Table 1.
Differential diagnoses of Ewing sarcoma.
| Entity | Morphology | IHC | Common Genetic Alterations |
|---|---|---|---|
| CIC-sarcoma | Sheets of undifferentiated round/spindle/epitheloid cells; mild nuclear pleomorphism; and necrosis | CD99 (mostly patchy), WT1, ETV4, DUX4, and NUT (CIC-NUTM1) | CIC-DUX4/FOXO4/LEUTX/NUTM1/2A fusions |
| BCOR-sarcoma | Sheets/nests/short fascicles of uniform; bland round-oval-spindle cells; rich capillary network; and myxoid matrix (variable) | BCOR, SATB2, cyclin D1, TLE1, CCNB3 (BCOR-CCNB3), and CD99 (50%) | BCOR-CCNB3/MAML3/ZC3H7B, KMT2D); BCOR ITD*; and YWHAE-NUTM2B; *ITD, internal tandem duplication |
| EWSR1-nonETS round-cell sarcomas | Cords/nests/pseudoacinar pattern of round-spindle cells; bland-pleomorphic spectrum; and fibro-/myxohyaline stroma | CD99, NKX2.2, and CKAE1/3 (focal, dot-like) | EWSR1/FUS-NFATc2 |
| Diverse morphology: round-spindle cells; fibrous stroma | Co-expression of myogenic markers (desmin/myogenin/MyoD1), neurogenic markers (S100/SOX10/MITF/GFAP) and keratins (AE1/3) | EWSR1-PATZ1 or EWSR1-VEZF1 | |
| Desmoplastic small round-cell tumor | Sheets/nests/cords of uniform; bland round cells; and desmoplastic stroma | Desmin (dot-like), keratin, EMA, and WT1 (C-terminus) | EWSR1-WT1 |
| Lymphoblastic lymphoma | Small-medium blastoid cells; minimal cytoplasm | CD99, TdT, CD45, CD34, CD1a, and B- and T-cel markers | Diverse |
| Small-cell carcinoma | Small-medium round-oval cells; salt and pepper chromatin; indistinct nucleoli; molding; and apoptosis | Keratins, CD56, synaptophysin, chromogranin, and TTF1 |
Diverse; TP53, PTEN mutations; RB1, 3p loss; and MYC amplification |
| NUT carcinoma | Poorly cohesive sheets of primitive/basaloid cells; abrupt keratinization; and coagulative necrosis | CK5/6, P40, P63, and NUT | NUT-BRD3/BRD4/NSD3/CIC/BCORL1/MGA/MXD4 |
| Myoepithelial carcinoma | Solid sheets/nests of cell with high nuclear grade or undifferentiated round-cell morphology; facultatively glandular component; necrosis; and high mitotic count | Pankeratins, S100, EMA, GFAP, SOX10, P63, SMA, calponin, desmin (focal); and INI1 loss (subset) | EWSR1 rearrangements (various fusion partners); PLAG1 rearrangements (mixed tumors) |
| ARMS | Nests with central discohesion-solid nests; monomorphic primitive round cells; and multinucleated wreath-like giant cells | Desmin, myogenin (strong, diffuse), MyoD1, keratin, neuro-endocrine markers (CD56, synaptophysin, and chromogranin) | PAX3/PAX7-FOXO1 |
| Sinonasal glomangiopericytoma | Solid-fascicular pattern; spindle-round cells with minimal atypia; arranged around staghorn vessels; and perivascular hyalinization | Beta-catenin (nuclear), SMA | CTNNB1 mutations |
| Glomus tumor | Solid-nested pattern; small, uniform round cells with round nucleus, amphophilic-slightly eosinophilic cytoplasm and sharply defined cell borders; and variable vascular pattern | SMA with membranous accentuation, caldesmon, and collagen IV | MIR143-NOTCH1/2/3, and BRAF/KRAS mutations |
| Rhabdoid tumor | Solid pattern; rounded-polygonal cells with vesicular nuclei and prominent nucleoli; and eosinophil hyaline-like cytoplasmic inclusions | Diverse; keratins, EMA, CD99, synaptophysin, SALL4, glypican-3, and INI1 loss | SMARCB1 biallelic loss, SMARCB1 or SMARCA4 (germline) mutations |
| Mesenchymal chondrosarcoma | Biphasic: poorly differentiated round cells and islands of hyaline cartilage; staghorn-like vessels | S100, CD99, SOX9, EMA, desmin, myogenin, and MyoD1 | HEY1-NCOA2 |
| Synovial sarcoma with round-cell features | Fascicles or sheets of small round hyperchromatic cells; high N/C ratio; staghorn vessels; necrosis; and thin fibrovascular septa | CD99, BCL2, CD56, TLE1, S100 (focal), EMA, and keratins (variable) | SS18-SSX1/2/4 |