF1 (the schwannoma/neurofibroma ratio = 1:9)
- Schwannomas are the most common histotypes in the general population (the schwannoma/neurofibroma ratio is 9:1)
Features | Schwannoma | Neurofibroma |
Origin | Schwann cells | Neurites (axons/dendrites) + fibroblast + Schwann cells |
Axon displacement | Centrifugally (displacing axon) | Centripetally (engulfing axon) |
Solitary or multiple (part of NF1) lesion | ||
Histology | Antoni A + B | Antoni A + B (B>A) |
Management
- Optic gliomas
- Unlike optic gliomas in the absence of NF1
- Rarely chiasmal (usually involving the nerve)
- Multiple
- Better prognosis
- Most are non progressive,
- Should be followed ophthalmologically and with serial imaging (MRI or CT)
- Surgical intervention
- Does not improve visual impairment.
- Therefore, surgery is reserved for special situations (large disfiguring tumors, pressure on adjacent structures…)
- Other neural tumours in patients with NF1 should be managed in the same manner as in the general population
- Focal, resectable, symptomatic lesions should be surgically removed
- Irresectable intracranial tumours (benign):
- Chemotherapy
- Radiation therapy
- Surgery for cases with increasing ICP
- When malignant degeneration is suspected (rare, but incidence of sarcomas and leukaemia's is increased), biopsy with or without internal decompression may be indicated
- Surveillance
- Annual exam by physician familiar with NF1
- Annual ophthalmologic exam in children, less frequent in adults
- Regular developmental assessment of children
- Regular BP monitoring
- MRI for follow-up of clinically suspected intracranial and other internal tumours
- Annual mammography in women starting at age 30 years & consider annual breast MRI in women age 30–50 years
- Also need early breast screening
- Women above 50 with NF1 have 5 times greater risk of developing breast cancer
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