Cutaneous Mesenchymal Neoplasms with EWSR1 Rearrangement
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1 Cutaneous Mesenchymal Neoplasms with EWSR1 Rearrangement 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
2 Financial disclosures Book Royalties
3 Y.Oda et al, Pathology International 2017;67:
4 Ewing Sarcoma/Primitive Neuroectodermal Tumor (ES/PNET)
5
6 Can occur at any body site Extremities most common Followed by trunk and Head&Neck regions Usually small (<2.5cm) and localized to the dermis and subcutis Metastasize less frequently comparing to bone and soft tissue counterparts Clinico-radiological correlation critical to exclude metastasis
7 (Adv Anat Pathol 2013;20:75 85)
8 Annals of Diagnostic Pathology 11 (2007)
9 Adamantinoma-like ES
10 CD99
11 Pancytokeratin Desmin (Am J Surg Pathol 2005;29: )
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13 Fluorescent In Situ Hybridization (FISH) for EWSR1 J Cutan Pathol 2011: 38:
14 CD99
15 ERG IHC ERG is a useful marker for confirming endothelial differentiation in both benign and malignant neoplasms Potentially useful marker to distinguish Leukemia Cutis vs reactive myeloid infiltrates Expression can also be seen in a subset of epithelioid sarcomas and a small percentage of Ewing sarcomas, as well as approximately 45% to 50% of prostatic carcinomas. ERG can be seen in selected bone and soft tissue tumor with cartilaginous differentiation Phosphaturic mesenchymal tumor
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18 Ewing Sarcoma with EWSR1- ERG FLI1 ERG
19 Ewing sarcoma with EWSR1-FLI1
20 EWSR1, FLI1, ERG and their fusion proteins in Ewing Sarcoma
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25 Ewing Sarcoma CIC-DUX4
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27 PAX7 a sensitive marker for Ewing Sarcoma Positive in NKX2-2 negative cases Also positive in both common and variant forms of Ewing Sarcoma PAX7 expression differentiates Ewing Sarcoma from CIC-DUX4 sarcoma
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31 To date IHC focused on the aberrant expression of one of the genes involved in the pathogenic translocation WT1 in DSMRCT (EWSR1-WT1) STAT6 in SFT (NAB2-STAT6) FLI1 in Ewing Sarcoma (ESWR1-FLI1) BCOR in undifferentiated sarcomas PAX7 in ES exploits a characteristic transcriptional read-out of the diseasecausing translocation
32
33 Differential Diagnosis Round blue cell tumors Lymphoblastic lymphoma Merkel cell carcinoma Small cell melanoma Poorly differentiated synovial sarcoma Rhabdomyosarcoma CIC and BCOR re-arranged round cell sarcomas
34 Lymphoblastic lymphoma Diffusely positive for CD99 and Fli-1 Often CD45 negative ERG often negative but may be expressed in myeloid leukemia Always include TdT, CD10 and CD43
35 Metastatic small cell carcinoma Usually lacks CD99 More extensive immunoreactivity for cytokeratins, synaptophysin, chromogranin and CD56 Merkel cell carcinoma Diffusely express neuroendocrine markers More specific cytokeratins such as CK20 IHC for Merkel cell polyoma virus large T antigen Small cell melanoma Strongly positive for Melan-A, HMB45, SOX-10
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37 Poorly differentiated Synovial Sarcoma Typically more classic areas of monophasic and biphasic synovial sarcoma Positive for high-molecular weight keratins Positive of TLE-1 Negative for FLI-1/ERG Alveolar rhabdomyosarcoma Greater nuclear variability Positive for myogenin and Myo-D1
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39 Angiomatoid Fibrous Histiocytoma (AFH)
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47 DESMIN EMA CD68
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49 t(2;22)(q33;q12) EWSR1/CREB1 t(12;22)(q13;q12)=ewsr1/atf1 t(12;16)(q13;p11)= FUS/ATF1
50 Differential Diagnosis Metastasis involving a lymph node Undifferentiated pleomorphic sarcoma Vascular tumor Benign fibrous histiocytoma with prominent intratumoral hemorrhage Ewing Sarcoma in cases with small cell morphology Follicular dendritic cell tumors
51 Myoepithelial Tumors
52 Cutaneous myoepithelial tumors Chondroid syringoma (mixed tumor) Tubuloductal differentiation Rearrangement of the PLAG1 gene (8q12) Cutaneous myoepithelioma Pure myoepithelial cell population Myoepithelial carcinoma
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58 S100 EMA AE1/AE3
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61 INI1 Absence of INI1 in myoepithelial carcinomas 10% (adults) 40% (children)
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64 EMA S100 AE1/AE3 GFAP
65 EWSR1-POU5F1 EWSR1-ZNF444 EWSR1-PBX1 EWSR1-ATF1
66
67
68 Differential Diagnosis Epithelioid fibrous histiocytoma Early stage juvenile xanthogranuloma Epithelioid sarcoma Spitz nevus
69 Prognosis and treatment Cutaneous myoepithelioma has a benign clinical course Local recurrence in 20% of cases Syncytial subtype very low local recurrence rate Myoepithelia carcinomas (also contain EWSR1 rearrangements) pursue a more aggressive clinical course
70 Clear Cell Sarcoma
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72 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
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74 S100-Protein Melan-A
75
76 t(12;22)(q13;q12) EWSR1-ATF1 t(2;22)(q34;q12) EWSR1-CREB1
77
78
79 Differential Diagnosis Melanoma Perivascular Epithelioid Cell Neoplasm (PEComa) Cellular Blue Nevus Cutaneous Melanocytoma with CRTC1- TRIM11 Fusion
80 Cellular Blue Nevus
81 Melanoma ex blue nevus
82
83 HMB45
84
85
86
87
88 S100-Protein NTRK1 HMB45 MelanA TRIM11
89 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)
90 Benign/Low Grade Fibroblastic Tumors Calcifying aponeurotic fibroma Recurrent FN1-EGF fusion Fibrous hamartoma of infancy EGFR internal tandem duplications Myofibroma/myopericytoma PDGFR mutations Lipofibromatosis-like neural tumors Recurrent NTRK1-related gene fusions
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92
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94 ERG
95 ERG
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100 EWSR1
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105 Specific gene breakpoints Cell type in which the fusion occurs Tissue site/microenviroment Epigenetic changes Other genetic alterations
106 Morphology, Morphology, Morphology 100% Job Security!!!
107 KonstantinosLin
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