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Appendix: Practical Approach to Neural Tumors – Flowcharts and Differential Diagnostic Tables

Table A.1 Classification of cutaneous neural tumors Cutaneous peripheral sheath proliferations Hamartomas True neuromas Palisaded encapsulated neuroma/solitary circumscribed neuroma Mucosal neuroma Fibrolipomatous hamartoma of nerve Other nonneoplastic and hyperplastic proliferations Traumatic neuroma Reparative perineurial Morton’s neuroma (interdigital neuritis) Epithelial sheath neuromaa Benign Neurofibromaa Granular cell tumor Nerve sheath myxoma Perineurioma Lipoblastic nerve sheath tumora Malignant neoplasms Malignant peripheral Malignant granular cell tumor Cutaneous proliferations of putative neural origin/differentiation Benign neoplasms Neurothekeoma Malignant neoplasms Primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma) Neurofollicular hamartoma Cutaneous neuroblastic and ganglionic proliferations Benign neoplasms Ganglion cell choristomaa Malignant neoplasms Cutaneous glial and meningothelial proliferations Heterotopias Glial heterotopia (nasal ) Meningothelial heterotopia/meningocele Benign neoplasms Cutaneous aThe etiologic nature of these entities is disputed or not decidedly established. Neuro­ fibroma is included under the neoplastic group for historical purposes

Z. Argenyi and C.H. Jokinen (eds.), Cutaneous Neural Neoplasms, Current Clinical Pathology, 127 DOI 10.1007/978-1-60327-582-8, © Springer Science+Business Media, LLC 2011 128 Appendix EMA variable, +/− variable, only a few few a only ** LMWK, CHG CD99, MB-2 Desmin CD68, lysozyme SMSA, NC1/3 Other/miscellaneous low molecular weight molecular low LMWK − ** NA −** NA − −/+ − +/− −/+ −/+ + + +/− ++ CD34 +/− + + + − + − − − − − − − − − SY PNECS neuroendocrine carcinoma of the glial fibrillaryGFAP acidic protein, reaction only at nerve of origin, of nerve at only reaction * − +/− + +/− + ++ ++ ++ + ++ ++ ++ ++ ++ ++ VIM usually strong immunoreactivity, +++ usually strong immunoreactivity, + − − − ++ − − − + − +capsule +capsule ++ +capsule −/+ EMA not applicable, not NA MPB myelin basic protein, − − +/− − − +++ − − − − − − − −/+ −/+ GFAP antibody to B-cell lymphoid determinations, lymphoid B-cell to antibody MB-2 − +/− +/− +/− − −/+ +/− + − − −/+ ++ ++ ++ +/− MBP fairly consistent reactivity, ++ fairly consistent reactivity, PNET peripheral neuroectodermal tumor, negative immunoreactivity, immunoreactivity, negative − NSE -specific enolase, − +/− +/− +/− − −/+ +/− + − −/+ +/− ++ ++ ++ +/− CD57 (Leu-7) + + + + −/+ + +/− + − −/+ −/+ ++ ++ ++ ++ NSE antibody to p30/32 mic2, p30/32 to antibody CD99 weak or focal immunoreactivity, + weak or focal immunoreactivity, + −/+ +/− − − +/− +/− − − − − +++ +++ −* + NF NF neural filaments, synaptophysin, synaptophysin, SY − − + − −/+ +/− +/− + +/− −/+ + +++ +++ +++ ++ Coll IV MPNST malignant peripheral nerve sheath tumor, − −/+ + −/+ −/+ + +/− ++ − − + +++ +++ +++ ++ S-100 variable, immunoreactivity often absent, often immunoreactivity variable, −/+ vimentin, VIM melanoma marker, NC1/3 melanoma marker, Coll IV collagen type IV, Main immunohistochemical findings of common cutaneous neural neoplasms

CHR chromogranin, S-100 S-100 protein, PNECS Cutaneous neuroblastoma PNET Cutaneous meningioma Nasal glioma MPNST Granular cell tumor Perineurioma Cellular neurothekeoma Nerve sheath myxoma Nerve PEN Traumatic neuroma Traumatic Schwannoma epithelial membrane antigen, membrane epithelial skin, PEN palisaded encamsulated neuroma, keratin, cases studied immunoreactivity often present, often immunoreactivity Ganglioneuroma Tumor Table A.2 Marker Appendix 129 PSCN Mid or upper dermis Plexiform fascicles fascicles Plexiform in wedge-shape None Spindle cells, some with mucin Mild Rare None None None Periadnexal, Periadnexal, perineurial spread plexiform fibrohis - plexiform PFHT PFHT Deep dermis or subcutis Plexiform and Plexiform multinodular None Fibroblasts cells Histiocytic Giant cells Rarely None to rare None None None Lymphocytes Microhemorrhages classical nerve sheath myxoma, sheath nerve classical CNSM CNSM Superficial or deep dermis Lobulated or plexiform Lobulated Yes, superficially Yes, incomplete Spindle and stellate cells Giant cells Rarely None to rare None None None Lymphocytes, abundant abundant Lymphocytes, mucin plexiform schwannoma, schwannoma, plexiform PS PS Superficial or deep dermis Plexiform and Plexiform multinodular Yes Spindle cells cells) (Schwann Often None to rare, but not None to rare, but abnormal Frequent Frequent None Predominantly hypercellular plexiform neurofibroma, plexiform PNF Schwann cells Schwann Perineurial cells Fibroblasts PNF Deep dermis or subcutis Plexiform Yes, superficially Yes, incomplete Spindle cells: None (if present may indicate malignancy) None None to rare None Rare, scattered Focally increased mucin Focally or fibrosis PPEN Superficial dermis Plexiform or Plexiform multinodular Yes, superficially Yes, incomplete Uniform spindle cells cells) (Schwann None None Yes, variable Yes, Rare Usually abundant Focal fibrosis and Focal mucin increase Histologic differential diagnostic features of cutaneous neoplasms with plexiform growth diagnostic features of cutaneous neoplasms with plexiform Histologic differential

Table A.3 Location in the skin the in Location Growth pattern Growth Encapsulation Constituent cell types Cytologic pleomorphism Mitotic figures Nuclear palisading Verocay bodies Verocay Nerve fibers Nerve plexiform spindle cell nevus PSCN plexiform tumor, tiocytic 1993;20:97–108 in cutaneous neural neoplasms. J Cutan Pathol. ZB. Recent developments Adapted with permission from Argenyi Other features plexiform, palisaded, encapsulated neuroma, encapsulated palisaded, plexiform, PPEN 130 Appendix NSE CEA − − − +/− + − CD99 DES desmin, − − − − +/− +/− NF CK cytokeratin, − + − − − + NSE SYN synaptophysin, + − − − − − AC S-100 S-100 protein, + − − − − − DES actin, AC − − − − +/− − Leu-7 CHG chromograninm, − − − − +/− − SYN NF neural filaments, VIM fimentin, − − − − +/− + CHG + + − + + − VIM − − − + − − LCA LCA leukocyte common antigen, − − + − − + EMA PNET peripheral neuroectodermal tumor, − − + − − − CEA − − + − − + CK EMA epithelial membrane antigen, +/− + +/− − − − S-100 Immunohistochemical reactivity of small round cell cutaneous tumors Immunohistochemical reactivity

variable present in primary mature , + present, − absent, +/− variable neuron specific enolase, CD99 antibody to p 30/32, *CD99 may not be expressed PNECS primary neuroendocrine carcinoma of the skin, carcinoembryonic antigen, Embryonal rhabdomyosarcoma Small cell melanoma Poorly differentiated Poorly differentiated eccrine carcinoma Malignant lymphoma PNET (neuroblastoma) PNECS (Merkel PNECS (Merkel cell tumor) Table A.4 Appendix 131

How to approach a slide with probable neural ? Surface Configuration and epidermal changes

Location Relationship to normal adjacent? Growing pattern structures

Structure

Evidence of Cell type neural differentiation?

Nerve fascicles Sensory end organs Cell products Schwann cells

Synthesis of Information

Special features

SPECIFIC DIAGNOSIS

Fig. A.1 How to approach a slide with probable neural neoplasm? (artwork by ZA) 132 Appendix An algorithmic approach of the diagnosis common cutaneous neural neoplasms (artwork by ZA)

Fig. A.2 Index

C polypoid dermal mass, 116 Cutaneous meningioma Schwann cells, 116 clinical findings, 121–122 silver impregnation, 117 definition, classification, and histogenesis, 121 S-100 protein expression, 117 differential diagnosis, 123 Granular cell tumor histopathology, 122–123 clinical findings, 68 Cutaneous neural tumors definition, classification and histogenesis, 68 cytogenetics, 11 differential diagnosis, 70–71 immunohistochemical findings, 7, 8 histopathology, 68, 70 luxol fast blue histochemical stain, 7, 10 , 11 H perineurial sheath, 11, 13–14 Hamartomas (neuromas), 15 peripheral nerve fascicle, 7, 9 silver impregnation, 7, 10 S-100 protein stains, 7, 9 L unmyelinated axons, 11, 12 Lipoblastic nerve sheath tumor, 81 Cytogenetics, 11

M E Malignant granular cell tumor, 90 Epithelial membrane antigen (EMA), 16 Meningocele Epithelial sheath neuroma clinical findings, 124 clinical findings, 33 definition, classification and histogenesis, definition, classification and histogenesis, 33 123–124 differential diagnosis, 34 differential diagnosis, 126 histopathology, 34 histopathology, 124–126 Morton’s neuroma (interdigital neuritis) clinical findings, 31 F definition, classification and histogenesis, 31 Fibrolipomatous hamartoma (FLH) differential diagnosis, 31 clinical findings, 26 histopathology, 31 definition, classification and histogenesis, 25 Mucosal (mucocutaneous) neuroma differential diagnosis, 26 clinical findings, 21–22 histopathology, 26 definition, classification and histogenesis, 21 differential diagnosis, 25 histopathology, 22–25 G Multiple endocrine neoplasia (MEN), 15 Ganglion cell choristoma (GCC), 118 Ganglioneuroma classification, 115 N clinical findings, 115 Nasal glioma definition, 115 clinical findings, 119, 120 differential diagnosis, 118 definition, classification and histogenesis, 119 histogenesis, 115 differential diagnosis, 120–121 neurofilaments immunostain, 117 histopathology, 119–121

133 134 Index

Nerve sheath myxoma (NSM) PEN clinical findings, 71–72 clinical findings, 15 definition, classification and histogenesis, 71 definition, classification and histogenesis, 15 differential diagnosis, 74, 76 differential diagnosis, 21 histopathology, 72, 74 histopathology, 15–16 Neuroblastoma proliferation, 15 clinical finidings, 113 reparative perineurial hyperplasia definition, classification and histogenesis, 113 clinical findings, 33 differential diagnosis, 115 definition, classification and histogenesis, 33 histologic features, 113–115 differential diagnosis, 33 Neurofibroma (NF) histopathology, 33 atypical/cellular, 39 traumatic neuroma Bodian stain, 42 clinical findings, 26 clinical findings, 37 definition, classification and histogenesis, 26 collagen-rich stroma, 43 differential diagnosis, 28, 31 definition, classification and histogenesis, 37 histopathology, 28 dendritic cell, 39 Nuclear palisading, 57 differential diagnosis, 50, 52 diffuse, 38–39 epithelioid, 47, 49 P immunohistochemical profile, 37, 39 Palisaded encapsulated neuron (PEN) lipomatous, 49–50 clinical findings, 15 myxoid, 47 definition, classification and histogenesis, 15 perineurioma-like, 49 differential diagnosis, 21 pigmented, 47 histopathology, 15–16 plexiform, 39 Perineurioma pseudomeissnerian bodies, 44 clinical findings, 76 Schwann cell nodules, 44 definition, classification and histogenesis, 76 Neurofollicular hamartoma (NFH) differential diagnosis, 81 clinical findings, 109 histopathology, 76, 78, 81 definition, classification and histogenesis, 109 Peripheral nerve and cutaneous neural tumors differential diagnosis, 109, 111 axons, 2 histopathology, 109 ectopias and heterotopias, 5 Neurothekeoma (NTK) endoneurium, 1–2 clinical findings, 93 , 3 definition, classification and histogenesis, 93 hamartomas, 5 differential diagnosis, 101, 103 neoplasm, 3, 5 histopathology, 93, 101 nerve fascicle, 1, 2 Non-neoplastic and hamartomatous lesions perineurium, 2–3 epithelial sheath neuroma primary neuroendocrine carcinoma (Merkel cell clinical findings, 33 carcinoma), 6 definition, classification and histogenesis, 33 Schwann cells, 1 differential diagnosis, 34 sensory information transmission, 1 histopathology, 34 Peripheral nerve differentiation FLH granular cell tumor clinical findings, 26 clinical findings, 68 definition, classification and histogenesis, 25 definition, classification and histogenesis, 68 differential diagnosis, 26 differential diagnosis, 70–71 histopathology, 26 histopathology, 68, 70 Morton’s neuroma (interdigital neuritis) lipoblastic nerve sheath tumor, 81 clinical findings, 31 malignant granular cell tumor, 90 definition, classification and histogenesis, 31 NF differential diagnosis, 31 atypical/cellular, 39 histopathology, 31 Bodian stain, 42 mucosal (mucocutaneous) neuroma clinical findings, 37 clinical findings, 21–22 collagen-rich stroma, 43 definition, classification and histogenesis, 21 definition, classification and histogenesis, 37 differential diagnosis, 25 dendritic cell, 39 histopathology, 22–25 differential diagnosis, 50, 52 Index 135

diffuse, 38–39 Putative neural differentiation epithelioid, 47, 49 NFH immunohistochemical profile, 37, 39 clinical findings, 109 lipomatous, 49–50 definition, classification and histogenesis, 109 myxoid, 47 differential diagnosis, 109, 111 perineurioma-like, 49 histopathology, 109 pigmented, 47 NTK plexiform, 39 clinical findings, 93 pseudomeissnerian bodies, 44 definition, classification and histogenesis, 2, 93 Schwann cell nodules, 44 differential diagnosis, 101, 103 solitary, 37–38 histopathology, 93, 101 NSM PCNC clinical findings, 71–72 clinical findings, 103–104 definition, classification and histogenesis, 71 definition, classification and histogenesis, 103 differential diagnosis, 74, 76 differential diagnosis, 108–109 histopathology, 72, 74 histopathology, 104, 107 perineurioma clinical findings, 76 definition, classification and histogenesis, 76 R differential diagnosis, 81 Reparative perineurial hyperplasia histopathology, 76, 78, 81 clinical findings, 33 schwannoma definition, classification and histogenesis, 33 clinical findings, 53 differential diagnosis, 33 definition, classification and histogenesis, 52–53 histopathology, 33 differential diagnosis, 68 histopathology, 53 sheath tumor (see Peripheral nerve sheath tumor) S Peripheral nerve sheath tumor Schwannoma classification, 83 ancient, 57 clinical findings, 83 Antoni A areas, 54 definition, 83 cellular, 62–64 differential diagnosis, 90 clinical findings, 53 eosinophilic mass, polygonal cells, 86 definition, classification and histogenesis, 52–53 histogenesis, 83 differential diagnosis, 68 homogenous spindle cells, 87 epithelioid, 57, 62 hypercellularity, 87 nuclear palisading, 57 hyperchromatic spindle cells, 84 pigmented, 68 necrotic areas, 85 plexiform, 64 neoplastic cells, 86 pseudoglandular, 66 neurofibroma, 88, 89 thick collagenous capsule, 54 nodular proliferation, 88 pleomorphism, 88 schwannian differentiation, 88, 90 T subcutaneous neoplasm, 85 Traumatic neuroma subcutaneous nodule, 85 clinical findings, 26 Plexiform fibrohistiocytic tumor (PFHT), 68 definition, classification and histogenesis, 26 Primary cutaneous neuroendocrine carcinoma differential diagnosis, 28, 31 (PCNC) histopathology, 28 clinical findings, 103–104 definition, classification and histogenesis, 103 differential diagnosis, 108–109 V histopathology, 104, 107 Verocay bodies, 57