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1 Mesenchymal Neoplasms with Melanocytic Differentiation By Konstantinos Linos MD, FCAP, FASDP Bone, Soft Tissue and Dermatopathology Assistant Professor of Pathology Dartmouth-Hitchcock Medical Center Geisel School of Medicine at Dartmouth Hanover, NH, USA Financial disclosures Book Royalties Melanotic Schwannoma Perivascular Epithelioid Cell Tumor (PEComa) Clear Cell Sarcoma Clear Cell Sarcoma-like Tumor of the GI Tract Malignant Peripheral Nerve Sheath Tumor Epithelioid Schwannoma 1

2 Melanotic Schwannoma Rare tumor of putative neural crest origin Most often in paraspinal nerve roots and gastrointestinal tract Association with other stigmata of Carney complex Skin pigmentary abnormalities, myxomas, endocrine tumors/endocrine hyperactivity Unknown cell of origin Hybrid light microscopic and ultrastructural features of Schwann cells and melanocytes Unpredictable behavior 13-26% metastases including histologically benign-appearing tumors 2

3 3

4 Myxoid Change Small cell pattern Rippled pattern Bone Invasion Pulmonary Metastasis 4

5 S100-protein HMB45 Loss of PRKRA1 5

6 Melanotic Schwannoma vs Melanoma No individual clinicopathologic features that are completely specific Melanotic Schwannoma Paravertebral, predominantly spindled, heavy melanin pigmentation, psammoma bodies, striking nuclear pleomorphism with low mitotic activity Detailed clinical history Careful dermatologic examination Gene Expression Profiling 6

7 Perivascular Epithelioid Cell Tumor (PEComa) Mesenchymal tumor composed of perivascular epithelioid cells (PEC) Distinctive neoplastic cell with no known normal counterpart Unique as it shows immunoreactivity for both melanocytic and smooth muscle markers Group of mesenchymal neoplasms Angiomyolipoma Clear cell sugar tumor of the lung and extrapulmonary sites Lymphangioleiomyomatosis Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres 7

8 Histologic Features Ill-defined dermal proliferation of epithelioid cells Arrangement in nests and trabeculae within an arborizing network of delicate capillaries Uniform round to ovoid vesicular nuclei Pink clear or granular cytoplasm Nuclei usually bland Low-mitotic activity Occasional multinucleated giant cells Immunohistochemistry Distinct immunophenotype Melanocytic HMB45, MiTF, Melan-A., tyrosinase Smooth muscle Desmin, SMA, calponin HMB45 the most sensitive Primary cutaneous less likely to demonstrate immunoreactivity for smooth muscle 8

9 9

10 HMB45 MelanA Desmin HMB45-94% MelanA- 35% NKI/C3-100% MiTF- 100% MSA-17% SMA-42% Desmin-30% Calponin-15% Caldesmon-8% 10

11 11

12 Differential Diagnosis Balloon Cell Nevus Clear cell melanoma Clear cell sarcoma Lack of strong diffuse positivity for S100-protein and SOX10 Dermal Clear Mesenchymal Neoplasm (DCCMN) Metastatic clear cell carcinoma Positive for PAX8, RCC, negative for melanocytic markers S100-protein and/or SOX10 MelanA HMB45 SMA Desmin Prognosis 12

13 Clear Cell Sarcoma 13

14 Usually lesions relatively small (<5cm) Primary cutaneous <1cm Otherwise similar clinical and pathologic features Natural history clinically protracted Multiple local recurrences Late metastases in lymph nodes, lung, bone Wide local excision with adjuvant radiation S100-Protein Melan-A 14

15 t(12;22)(q13;q12) EWSR1-ATF1 t(2;22)(q34;q12) EWSR1-CREB1 15

16 Differential Diagnosis Melanoma Perivascular Epithelioid Cell Neoplasm (PEComa) Cellular Blue Nevus Cutaneous Melanocytoma with CRTC1- TRIM11 Fusion 16

17 Cellular Blue Nevus Melanoma ex blue nevus 17

18 18

19 S100-Protein NTRK1 HMB45 MelanA TRIM11 No activating mutations of the MAP-kinase pathway such as BRAF and NRAS No htert mutations In some cases only a whole gain of chromosome 7 No local recurrences or metastatic evolution (short follow-up) Clear Cell Sarcoma-like Tumor of the GI Tract Similar morphologic, immunophenotypic and molecular genetic features with clear cell sarcoma of tendons and aponeuroses However many lack evidence of melanocytic differentiation EWSR1-CREB1>> or EWSR1-ATF1 fusions 19

20 20

21 S100-Protein SOX-10 Synaptophysin CD56 21

22 Cutaneous Malignant Peripheral Nerve Sheath Tumor Defined as an MPNST predominatly localized in the dermis and/or subcutis In contrast to their deep soft tissue and visceral counterparts rarely a/w with NF1 Two main subtypes Conventional/spindled Epithelioid 22

23 S100 23

24 S100-protein INI-1 MelanA 24

25 S100 INI1 25

26 26

27 S100 SOX10 EMA KonstantinosLin 27

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