Surgical Pathology Evening Specialty Conference USCAP 2015
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1 Surgical Pathology Evening Specialty Conference USCAP 2015 John R. Goldblum, M.D. Chairman, Department of Pathology, Cleveland Clinic Professor of Pathology, Cleveland Clinic Lerner College of Medicine Cleveland, Ohio
2 Case History 33-year-old female presents with a 6.4 cm slowly enlarging mass in the soft tissue just proximal to the knee
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7 Tumor Immunophenotype / Molecular Studies CD99 focal + CD34 - Desmin - Myogenin - Cytokeratin (AE1/AE3) - CD43 - CD45 - CD56 + EWSR1 FISH - CD99
8 Original Diagnosis High-grade round cell sarcoma, not further classifiable Long comment (blah, blah) Somewhat resembles Ewing family of tumors but EWSR1 FISH negative
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10 Courtesy of Drs. Patel, Lucas
11 Final Diagnosis CIC-DUX Sarcoma (undifferentiated small round cell sarcoma with t(4;19) CIC-DUX4 fusion)
12 Treatment and Follow-Up Resection of primary tumor followed by local radiotherapy No evidence of disease at 18 months postop
13 Goals of Case Presentation Brief overview of the approach to a round cell tumor Discussion of most useful immunohistochemical stains and molecular diagnostic tests Quick introduction to a relatively new and littleknown entity CIC-DUX sarcoma family
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15 Round Cell Tumors Benign Glomus Tumor Eccrine Spiradenoma Giant Cell Tumor
16 Round Cell Pattern ES/PNET Alv RMS DSRCT Neuroblastoma Small cell/merkel cell Lymphoma Mesenchymal CS Round cell LS Poorly diff SS Ewing-like CIC-DUX BCOR-CCNB3 CIC-FOXO4
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20 CD99
21 ES/PNET: Cytogenetics t(11;22)(q24;q12) FLI1;EWSR1 Translocation NH 2 EWSR1 FLI1 ETS DNA binding domain COOH t(21;22)(q22;q12) t(7;22)(p22;q12) t(17;22)(q12;q12) t(2;22)(q33;q12) ERG/EWSR1 ETV1/EWSR1 FEV/EWSR1 E1AF/EWSR1 Very rare involvement of FUS in lieu of EWSR1
22 EWSR1 (22q12) Break-apart probe t(11;22), t(21;22) ES/PNET (FLI1/EWSR1, ERG/EWSR1) t(11;22) - DSRCT (WT-1/EWSR1) t(12;22), t(2;22) Clear Cell Sarcoma (ATF1/EWSR1), GNET t(9;22) ES Myxoid Chondrosarcoma (NR4A3/EWSR1) t(12;22) Myxoid/Round Cell Liposarcoma (DDIT3/EWSR1) t(2;22) Angiomatoid fibrous histiocytoma (CREB1/EWSR1) t(6;22) Soft tissue myoepithelioma (Pou5F1/EWSR1)
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26 MyoD1/Myogenin part of the Myo-D superfamily of genes encode for DNA binding proteins which activate transcription of skeletal musclespecific genes results in commitment to skeletal muscle differentiation can detect skeletal muscle differentiation at an earlier stage than with markers currently available
27 Myogenin
28 Alveolar Rhabdomyosarcoma t(2;13)(q35;q14) t(1;13)(q36;q14) PAX3/FOXO1A PAX7/FOXO1A *up to 25% lack t(2;13) or t(1;13)
29 Ewing-like Sarcoma CIC-DUX BCOR-CCNB3 CIC-FOXO4
30 CIC-DUX Sarcomas Summary Age: 6-62 years (mean:20 years) Gender: 11F/8M Tumor size: cm (mean: 8.4 cm) Location Extremity 8 Trunk 4 Pelvis 5 Head & neck 2
31 Lobular growth Geographic necrosis Round cells High-grade nuclei Patchy clear cytoplasm Foci of myxoid change CIC-DUX Sarcomas
32 CIC-DUX Sarcomas Immunophenotype S-100 protein negative TLE1 Desmin Myogenin WT1 INI1 negative negative negative negative retained
33 CIC-DUX Sarcomas Immunophenotype CD99 7/7 (focal 5/7; cytoplasmic, not membranous) ERG 9/10 FLI1 8/8 Choi et al. AJSP 2013 Smith et al. Mod Pathol 2014
34 CIC-DUX Sarcomas Other Findings t(4;19) 8/10 t(10;19) 2/10 Trisomy 8 3/3 MYC staining 10/10 (diffuse) MYC amplification (FISH) 6/7 Smith et al. Mod Pathol 2014
35 CIC-DUX Sarcomas Clinical Outcome (N=13) Died of disease 8 (9-17 mos; mean: 12 mos) Alive with disease 1 (24 mos) No evidence of disease 4 (6-30 mos) Metastases: Lung (10); Brain (2); Pelvis (2); Bone (1)
36 BCOR-CCNB3 Sarcomas Gender: Age: Location: 9M / 1F yrs 7 bone / 3 deep soft tissue Follow-up: mos (median: 695 mos) AWOD 6/10 AW mets 1/10 DOD 3/10 Puls et al AJSP 2014
37 BCOR-CCNB3 Sarcoma Morphology Round cell resembling atypical Ewing sarcoma : 7 cases Spindle cell sarcoma: 3 cases Immunophenotype CCNB3 10/10 bcl2 9/10 CD99 7/10 CD117 6/10 Desmin 0/10 AE1/3 0/3 RT-PCR: 9/9 BCOR-CCNB3 fusion Puls et al AJSP 2014
38 BCOR-CCNB3 CCNB3 stain Courtesy of Dr. Florian Puls
39 BCOR-CCNB3 CCNB3 stain Courtesy of Dr. Florian Puls
40 CIC-DUX Sarcomas Takeaway Points Round cell sarcoma which is Ewing-like but EWSR1-negative Has a fairly characteristic constellation of histologic features which, if recognized, should prompt the appropriate molecular work-up Aggressive clinical behavior
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