Tumor Patterns. Common Morphologic Patterns in Soft Tissue Tumors. Update on Lipomatous Tumors. MFH-like. Highly cellular spindle cell pattern
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1 Common Morphologic Patterns in Soft Tissue Tumors John R. Goldblum, M.D. Chairman, Department of Anatomic Pathology The Cleveland Clinic Professor of Pathology Cleveland Clinic Lerner College of Medicine Cleveland, Ohio Tumor Patterns MFH-like Highly cellular spindle cell pattern Myxoid soft tissue lesions Round cell pattern 1
2 MFH-like Pattern Pleomorphic sarcoma with a specific line of differentiation Dedifferentiated sarcoma Pseudosarcoma with MFH-like pattern True MFH (diagnosis of exclusion) Desmin 2
3 Pleomorphic Sarcomas Pleomorphic liposarcoma Pleomorphic MPNST Pleomorphic leiomyosarc Pleomorphic RMS Extraskeletal osteosarcoma pleomorphic lipoblasts nerve origin; arises from NF S100+ in NF-1; EM diffuse SMA/MSA/desmin; EM skeletal muscle markers; EM malignant bone/osteoid MFH-like Pattern Dedifferentiated Sarcoma Well-differentiated liposarcoma Chondrosarcoma Chordoma Dermatofibrosarcoma protuberans 3
4 MFH-like Pattern Pseudosarcomas Sarcomatoid carcinoma Sarcomatoid mesothelioma Melanoma Ki-1 anaplastic lymphoma AE1/AE3 4
5 Tumor Pseudosarcomas Useful markers MFH: Fact or Fiction? 159 Pleomorphic Tumors Sarcomatoid CA Cytokeratins (multiple) Sarcomatoid mesoth CAM 5.2 Melanoma S-100 (+/- melanocytic markers) Pleomorphic sarcoma Pseudosarcomas with specific (N=20; 12.6%) differentiation (N=97; 61%) Anaplastic lymphoma CD30; ALK-1 Unclassifiable?MFH (N=42; 26.4%) Highly Cellular Spindle Cell Tumors Cellular schwannoma MPNST Fibrosarcoma Leiomyosarcoma Monophasic synovial sarcoma 5
6 Cellular Schwannoma Definition Highly cellular schwann cell proliferation composed predominantly/ exclusively of Antoni A areas Absence of well-formed Verocay bodies 6
7 7
8 Cellular Schwannoma Worrisome Features High cellularity Mitotically active (usual < 4/10HPF) Nuclear atypia Focal necrosis Bony erosion S100 * THE PERFECT PSEUDOSARCOMA* Cellular Schwannoma Behavior Recurred Bony erosion Mets F/U (mean) Woodruff (14) 0% 7% 0% 2.2 yrs Fletcher (18) 5% 11% 0% 14 yrs White (58) 5% 19% 0% 7 yrs Lodding (29) 0% 3% 0% 7 yrs 8
9 Desmin 9
10 Cellular Schwannoma vs MPNST Encapsulated Cellular schwannoma + MPNST - Cellularity Necrosis rare common Pleomorphism Mitoses Divergent diff. - + (10%) S100 S-100 diffuse focal (60%) 10
11 11
12 AE1/3 S100 12
13 Spindle Cell Sarcomas Cytokeratin Subsets Monophasic SS MPNST Synovial Sarcoma t(x;18)(p11;q11) SSX1 S-100 EMA or AE1/3 10/29 (34%) 25/29 (86%) 21/28 (75%) 10/28 (36%) SYT SSX2 CK7 CK19 26/29 (88%) 26/29 (88%) 2/28 (7%) 0/28 (0%) SSX4 TA Smith et al, AJCP, 1999 SYT (18q11) - Break Apart Probe SYNOVIAL SARCOMA POSITIVE 13
14 Cellular Spindle Cell Pattern S-100 CK7/19 SMA Cellular schwannoma + (diffuse) - - MPNST 60% (focal) - - Synovial sarcoma 30% (focal) + - Leiomyosarcoma Fibrosarcoma - - rare *CD99 and bcl-2 often in synovial sarcoma Myxoid Soft Tissue Lesions Evaluation of Myxoid Soft Tissue Lesions Benign Nodular fasciitis Myxoma intramuscular juxta-articular cutaneous Nerve sheath tumors neurofibroma neurothekeoma Malignant Myxoid liposarcoma Myxofibrosarcoma ( myxoid MFH ) Myxoid chondrosarcoma Low-grade fibromyxoid sarcoma DFSP All other sarcomas Cellularity Cellular arrangement Pleomorphism Vascularity 14
15 15
16 16
17 ARS slide to follow Q: What is the best diagnosis? 1. Myxoma 2. Neurofibroma 3. Myxoid liposarcoma 4. Myxofibrosarcoma 5. Man I need to see more! 17
18 Myxoid Soft Tissue Tumors Tumor Defect Genes Myxoma activating Gsα mutations LGFMS/HSCT t(7;16)(q33;p11) CREB3L2/FUS t(11;16)(p11;p11) CREB3L1/FUS MLS/RCLS t(12;16)(q13;p11) DDIT3/FUS t(12;22)(q13;q12) DDIT3/EWS ESMCS t(9;22)(q22;q12) NR4A3/EWS t(9;17)(q22;q11) NR4A3/TAF2N MyxoFS None characteristic Tumor Myxoma Evans tumor Low-grade MFS Myxoid LS Myxoid CS Myxoid Soft Tissue Lesions Cellularity Low Low Low-mod Low Low-mod Atypia None None-low Low-mod Low Low Architecture Even cell distribution Abrupt myxoid collagen zones; swirling Perivascular cellularity Vessels Few Prominent in myxoid zones Curvilinear; thick Even cell Plexiform, distribution fine Cords, chains Random,thick 18
19 Round Cell Tumors Benign Glomus Tumor Eccrine Spiradenoma Giant Cell Tumor ES/PNET Round Cell Pattern Rhabdomyosarcoma Neuroblastoma Lymphoma DSRCT Mesenchymal chondrosarcoma Round cell liposarcoma Small cell osteosarcoma Synovial Sarcoma Small cell/merkel cell carcinoma 19
20 PAS/D 20
21 ES/PNET: Histologic Spectrum ES PNET Cell shape regular irregular Chromatin fine coarse Nucleoli pinpoint prominent Glycogen abundant scant Rosettes absent present ES/PNET: Ultrastructure ES/PNET: Ultrastructural Spectrum Feature ES PN Organelles scarce abundant Dense-core granules absent abundant Neurotubules absent abundant Neuritic processes absent abundant 21
22 MIC - 2 Gene Product (CD99) Diagnosis Positive (%) CD99 ES/PNET 93% Small Cell Osteosarcoma 12% Desmoplastic Round Cell Tumor 20% Neuroblastoma 0% Rhabdomyosarcoma 15% Small Cell Carcinoma 9% T-LL/ALL 92% ES/PNET: Cytogenetics EWS (22q12) Break-apart probe t(11;22)(q24;q12) FLI1;EWS Translocation NH 2 EWS 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;EWS ETV1/EWS FEV/EWS E1AF/EWS t(11;22), t(21;22) EWS/PNET (FLI1/EWS, ERG/EWS) t(11;22) - DSRCT (WT-1/EWS) t(12;22) Clear Cell Sarcoma (ATF1/EWS) t(9;22) ES Myxoid Chondrosarcoma (NR4A3/EWS) t(12;22) Myxoid/Round Cell Liposarcoma (DDIT3/EWS) t(2;22) Angiomatoid fibrous histiocytoma (CREB1/EWS) 22
23 23
24 Rhabdomyosarcoma Classification Conventional Scheme Embryonal Botryoid Alveolar Pleomorphic Horn RC, Enterline HT. Cancer
25 Rhabdomyosarcoma Classification Scheme K (inter) K (intra) Modified Conventional SIOP NCI Cytohistologic Asmar L et al. Cancer, 1994 Rhabdomyosarcoma International Classification Favorable Prognosis Botryoid Spindle cell Intermediate Prognosis Embryonal Poor Prognosis Alveolar Newton WA et al, Cancer 1995 Rhabdomyosarcoma Myogenic Markers Desmin HHF-35 Sarcomeric actin SMA Embryonal (n=61) Alveolar (n=19) Botryoid (n=9) Spindle cell (n=6) Total (n=95) 97% 97% 71% 12% Wijnaendts LCD et al, J Pathol
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 Myogenin Myogenin in Pediatric Tumors Alveolar Rhabdomyosarcoma Tumor Cases stained Rhabdomyosarcoma (69) 69/69 (100%) Alveolar (48) Embryonal (20) Spindle cell (1) Other pediatric sarcomas (50) 0/50 (0%) ES/PNET (16) DSRCT (6) Neuroblastoma (4) Others (24) t(2;13)(q35;q14) PAX3/FKHR t(1;13)(q36;q14) PAX7/FKHR Kumar S et al, Mod Pathol
27 Alveolar Rhabdomyosarcoma Fusion Transcript Subtype PAX3/FKHR PAX7/FKHR Age Adolescents Young children Site Wide distribution Extremities Stage Metastatic Localized Prognosis Poor Better Kelly KM et al, J Clin Oncol
28 Desmoplastic Round Cell Tumor Gender: 90M / 19F Age: 6-49 years (mean: 22 years) Sites: Abdominal cavity 103 Thoracic region 4 Cranial fossa 1 Extremity 1 Prognosis: poor, but may respond to aggressive therapy Desmin Gerald W et al, J Clin Oncol 1998 Desmoplastic Round Cell Tumor CK 86% Vim 97% WT-1 95% Des 90% NSE 81% CD99 20% EWS (22q12) - Break Apart Probe Desmoplastic Small Round Cell Tumor 28
29 Round Cell Pattern CD99 TdT Myo CAM5.2 CK20 Des ES/PNET 95% % - - RMS 15% DSRCT 20% (dot-like) Lymphoma 90% Small Cell <10% % Rare - Merkel Cell <10%
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