Cellular Neurothekeoma

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1 Cellular Neurothekeoma Scott W Binder, MD Pritzker Professor of Pathology & Dermatology Sr. Vice Chair Director, Pathology Clinical Services Chief, Dermatopathology Geffen/UCLA School of Medicine Clinical Predilection for the upper limbs and head and neck Young female pts (mean 25 years) Present as solitary, superficial, slowgrowing painless nodules or masses Mean tumor size: 1.1 cm (range cm) Behave in a benign fashion and rarely recur, if incompletely excised (3.3%) 1

2 Updated January Updated January

3 Updated January Typical histological appearance Non-encapsulated, lobulated or micronodular architecture 3

4 Background of dense hyaline collagen Nests and bundles of epithelioid to spindled cells with palely eosinophilic cytoplasm Mitotic rate: 3/10 HPF Sometimes have atypical features: scattered pleomorphic cells, infiltrative growth into fat or skeletal muscle, vascular invasion, perineural invasion, and high mitotic rate (>10/HPF) Mild cytologic atypia with nuclear variability and small nucleoli Background of dense hyaline collagen 4

5 Immunohistochemical Profile Positive NKI/C3 (100%) NSE (66-89%) CD10 (97-100%) MITF (81-100%) Immunohistochemical Profile S100A6 (95-100%) PGP9.5 (60%) Focal SMA (20-57%) CD68 (50-59%) All negative for S-100 (100%) 5

6 Molecular studies Of probable fibrohistiocytic origin based on microarray-based gene expression profile studies done in our institution (2010) Principal component analysis using 452 differentially expressed genes between neurothekeomas and nerve sheath myxomas demonstrates one major group composed of schwannomas and nerve sheath myxomas and another major group composed of neurothekeomas and cellular fibrous histiocytomas (>threefold change; P-value <0.005). Histologic overview of variants myofibroma-like variant xanthomatous variant chondroid-like variant diffuse variant with abundant inflammation epithelioid variant granular cell variant 6

7 Myofibroma-like variant nests of cells fibrotic dermis dome-shaped proliferation hyalinized fibroblastic tissue separates nests tumor cells are cytologically bland with round to oval nuclei cells that demonstrate an unusual blue tinged cytoplasmic hue 7

8 Xanthomatous Variant fibrotic dermis dome-shaped proliferation hyalinized fibroblastic tissue separates nests clear cells with foamy cytoplasm tumor cells are cytologically bland with round to oval nuclei 8

9 low mitotic index xanthomatous-like cells Tumor cells are bland Diffuse Variant with Inflammation Case 2 Case 1 9

10 Diffuse with Inflammation #1 Fibrotic dermis Diffuse proliferation Tumor cells are cytologically bland with a fibrohistiocytic appearance Hyalinized stroma Eosinophils and lymphocytes 10

11 Diffuse with Inflammation #2 lymphocytic infiltrate Proliferation of spindle and epithelioid cells Pale histiocytoid and spindle cells Lymphoid infiltrate 11

12 Granular cell variant Granular cell NK Non-neural Granular Cell Tumor Granular cell variant Hyalinized collagen bundles Dome-shaped proliferation 12

13 Low mitotic index No nuclear pleomorphism Hyalinized background stroma Bland epithelioid cells with granular cytoplasm 13

14 NNGCT (Non-neural granular cell tumor) Low mitotic index No nuclear pleomorphism 14

15 Bland epithelioid cells with granular cytoplasm 15

16 Molecular Findings 54 genes in common between NK and variants. Most of these genes are expressed by fibroblasts or macrophages, pointing to their similar fibrohistiocytic origin fibroblast growth factor 5, platelet-derived growth factor receptor-like, platelet-derived growth factor receptor, alpha polypeptide, platelet derived growth factor D, chemokine (C-C motif) ligand 13, beta 5 integrin, lysyl oxidase, collagen type X alpha 1 VARIANT NK TYPICAL NK Conclusions Variants of cellular NK with bland cytologic features exist (we note 6 different variants) myofibroma-like variant xanthomatous variant chondroid-like variant diffuse variant with abundant inflammation epithelioid variant granular cell variant 16

17 Conclusions These variants of cellular NK are closer to a fibrohistiocytic origin than a neural one Immunohistochemical stains are important in diagnosing these variants as they are morphologically different from the typical cellular NK, although their IHC pattern is the same (always S100 negative; NKI/C3 positive, and usually at least focally positive for NSE and MITF) NNGCT is molecularly different from the granular variant of cellular NK This study is limited by the small sample size of each of the variants. More samples of each of the variants is required in order to accurately investigate their molecular characteristics References Busam KJ, Mentzel T, Copaert C, et al. Atypical or worrisome features in cellular neurothekeoma. Am J Surg Pathol. 1998;22: Fetsch Jf, Laskin WB, Hallman JR, et al. Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and long-term patient follow-up information. Am J Surg Pathol. 2007; 31: Hornick JL, Fletcher CDM. Cellular neurothekeoma: detailed characterization in a series of 133 cases. Am J Surg Pathol. 2007;31: Bhatia S, Chu P, Weinberg JM. Atypical cellular neurothekeoma. Dermatol Surg. 2003;29: Campanati A, Brandozzi G, Sisti S, et al. Atypical neurothekeoma: a new case and review of literature. J Cutan Pathol. 2007;34: Mertz K, Mentzel T, Grob M, et al. A rare case of atypical cellular neurothekeoma in a 68-year-old woman. J Cutan Pathol. 2009;36: Sheth S, Li X, Binder S, et al. Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis. Mod Pathol. 2011;24: Stratton J, Billings SD. Cellular neurothekeoma: analysis of 37 cases emphasizing atypical histologic features. Mod Pathol. 2014;27: Fried I, Sitthinamsuwan P, Muangsomboon S, et al. Sox-10 and MiTF expression in cellular and mixed neurothekeoma. J Cutan Pathol. 2014;41: Satoh T, Narisawa Y. Cellular neurothekeoma with histiocytic differentiation. J Cuan Pathol. 2004;31: King R, Mihm MC, Googe PB. Microphthalmia transcription factor and NKI/C3 expression in cellular neurothekeoma. Mod Pathol. 2004;17: Chu P, Weinberg JM. Atypical cellular neurothekeoma. Dermatol Surg. 2003;29: Gleason BC, Thomas AB, Billings SD, et al. Cellular neurothekeoma with fascicular growth features mimicking cellular dermatofibroma. Am J Dermatopathol. 2011;33: White WL, McCalmont TH. Desmoplastic cellular neurothekeoma: clinicopathological analysis of twelve cases. J Cutan Pathol. 2009;36: Lazar AJ, Fletcher CD. Primitive nonneural granular cell tumors of skin: clinicopathologic analysis of 13 cases. Am J Surg Pathol. 2005;29: Chaudhry IH, Calonje E. Dermal non-neural granular cell tumor (so-called primitive polypoid granular cell tumor): a distinctive entity further delineated in a clinicopathological study of 11 cases. Histopathology. 2005;47: Yeh I, Tran DT, Davis TL, et al. An infiltrative variant of non-neural granular cell tumor: a case report. J Cutan Pathol. 2009;36 Suppl 1: Habeeb AA, Weinreb I, Ghazarian D. Primitive non-neural granular cell tumor with lymph node metastasis. J Clin Pathol. 2009;62:847. Newton P, Schenker M, Wadehra V, et al. A case of metastatic non-neural granular cell tumor in a 13-year-old girl. J Cutan Pathol. 2014;41:

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