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A Problematic Peripheral Nerve Sheath Tumor
Anat Stemmer-RachamimovMassachusetts General Hospital
Boston, MA
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Clinical History
• A 64 year old woman• Presented with progressive enlargement of a
painful mass in the left foot
On examination:• Skin fold freckling in the right torso (front and
back), stops at midline • No dermal lesions
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History:• A previous surgery for resection of a mass from the
left leg diagnosed as a schwannoma (2013)• 2 raised dermal lesions were biopsied and
diagnosed as dermal nevi• There is no family history of any type of
neurofibromatosis• The current biopsy was seen in an outside hospital
and diagnosed as Schwannoma.• She was referred to the MGH NF clinic for
evaluation
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Imaging
• MRI showed a multinodular lesion in the lateral foot
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So - what’s the problem?Clinical considerations
• This patient has multiple peripheral nerve sheath tumors and therefor has an underlying syndrome: NF1, NF2 or schwannomatosis
• Her clinical and pathological findings do not fit any of the NF syndromes
• Skin fold freckling are s/o NF1, multiple schwannomas are c/w schwannomatosis or maybe NF2
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Multiple PNSTs - What type of NF?
Neurofibromatosis 1neurofibromas Neurofibromatosis 2
schwannomas
Schwannomatosisschwannomas
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NF1• NF1 most common 1 in 3,000 individuals. • Autosomal dominant• Germline mutations in the NF1 gene • Half of the patients are founders - have a sporadic
mutation and negative family history
• The hallmark of NF1 is the plexiform neurofibroma – often present in childhood. – carry a risk (9%) of malignant transformation to
malignant peripheral nerve sheath tumor (MPNST).
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– Other types of neurofibromas (dermal, diffuse, subcutaneous)
– Other types of malignancies including pheochromocytoma, leukemia, gliomas, breast cancer and others.
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Non tumor manifestations• Short stature• Macrocephaly• Learning disabilities – the most common clinical
feature, low IQ, attention deficit disorder• Cutaneous manifestations (café au lait, freckling)
• Café au lait patches are very early manifestation (birth)• Freckling – age 3 years
• Bone/Skeletal abnormalities• Abnormality of maintaining bone structure (osteopenia,
scoliosis, pseudoarthrosis of tibia)
• Eyes - Lisch nodules• Cardio-Vascular: fibromuscular dysplasia of renal
artery
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Diagnostic Criteria for NF1
• 2 or more have to be present:– at least 6 café au lait spots (>5 mm in
prepubertal; >15 mm after puberty– 2 neurofibromas OR 1 plexiform neurofibroma– Freckling– Tumor of the optic pathway– NF1 associated skeletal abnormality– A first degree relative with NF1
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NF2• NF2 affects 1 : 25,000 individuals • Germline mutation in the NF2 gene• Autosomal dominant disorder • 50% of patients have sporadic (de nuovo)
mutations with no family history• Vestibular schwannomas usually present (with
clinical symptoms or on MRI) by age 30• In addition: multiple schwannomas,
meningiomas,ependymomas.
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Clinical criteria for diagnosis
• Bilateral VSOR• First degree family with NF2 AND
– unilateral VS <30 yrs OR– 2 NF2 associated lesions
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Somatic Mosaics• Mosaic forms of NF1 and NF2 are common (30%)• Somatic mutation, later in development- only some
of the cells have the mutation• Manifestations are segmental, some of the clinical
criteria may be late in developing or absent • Clinical distinction between the different forms of
NF becomes difficult• Germline mutation may be not be detected - normal
genetic testing• Genetic risk to offsprings is undefined. If affected
offspring often has more severe disease
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Schwannomatosis• 1:25,000. • Most cases (85%) sporadic• 15% are familial; SMARCB1, LZTR1• Many cases are segmental (30%)• Characterized by multiple schwannomas and
meningiomas in the absence of vestibular schwannomas.
• Severe disabling pain• Malignancies?• Genetic risk is low
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•When multiple - different forms of NF:•Neurofibroma : NF1•Schwannomas : Schwannomatosis OR NF2
•Different risks for malignant transformation
•Different criteria for diagnosis of malignancy (cellular schwannoma vs MPNST)
•Different risk for offsprings
Neurofibroma or Schwannoma?
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S
M
F
S
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Diagnosis?
• A) Hybrid tumor• B) Schwannoma• C) Neurofibroma• D) Two of the above….
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Immunostains
S100
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Sox 10
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SMA
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SMA
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Glut1
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In summary
• A benign peripheral nerve sheath tumor with areas of solid Schwann cell proliferation
• Mixed cell population (Schwann cells, myofibroblasts, perineurial like cells)
• Diagnosis:Peripheral nerve tumor with hybrid features; most consistent with Schwann cell rich neurofibroma
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What are hybrid tumors and why should we report them?
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Feany et al, 2001
Nerve sheath tumors with hybrid features of neurofibroma and schwannoma: a conceptual challenge
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Hybrid Tumors
Difficult to classify – have mixed features
Schwannoma/neurofibroma
Perineurioma/schwannoma
Neurofibroma/perineurioma
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Facundo et al; Brain pathology, 2013
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1st author, year SC-NF SC-PN NF-PN S-N-P Association with NFYamamoto, 1990 1 No signs of NFHalliday, 1991 1 1 NF2Feany, 1998 9 1 NF1Kazakov, 2005 1 2 No signs of NFMurarescu, 2005 1 No signs of NFEmanuel, 2006 1 No signs of NFYouens, 2008 1 No signs of NFHornick, 2009 42 No signs of NFKuroda, 2010 1 No signs of NF1Macarenco, 2010 1 No signs of NF
Hayes, 2011 1 No signs of NFAgaimy, 2011 2 No signs of NF1/2Ohata, 2012 2 No signs of NFPark, 2012 1 No signs of NF1/2Harder, 2012 60 2 NF1, 6 NF2, 18 schwannomatosisLang, 2012 15 Negative genetic testing for NF1
No signs of NF2 or schwannomatosis
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Hybrid schwannoma/neurofibroma
• Myxoid schwannoma
• May be difficult to classify; some will remain unresolved - true hybrids
• Original series of schwannomatosis patients; 10% were misdiagnosed as neurofibromas or not classified (PNST)
Maccolin, 2003
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S100
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S100 SOX 10
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Glut1
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How does that affect clinical practice?• In the case of a tumor without history of NF:
The tumor should be diagnosed as “Hybrid tumor” or if immunohistochemical analysis led to a diagnosis of Neurofibroma or schwannoma –”schwannoma (or neurofibroma) with hybrid features (see note)”
• In cases where NF is suspected: correct pathological diagnosis
• Workup: S100, Sox10, Neurofilament, Glut1, EMA,SMA
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Selected References• MacCollin M et al. Diagnostic criteria for schwannomatosis. Neurology, 64(11):1838-45, 2005.• Harder A et al. Hybrid Neurofibroma/Schwannoma is overrepresented among schwannomtosis and
neurofibromatosis patients. American Journal of Surgical Pathology, 36(5):702-709, 2012• MacCollin M et al. Familial schwannomatosis: exclusion of the NF2 locus as a germline event.
Neurology, 60 (12):1968-74, 2003• Smith MJ et al. Frequency of SMARCB1 mutations in familial and sporadic
schwannomatosis. Neurogenetics. 2012 ;13(2):141-5.• Patil S et al. Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of
schwannomas, but not in solitary, sporadic schwannoma. Brain Pathol; 18(4):517-9, 2008• Carroll SL: Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms, Acta
Neuropathol, 123:321-348, 2012• Paganin I , Serrano C et al. BRAF V600E and KRAS G12S mutations in peripheral nerve sheath
tumours. Histopathology .2013;62(3):499-504.• Nonaka D et al. Sox10: a pan-schwannian and melanocytic marker. ,2008 ;32(9):1291-8.
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Thank You !