Round cell tumors | Ewing sarcoma | Small blue round cells, EWSR1::FLI1 or EWSR1::ERG | FISH or NGS for rearrangement of EWSR1 or fusion of EWSR1::FLI1, or EWSR1::ERG; ICC CD99+, NKX2.2+, PKCBII+ |
| Rhabdomyosarcoma | Primitive round and spindle cells, rhabdomyoblasts, desmin+, myogenin+, MyoD1+ | ICC Desmin+, myogenin+, MyoD1+ |
| Lymphoma | Lymphoid cells, CD45 (LCA)+ | Flow cytometry for CD45 (LCA) and other CD markers |
| Neuroblastoma | Primitive small round cells with neuroblastic component, NSE+, Synaptophysin+, NMYC amplification | FISH or NGS for amplification of NMYC; ICC NSE+, synaptophysin+ |
| Desmoplastic small round cell tumor | Nests of small round cells with desmoplasia, EWSR1::WT1, multilineage immunoreactivity | FISH or NGS for rearrangement of EWSR1 or fusion of EWSR1::WT1; ICC WT1 (c-terminus)+, cytokeratin+, desmin (dot-like)+ |
Spindle cell tumors | Leiomyosarcoma | Plump spindle cells with eosinophilic cytoplasm, cigar-shaped nuclei, fascicular pattern, showing nuclear pleomorphism | ICC Desmin+, SMA+, SMMS-1+, Caldesmon+ |
| Synovial sarcoma | Spindle cells, monophasic or biphasic pattern, SS18::SSX1/2/4 | FISH or NGS for rearrangement or fusion of SS18::SSX1/2/4; ICC TLE1+, SS18-SSX fusion protein+, SSX protein (C-terminus)+ |
| Gastrointestinal stromal tumor (GIST) | Spindle cells, epithelioid, or mixed morphology, perinuclear vacuoles, KIT (CD117)+ | (KIT) mutation for KIT and/or PDGFRA; ICC CD117+, DOG1+ |
| Fibrosarcoma | Herringbone pattern, uniform spindle cells | ICC Vimentin+, lacks specific markers |
| Nodular fasciitis | Reactive proliferation, feathery spindle cells, myxoid stroma | FISH or NGS for USP6 rearrangement |
Pleomorphic cell tumors | Undifferentiated pleomorphic sarcoma | Pleomorphic spindle and round cells, bizarre nuclei | ICC Vimentin+, no specific markers |
| Dedifferentiated liposarcoma | Pleomorphic, spindle, or epithelioid cells, lipoblasts, lipogenic differentiation | FISH or NGS for MDM2 amplification; ICC MDM2+, CDK4+ |
| Pleomorphic liposarcoma | Pleomorphic, lipoblasts | No MDM2 or CDK4 amplification; ICC Vimentin+, lacks specific markers |
| Pleomorphic rhabdomyosarcoma | Pleomorphic round cells, cross striations, desmin+ | ICC Desmin,+ myogenin+, MyoD1+ |
| Malignant peripheral nerve sheath tumor (MPNST) | Spindle cells with wavy nuclei, S100 variably positive | ICC S100±, SOX10±, H3K27me3 loss |
Epithelioid cell tumors | Epithelioid sarcoma | Epithelioid cells with central necrosis | ICC, Cytokeratin+, EMA+, INI1 loss |
| Clear cell sarcoma | Epithelioid, melanoma-like cells, EWSR1::ATF1 | FISH or NGS for fusion of EWSR1::ATF1;ICC S100+, SOX10+, HMB45+, Melan-A |
| Epithelioid angiosarcoma | Epithelioid cells, vascular channels, ERG+ | ICC CD31+, ERG+ |
| Alveolar soft part sarcoma | Nests of epithelioid cells, PAS+ crystalline inclusions, rich sinusoidal caplillaries | FISH for fusion of ASPSCR1::TFE3; PAS+ crystals; ICC TFE3+ |
Myxoid tumors | Myxoid liposarcoma | Myxoid background, signet ring-like lipoblasts, plexiform vasculature | FISH or NGS for DDIT3 rearrangement or fusion of FUS::DIT3 or EWSR1::DDIT3; ICC DDIT3+ |
| Myxofibrosarcoma | Myxoid stroma, curvilinear vessels, spindle cells with variable pleomorphism | ICC Vimentin+, lacks specific markers |
| Extraskeletal myxoid chondrosarcoma | Myxoid stroma, cords of bland cells with eosinophilic cytoplasm, NR4A3 rearrangement | FISH or NGS for rearmament of NR4A3 or fusion of EWSR1:: NR4A3 |
| Myxoinflammatory fibroblastic sarcoma | Myxoid stroma, inflammation, epithelioid or bizarre cells | ICC Vimentin+, lacks specific markers |