Nervous About Nerve Sheath Tumours?

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1 Goals Nervous About Nerve Sheath Tumours? Rajiv M. Patel, M.D. RCPA NZ ASM 2017 (3:30-4:15pm, Saturday, ) Review spectrum of cutaneous nerve sheath tumors Vast majority are benign & include neurofibromas, schwannomas, perineuriomas, granular cell tumors, & various neuroma subtypes Malignant granular cell tumor & malignant peripheral nerve sheath tumor are also rarely encountered in the skin Diagnostic criteria and practical considerations are emphasized 2 Benign nerve sheath tumors Malignant nerve sheath tumors Neuromas Neurofibroma Diffuse Plexiform Schwannoma Cellular Neuroblastoma-like Plexiform Perineurioma Hybrid nerve sheath tumor Granular cell tumor Malignant peripheral nerve sheath tumor (MPNST) Atypical neurofibroma vs MPNST Epithelioid MPNST Malignant granular cell tumor year-old-female with a left cheek papulonodule 6 1

2 Diagnosis? Solitary circumscribed neuroma (SCN) Key pathologic features: Solitary circumscribed neuroma AKA palisaded encapsulated neuroma Usually present on head and neck, especially face Well circumscribed with thin incomplete capsule Some may have a plexiform growth pattern Fascicles of spindled cells with distinct clefting S100+, NF+ axons, EMA+ perineurium Differential: Solitary circumscribed neuroma Schwannoma Developed capsule Cellular Antoni A and hypocellular Antoni B areas Verocay bodies Lack clefting artifact Neuofibroma More heterogeneous appearance Plexiform NF must be distinguished from SCN with plexiform growth pattern Mucosal neuromas Multiple lesions MEN2b Leiomyoma SMA+, S Other neuromas Traumatic Sites of previous injury or trauma prone areas Disorganized, but relatively normal nerve twigs Often present in a fibrotic stroma related to the prior injury Morton s neuroma a painful variant of traumatic neuroma that typically arises between the 2 nd and 3 rd toes Pacinian Rare Occur on the digits at sites of trauma Clusters of enlarged pacinian corpuscles Rudimentary polydactyly (supernumerary digit) Polypoid lesion at base of 5th finger Almost always present at birth

3 13 14 SND 15 Key pathologic features: Neuromas Disorganized but relatively normal nerves or neural structures Some degenerative changes common Rudimentary polydactyly: polypoid lesion at base of 5th finger Neurofibromas: Clinical features Most common cutaneous NST Young adults, but any age M=F Polypoid, may resemble IDN & skin tags, or be deeper dermal papulonodules Most sporadic some associated with NF1 Multiple Deep locations

4 year-old-male with an elevated plaque on the neck

5 Diagnosis? 26 Diffuse neurofibroma: Clinical features Diffuse neurofibroma Head & neck of children & young adults Subset of pts have NF1 Plaque-like elevation of the skin Rare cases may be quite large May contain melanin pigment or mature fat and ectatic vessels in pts with NF1 28 Diffuse neurofibroma: Pathologic features Components same as localized neurofibroma, but: Poorly circumscribed, infiltrates around preexisting dermal structures, extends into subcutis tumor cells more evenly distributed compared to conventional neurofibroma Meissner body-like formations S100+, CD34 +/

6 31 32 Diffuse neurofibroma: Differential Dermatofibrosarcoma protruberans (DFSP), particularly myxoid DFSP CD34+, S100 -, t(17;22) Dermatofibromas Collagen trapping, secondary elements, S-100- Neurotized nevi Superficial nested component, lacks NF stroma Other benign nerve sheath tumors 33 DFSP DF Myxoid DFSP 6

7 Ankle-type DF 22-year-old female with 8-year history of a slow growing mass involving the buttock & right leg Chiu H, Liao Y. N Engl J Med 2013;368:e

8 Diagnosis? Plexiform neurofibroma Diagnostic criteria for NF1 Six or more café au lait macules (>0.5 cm in children or >1.5cm in adults) Two or more cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma Axillary or groin freckling Optic pathway glioma Two or more Lisch nodules (iris hamartomas) Bony dysplasia (sphenoid wing dysplasia, bowing of long bone +/- pseudoarthrosis) First degree relative with NF1 Plexiform neurofibroma: Clinical features Pathognomic for NF1 Develop early in life Soft tissue mass with overlying loose hyperpigmented skin (elephantiasis neuromatosa) Dx macroscopically based on imaging or gross features Large plexiform soft tissue masses with bag of worms appearance Must be distinguished from neurofibromas with merely a microscopic plexiform growth pattern, which is not associated with NF1 Significant risk of transformation to MPNST National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis Arch Neurol Chicago. 1988;45: Plexiform neurofibroma: Pathologic features Components same as localized neurofibroma: Tangled, markedly expanded nerve fibers composed of spindled to comma-shaped nuclei that resemble the tumor cells of conventional neurofibroma May also have areas resembling diffuse neurofibroma

9 Plexiform neurofibroma: Differential Other forms of neurofibroma Plexiform schwannomas much smaller & have distinct Antoni A and Antoni B areas Often difficult, if not impossible, to make a diagnosis of plexiform neurofibroma on small skin biopsies. Diagnosis is reserved for large tumors that are suspected to be plexiform neurofibromas by gross examination or imaging Key pathologic features: Neurofibroma Bland spindled cells with wavy nuclei in collagenous to myxoid stroma May have focal atypia Variably positive for S100, EMA, CD34 Diffuse neurofibroma Infiltrative growth pattern Meissner corpuscle-like bodies Plexiform neurofibroma Plexiform growth pattern by imaging or gross pathologic examination Associated with neurofibromatosis Schwannomas: Clinical features Wide age range, no gender predisposition In cutaneous lesions, the dermis & subcutis of the head & neck & the flexor surfaces of the extremities are most commonly involved, but can arise in any superficial location Solitary, slow-growing, asymptomatic mass present for a few years Occasional patients have pain or paresthesia Schwannomas: Clinical features Most sporadic, multiple lesions should prompt evaluation for syndromic or familial causes (10%) Bilateral vestibular nerve schwannomas are a well-known pathognomonic feature of neurofibromatosis type 2 Benign tumors with simple enucleation being curative benign tumors with simple enucleation being curative Cellular schwannoma has a higher risk of local recurrence. Plexiform schwannoma can recur and be locally infiltrative and aggressive, metastasis does not occur Malignant transformation is exceptionally rare Key pathologic features: Schwannoma Fibrous capsule Hypercellular (Antoni A) and hypocellular (Antoni B) areas composed of bland spindled cells Hyalinized vessels often present May have degenerative atypia Spindled cells strongly positive for S100, but negative for CD

10 50-year-old male with a 5cm subcutaneous thigh mass 56 S Diagnosis? Cellular schwannoma 10

11 Pathologic features: Cellular schwannoma Composed almost exclusively of cellular Antoni A areas without Verocay body formation or nuclear palisading Arranged in long fascicles similar to the herringbone pattern seen in fibrosarcoma Loose or cystic areas account for no more than 10% of the entire tumor Most cases are deeply located, but subcutaneous cases are occasionally seen Mitotic figures are more common compared to conventional schwannoma and range from 0-4/10 per high power fields Pathologic features: Cellular schwannoma Misdiagnosed as spindle cell sarcomas (MPNST, LMS) Circumscription and encapsulation are crucial hints to its benign nature Careful sampling and searching for the paucicellular Antoni B areas of conventional schwannoma can be helpful if present Diffuse and intense S100 positivity is not a feature of typical MPNST, if seen in a biopsy of a cellular spindle cell neoplasm it strongly suggests cellular schwannoma (there are exceptions) year-old-male with a multinodular mass in left hand 66 11

12 67 68 Diagnosis? Plexiform schwannoma Pathologic features: Plexiform schwannoma Dermis or subcutaneous tissue May recur & be locally infiltrative & aggressive in some cases, metastasis does not occur Multinodular growth pattern, individual thin fibrous capsules Cytomorphology is predominantly Antoni A although cellularity is usually higher & Verocay bodies less frequently Antoni B areas with hyalinized vessels and foci of cystic change may be seen Mitotic activity is typically inconspicuous, but cases with as many as 8/10 HPF have been reported Pathologic features: Plexiform schwannoma In some cases significant nuclear atypia is also present Melanin pigment has been reported in rare cases Can be congenital and present extremely worrisome features including, infiltrative growth, high cellularity & mitotic counts (up to 31/10HPF), & lack features characteristics of conventional schwannomas occasional cases arise in patients with NF1 or NF2, but association is weak at best Must be distinguished from plexiform neurofibroma, which is diagnostic of NF1 & carries risk of malignant transformation to MPNST S100 protein strongly & diffusely positive in plexiform schwannoma, only highlights a subset of cells in plexiform neurofibroma

13 56-year-old male with a papule on the nose 74 Diagnosis? 75 Microcystic/reticular schwannoma 78 13

14 Pathologic features: Reticular/microcystic schwannoma Predilection for the gastrointestinal tract, dermal and subcutaneous cases have been described Well-circumscribed or multilobular, may not be entirely encapsulated Microcystic and reticular areas composed of anastomosing cords and strands of tumor cells embedded in a variably myxoid to collagenous stroma Individual cells are spindled to ovoid & may be signet-like in some cases Areas of conventional schwannoma, seen in some cases, can be a helpful diagnostic clue S100+, variably GFAP+ Differential: Reticular/microcystic schwannoma Reticulated perineurioma EMA+, S100 & GFAP-, lacks microcystic areas, acral sites favored Myoepithelial neoplasms CK & EMA, SMA, p63, GFAP, S100+ Dermal nerve sheath myxoma GFAP & S100+, variable NSE & CD57, distinctly myxoid, arises in fingers Ossifying fibromyxoid tumor Bony shell (80%), S100+ (less diffuse & intense), SOX10- Extraskeletal myxoid chondrosarcoma Only 20% S100+ (usually scattered), deep seated, multinodular, EWSR1- NR4A3 translocation Key pathologic features: Schwannoma Cellular schwannoma Lacks hypocellular areas May have mitotic rate up to 4/10 HPF Plexiform schwannoma Multinodular growth pattern Microcystic/reticular schwannoma Rare Reticulated, cord-like growth pattern 38-year-old male with dermal/ subcutaneous mass in the upper extremity 81 Diagnosis? 83 14

15 Epithelioid schwannoma Clinicopathologic features: Epithelioid schwannoma Predominantly epithelioid cells (>50%) Dermis & subcutis of the extremities <5cm, well-circumscribed, perineurium, ¼ multinodular Hyalinized vessels (95%), giant collagen rosettes may be seen Atypical variants (nuclear atypia, nuclear size variation > 3:1, mitoses >3/10HPF) fall short of criteria for dx of epithelioid MPNST, prognosis no different from typical schwannoma

16 Differential: Epithelioid schwannoma Long list of epithelioid neoplasms in differential Nodular or metastatic melanoma Unencapsulated, more atypia & mitotic activity, melanocytic markers+ (e.g., HMB45, MelanA, MiTF) Epithelioid MPNST Multinodular, superficial Significant atypia & mitotic activity, necrosis, myxoid stroma Lacks secondary elements of schwannoma (hyalinized vessesl, hemosiderin, foam cells) SMARCB1/INI1 loss in 50% 44-year-old female with a rapidly enlarging mass of the posterolateral neck Diagnosis? 96 16

17 Neuroblastoma-like schwannoma 98 Clinicopathologic features: Neuroblastoma-like schwannoma Tumor cells palisade around central collagenous cores mimicking rosettes of neuroblastoma Neuroblastoma deep seated tumor of infants, typically in adrenal gland Have a capsule & immunophenotype of conventional schwannoma Resembles hyalinizing spindle cell tumor with giant collagen rosettes variant of LGFMS Lacks capsule MUC4+, S100-, FUS-CREB3L fusion Key pathologic features: Schwannoma Epithelioid schwannoma Predominantly composed of epithelioid Schwann cells 25% multinodular Mitotic rate low Neuroblastoma-like schwannoma Collagenous nodules surrounded by tumor cells Also has features of conventional schwannoma Clinicopathologic features: Perineurioma Benign PNST with perineurial differentiation No association with neurofibromatosis Intraneural Females under 40 Ulnar, radial, median, peroneal and sciatic nerves most affected with deficits Imaging show segmental enlargement of involved nerve Extraneural/soft tissue (most common) Wide age range, equal sex distribution Extremities & trunk fewer cases in head & neck 10% dermal, 50% subcutaneous, 1/3 deep soft tissues Most painless, but a subset painful

18 Key pathologic features: Perineurioma Positive for EMA (may be very focal), variably positive for CD34, negative for S100 Soft tissue perineurioma Swirling to fascicular growth pattern Myxoid to collagenous stroma Bland spindled cells with elongated cytoplasmic processes Intraneural perineurioma Concentric proliferation of perineurial cells around nerves imparting an onion bulb appearance 10-year-old male with a nodule on the thumb EMA Diagnosis? GLUT

19 Sclerosing perineurioma 110 Clinicopathologic features: Sclerosing perineurioma Distinct variant of perineurioma Almost exclusively occurs in the dermis & /or subcutis of acral sites of young people with a male predominance Non-acral examples have been described Benign tumors, very low risk of local recurrence Cell spindled to distinctly rounded, arranged in cords, trabeculae & chains within dense sclerotic stroma EMA & GLUT1+, 50% SMA+, CD34+/- fingerprint pattern, laminin and collagen IV surround tumor cells MUC4, desmin, S100, CK- Loss of chrm 22, rearrangement/deletions of 10q & deletions of NF2 Differential: Sclerosing perineurioma Other acral tumors Fibroma of tendon sheath Variant of fasciitis, lacks cord-like growth pattern, EMA- Superficial acral fibromyxoma Spindled to stellate, rather than epithelioid, cells, random to fascicular growth pattern, myxoid change CD34+, variable EMA, claudin Key pathologic features: Perineurioma Sclerosing perineurioma Usually acral location Spindled to epithelioid cells in cord-like pattern Dense collagenous stroma 32-year-old female with a back mass

20 EMA S Diagnosis? Hybrid schwannoma/ perineurioma Clinicopathologic features: Hybrid schwannoma/ perineurioma Young to middle-aged adults, affecting men and women equally Painless masses of the subcutis &/ or dermis and have a wide anatomic distribution Benign tumor with rare local recurrence after excision Circumscribed but unencapsulated Distinct areas of schwannoma & perineurioma Degenerative atypia & some mitotic activity Hybrid lesions are immunoreactive for S100 protein, EMA and CD34. Most tumors also express Claudin-1 The S100 protein-positive cells and EMA-positive cells are arranged in parallel layers in a laminated fashion

21 Differential: Hybrid schwannoma/perineurioma Low-grade fibromyxoid sarcoma (LGFMS) Resembles perineurioma component MUC4 positive, t(7;16) by PCR or FISH Soft tissue perineurioma S100- Neurofibroma Schwann cells tend to be shorter & perineurial cells more scattered than in hybrid schwannoma-perineurioma Lacks lamellar pattern Key pathologic features: Hybrid schwannoma/ perineurioma Sclerosing perineurioma Usually acral location Spindled to epithelioid cells in cord-like pattern Dense collagenous stroma year-old male with hyperkeratotic nodule of left thigh

22 Diagnosis? Granular cell tumor Clinical features: Granular cell tumor Described 1926 by Abrikossoff Adults 3 rd & 4 th decades, but all age groups are affected, males=females, predilection for people of African descent Tongue one of the most common sites, a significant portion occur in the skin In 5-10% of cases lesions may be multiple Association between multiple lentigines (LEOPARD) syndrome & multiple granular cell tumors Asymptomatic or pruritic, small, cutaneous nodule averaging just over 1 cm in size Benign, simple excision, recurrence rare 129 Pathologic features: Granular cell tumor Large, polygonal cells in vague nests or trabeculae, syncytial appearance due indistinct cell borders, spindling in some cases Cytoplasm granular & eosinophilic (phagolysosomes), PAS positive, diastase resistant Pustulo-ovoid bodies of Milan: eosinophilic granule surrounded by halo Nuclei small & hyperchromatic to vesicular with nucleoli Degenerative nuclear atypia pseudoepitheliomatous hyperplasia

23 GCT - Pseudoepitheliomatous hyperplasia (PEH) Irregular rete ridges proliferating into underlying GCT/stroma often with squamous pearls *(mimics SCCa) No nuclear atypia or dyskeratosis Squamous epithelium of PEH does not extend beyond limits of GCT Pathogenesis unclear (humoral, EGF, TGFα?) Pathologic features: Granular cell tumor Dense fibrosis mimicking desmoplasia seen in malignancy Intimate association with small nerves misinterpreted as perineural invasion Strongly & diffusely positive for S100 protein, SOX10, TFE3, calretinin, & inhibin. CD68, CD163, NKI-C3, Melan-A (rare), MiTF +/- but nonspecific Desmin, cytokeratin, GFAP, & HMB S-100 protein CD

24 Differential Diagnosis Squamous cell carcinoma Adult rhabdomyoma Hibernoma Oncocytic salivary gland tumors Paraganglioma Crystal storing histiocytosis Congenital granular cell epulis 139 Rhabdomyoma Rhabdomyoma Hibernoma Oncocytoma 24

25 Paraganglioma Synaptophysin Crystal-storing histiocytosis GCT - Treatment Complete local excision usually curative True recurrences rare in histologically benign tumors (~ 6%) Recurrences most likely represent residual or separate (multifocal) lesions CD68 (KP1) Key pathologic features: Granular cell tumor Large polygonal cells with abundant eosinophilic granular cytoplasm Usually bland nuclear features May have overlying pseudoepitheliomatous hyperplasia S100+, SOX10+, TFE3+, calretinin+, inhibin+, PAS+ Key pathologic features: Malignant granular cell tumor Similar to conventional granular cell tumor Must have 3 of following 6 features Necrosis, spindling, high N:C ratio, vesicular nuclei with large nucleoli, increased mitotic activity (>2/10 HPF 200X fields)

26 Prognosis: Malignant granular cell tumor In the AFIP series, 39% of malignant granular cell tumors with follow-up information succumbed to disease within a median interval of 3 years Unfavorable prognostic indicators: older age, large tumor size, local recurrence, metastasis, Ki-67 labeling index greater than 10%, & p53 immunoreactivity Behavior of atypical granular cell tumor appears to be the same as conventional granular cell tumor None of the atypical AFIP cases metastasized Still recommend complete excision of atypical granular cell tumors given the limited experience with this entity Differential: Malignant granular cell tumor Other tumors with eosinophilic cytoplasm & significant atypia Melanoma positive for melanocyte specific markers (e.g., HMB45, Melan-A & MiTF) Other S100+, melanocyte marker negative tumors (NST) Myoepithelial carcinoma Variable positivity for cytokeratins, EMA, p63, calponin & smooth muscle actin Epithelioid MPNST Lobulated growth pattern, lacks granular cytoplasm Loss of INI1 staining (50% of cases) is helpful in confirming the diagnosis 41-year-old female with a multinodular mass of her right index finger

27 S-100 GFAP Diagnosis? Nerve sheath myxoma

28 Clinicopathologic features: Nerve sheath myxoma Young to middle aged adults (3 rd -5 th decades), M=F Extremities (particularly hands & fingers), head & neck Flesh-colored papules or nodules Nodular growth pattern, fibrous septae Paucicellular, abundant myxoid stroma, avascular Bland spindled to stellate cells S-100 protein, GFAP and type IV collagen Extremities, local recurrence (40%-50%), complete excision 163 Differential: Nerve sheath myxoma Myxofibrosarcoma Subcutis of the extremities of older adults Atypia & pleomorphism, distinict curvilinear vasculature S100- Acral fibromyxoma Lacks multinodular growth S100- Plexiform neurofibroma with myxoid change NF1 Cells with buckled nuclei, shredded carrot collagen bundles S100 not as uniform & strong as in nerve sheath myxoma Differential: Nerve sheath myxoma Cellular neurothekeoma Nodular to nested appearance, less compact, less myxoid & not separated by distinct fibrous septations in most cases Epithelioid to spindled cells with more abundant eosinophilic cytoplasm Variably positive for non-specific markers NKI/C3, PGP9.5, CD68, MiTF & SMA Negative for S100 protein & GFAP Key pathologic features: Dermal nerve sheath myxoma Myxoid nodules separated by fibrous septae Spindled to stellate cells in myxoid stroma S100+ and GFAP+ Benign, but local recurrence rate ~40-50% A 72-year-old female presented with an ulcerated, polypoid, right upper arm tumor

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30 S-100 Cutaneous MPNST arising in neurofibroma MPNST 5-10% of all STS 25-50% in setting of NF1 10% lifetime risk 30% in patients with symptomatic PNF Long latency (10 to 20 yrs) 10-20% therapeutic or occupational radiation (>15 yr latency) Subset epithelioid (E-MPNST) Heterologous differentiation may be seen MPNST: Clinical Features years of age (median 35) Present earlier & with larger lesions in NF1 M > F in NF1 Ratio equal in sporadic cases Enlarging mass arising from major nerve trunk Sensory & motor symptoms Sudden pain and enlargement in the setting of NF1 should prompt immediate bx Cutaneous MPNST Most often seen in association with NF1 E-MPNSTs typically not NF1 associated Nearly all arise in pre-existing diffuse NF E-MPNST may arise in schwannomas Most low-grade with spindle cell morphology 5% E-MPNST In general indolent protracted course as compared to deep seated counterparts 30

31 Key pathologic features: Malignant peripheral nerve sheath tumor (MPNST) Rare Often arise in association with precursor neurofibroma Conventional MPNST Fascicles of atypical hyperchromatic spindled cells Variably positive for S100 Frequent loss of histone H3K27 methylation Epithelioid MPNST Sheets of atypical epithelioid cells Strongly positive for S MPNST in NF MPNST in NF MPNST in NF 31

32 Cutaneous Epithelioid MPNST Epithelioid malignant cells May arise from schwannomas Infrequent associated with NF1 Most superficial LE, trunk Mostly adults but wide age range Diffuse S-100+, 2/3 loss of INI-1 Low risk for recurrence & metastases, recent series suggests aggressive potential Complete excision & LTFU Luzar B, Shanesmith R, Ramakrishnan R, Fisher C, Calonje E. Cutaneous epithelioid malignant peripheral nerve sheath tumor: a clinicopathological analysis of 11 cases. Histopathology 2016; 68(2): Epithelioid MPNST Immunohistochemistry Subset express markers of Schwann cell differentiation SOX 10 (30%) S-100 (40-50%, often focal) Epithelioid & superficial MPNSTs may be strongly & diffusely positive GFAP (30%) HMB45, Melan-A, MiTF, tyrosinase negative No marker sensitive & specific enough to establish diagnosis with certainty S-100 Differential of Superficial MPNST Melanoma CCS CBN Fibrosarcomatous DFSP Metaplastic carcinoma Myxofibrosarcoma LMS AFX Metastatic sarcoma Atypical neurofibroma Cellular schwannoma Cellular BFH 32

33 194 MPNST: Molecular & Cytogenetic Findings Many complex karyotypic abnormalities described Gains: 7p, 8q & 17q Losses: 9p, 11q, 13q, 17p Homozygous deletion of CDKN2A common Germ line mutations in NF1 Biallelic mutations of NF1 seen in high percentage of MPNSTs Recent evidence suggest stepwise molecular progression from NF to ANF to MPNST Conventional MPNST Alterations Gains: 5q22, 7p, 7q36, 17q, 18p11 Losses: 1p, 3p, 4p, 9p, 10p, 13q33, 17p, Chromothripsis: 10q, 17q, 19q, 20, 22 Neurofibroma MPNST (6 cases) Neurofibroma (3 cases) Alterations None 33

34 MPNST (6 cases) MPNST (6 cases) Neurofibroma (3 cases) Neurofibroma (3 cases) NF1 deletion SNP array: MPNST component SNP array: MPNST component NF component MPNST Gains: 5p, 8q, 11, 22 Losses: 2, 5q, 8p, 9p, 12, 15, 15, 17q11.2 (NF1), 19 MPNST Gains: 5p, 8q, 11, 22 Losses: 2, 5q, 8p, 9p, 12, 15, 15, 17q11.2 (NF1), 19 NF Gains: 5p, 8q Losses: 17q11.2 (NF1) Key Points Dermatopathology Molecular Diagnostic and Research Laboratory MPNST may superficial locations both sporadically & in patients with NF1 Must be distinguished from histologic mimics as treatment & prognosis differ Superficial MPNST generally have a more indolent & protracted course as compared to deep seated counterparts Diagnosis of conventional MPNST are relatively straightforward for the experience observer Borderline & difficult to classify lesions remain problematic for generalists & experts Rapidly evolving area with many new developments Min Wang Doru Andea 34

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