Nerve Sheath Tumors in the Young Cheryl M. Coffin, M.D. Clinical Professor of Pathology, Microbiology, and Immunology Vanderbilt University, Nashville, TN

Objectives To review the WHO classification of nerve sheath tumors To summarize the clinicopathologic features of nerve sheath tumors which occur in children and adolescents To discuss diagnostic pitfalls and differential diagnosis

Nerve Sheath Tumors: WHO 2013 Benign: Schwannoma* Neurofibroma* Perineurioma Granular cell tumor Dermal nerve sheath myxoma* Solitary circumscribed neuroma Ectopic meningioma* Nasal glial heterotopia* Hybrid nerve sheath tumors* Rarely metastasizing: Melanotic schwannoma Malignant: Malignant peripheral nerve sheath tumor* Malignant granular cell tumor Ectomesenchymoma*

Pediatric Nerve Sheath Tumors* Neurofibroma 59% Schwannoma 7% Granular cell tumor 8% Other benign lesions Rare Intermediate neoplasms Rare MPNST 17% Other malignant tumors Rare *Minnesota pediatric soft tissue tumor database

Diagnostic Evaluation Clinical features: age, sex, site, size, growth rate, pain, syndrome, family history Site Circumscription, association with nerve, necrosis Cellularity, architecture, cellular morphology, mitoses, atypia Immunohistochemistry and other adjuncts

Key Immunohistochemical Stains S100 protein: schwann cells, glia, melanocytes GFAP: schwann cells, glia, ependyma EMA, claudin 1, GLUT1: perineurial cells FoxD3, SOX9, SOX10: schwann cells Neurofilaments, synaptophysin: neurites, neuroendocrine cells Chromogranin, CD56: neuroendocrine cells CD57, collagen IV, laminin: nonspecific

Neurofibroma A benign peripheral nerve sheath tumor composed of differentiated Schwann cells, perineurial-like cells, fibroblasts, mast cells, and residual interspersed myelinated and unmyelinated axons embedded in extracellular matrix (WHO, 2013). Associated with neurofibromatosis type 1 and NF1 genetic abnormalities Wide anatomic distribution, early onset in NF-1 Positive for CD34, variable S100

Schwannoma Conventional schwannoma is a common, benign, usually encapsulated nerve sheath tumor that is composed of well-differentiated Schwann cells WHO, 2013). Associated with neurofibromatosis type 2 (NF2 mutation, early onset, bilateral vestibular tumors) or schwannomatosis (SMARCB1 mutation, multifocal tumors) Head, neck , extremities Positive for S100, collagen IV, laminin; variable GFAP, CD34, AE1/AE3

Schwannoma Variants Benign: cellular, plexiform, microcystic Aggressive: Melanotic schwannoma is a rarely metastasizing nerve sheath tumor with a uniform composition of variably melanin-producing Schwann cells WHO, 2013). Mainly adults, paraspinal, spinal, GI Associated with Carney complex (CNC1 and CNC2 genes) Positive for S100, HMB45, Melan A, laminin, collagen IV

Malignant Peripheral Nerve Sheath Tumor (MPNST) MPNST is a malignant nerve sheath tumor arising from a peripheral nerve, from a pre-existing benign nerve sheath tumor (usually neurofibroma) or in a patient with neurofibromatosis type 1. In the absence of these settings, the diagnosis is based on the constellation of histologic, immunohistochemical, and ultrastructural features, suggesting Schwann cell differentiation. - WHO, 2013

MPNST in Children 3-7% of pediatric soft tissue sarcomas 11% of non-RMS STS in COG ARST0332 Association with NF-1: 10% lifetime risk of MPNST 100-fold increased relative risk Earlier onset Aggressive sarcoma with poor prognosis

Clinicopathologic Features of Pediatric MPNST Median age 10-14 years Male-to-female ratio 0.7-1.4 NF-1 in 17-56% Sites: Extremities 33-50% Trunk 32-46% Head/ Neck 8-25%

Outcome of Pediatric MPNST 5 year survival 39-51% Local recurrence in 25-60% Metastasis in 14-53% Sites of metastasis: lung, bone, CNS, liver, lymph nodes

Adverse Prognostic Indicators NF-1 Non-extremity site Tumor >5 cm Incomplete resection Grade (necrosis >25%, mitoses >10/ 10hpf)

Diagnostic Pitfalls Morphologic and immunohistochemical overlap Distinction between “atypical neurofibroma” and “low grade MPNST” Mimics: hybrid nerve sheath tumors, perineurioma, other soft tissue tumors (solitary fibrous tumor, low grade fibromyxoid sarcoma, synovial sarcoma, fibrosarcoma, embryonal rhabdomyosarcoma, clear cell sarcoma, Ewing sarcoma, epithelioid sarcoma…)

Atypical Neurofibroma or MPNST? Atypical neurofibroma: hypercellularity, smudged dark nuclei, mitotic activity controversial, p53 non-reactive MPNST: hypercellularity, enlarged (3-fold) hyperchromatic nuclei, mitoses (may be scarce), p53 reactivity What about transitional forms in NF-1?

Hybrid Nerve Sheath Tumors Hybrid nerve sheath tumors are benign peripheral nerve sheath tumors with combined features of more than one conventional type (neurofibroma, schwannoma, perineurioma). (WHO, 2013). Peak in early adulthood, wide age range Sporadic or associated with NF-1 Wide anatomic distribution Positive for S100, EMA, CD34

Perineurioma Soft tissue perineuriomas are nearly always benign peripheral nerve sheath tumors composed entirely of perineural cells. Intraneural and mucosal types also exist (WHO, 2013). Mostly sporadic, rare Lower extremities, upper extremities, trunk Positive for EMA, claudin, Glut-1, CD34; negative for S100, GFAP

Rare Lesions in the Young Ectopic meningioma/meningothelial hamartoma Nasal glial heterotopia Dermal nerve sheath myxoma Granular cell tumor (benign, malignant) Benign triton tumor Ectomesenchymoma

Meningothelial Hamartoma Ectopic Meningioma/ Meningothelial Hamartoma Ectopic meningioma is a meningothelial neoplasm occurring entirely outside anatomic regions normally containing meningothelial (arachnoidal cap) cells, such as intracranial and intraspinal compartments. In contrast, meningothelial hamartoma represents a developmental rest with collections of non-neoplastic arachnoidal cells found typically on the scalp. - WHO, 2013

Meningothelial Hamartoma Infants and young children Superficial lesion on head, scalp, neck, upper back Hair collar sign Positive for EMA, vimentin (like meningioma)

Nasal Glial Heterotopia A mass of mature heterotopic neuroglial tissue isolated from the cranial cavity, most often presenting in and around the nose (WHO, 2013). Infants and young children (90% by age 2 yr) Nose, nasal cavity, other head/neck sites, may have nasal bone defect Positive for GFAP, NSE, S100

Dermal Nerve Sheath Myxoma Nerve sheath myxoma is a benign peripheral nerve sheath tumor that typically arises in skin or subcutis and often has a multinodular growth pattern. It features small epithelioid ring-like, and spindled Schwann cells embedded in abundant myxoid matrix (WHO, 2013). Extremities, especially fingers Positive for S100, GFAP, CD57

Granular Cell Tumors Benign: A benign tumor showing neuroectodermal differentiation and composed of large, oval to round cells with copious eosinophilic, distinctively granular cytoplasm (WHO, 2013). Malignant: A rare high grade sarcoma with a schwannian phenotype, composed of malignant granular cells with cytoplasmic lysosomal inclusions (WHO, 2013).

Granular Cell Tumors Both types rare in children Benign form with multiple lesions associated with Noonan syndrome Head and neck, breast, proximal extremities Benign form positive for S100, CD68, MITF, TFE3

Benign Triton Tumor An expansile intraneural mass characterized by the intimate interposition of mature skeletal muscle fibers with nerve fibers (WHO, 2013). Rare, but most occur in childhood Large nerves and plexi (sciatic, brachial) Rare cases regress

Ectomesenchymoma Ectomesenchymoma consists of rhabdomyosarcoma with a neuronal or neural component. These are possibly of neural crest origin or may represent a variant of rhabdomyosarcoma (WHO, 2013). Young children (usually before 5 yr) Paratesticular soft tissue, external genitalia, pelvis, abdomen, head and neck Components stain as expected for muscle, neuroblastic and schwannian markers Outcome same as rhabdomyosarcoma

Summary Morphologic similarities lead to challenges in differential diagnosis for nerve sheath tumors Growth rate, symptoms, syndromic features and family history are useful information Although not specific, immunohistochemistry aids differential diagnosis Neurofibroma, cellular schwannoma, and MPNST are potential mimics of each other