Table 5.
Ancillary testing in differential diagnoses of Adamantinoma-like Ewing Sarcoma
| Tumor | Immunophenotype | Clinically relevant Molecular alterations | References |
|---|---|---|---|
| Adamantinoma-like Ewing Sarcoma | CD99, NKX2.2, AE1/AE3, p40, p63, HMWCK, Fli1 (v), Synaptophysin (v), Chromogranin (v), p16 (v) | EWSR1::FLI1 | [2–18, 22] |
| Predominantly round cell morphology [2, 19–30] | |||
| Classic Ewing sarcoma | CD99 (membranous), NKX2.2, Fli1 (fusion pos), ERG (fusion pos), AE1/AE3 (25%), S100 (-/ +) | EWSR1::FLI1 ((about 85%), EWSR1::ERG (about 10%), others members of FET (TAF15, FUS, EWSR1) and ETS family | [2, 19–22] |
| Sarcoma with BCOR | BCOR, SATB2, TLE1, cyclin D1, CD99 (50%) | BCOR rearrangements (mostly, BCOR::CCNB3); BECOR-ITD | [22, 23] |
| CIC-related sarcoma |
WT1, CD99 (focal; 20% diffuse), ETV-4, calretinin (v), ERG (v) Occ pos-Keratins, S100, desmin; CIC-NUTM1 express NUT NKX2.2 is negative |
CIC::DUX4 (95%); CIC::NUTM1 | [22, 24, 25] |
| Round cell sarcoma with EWSR1-non-ETS |
Variable co-expression of myogenic markers (desmin, myogenin, MYOD1) and neurogenic markers (S100P, SOX10, MITF, GFAP) CD34 can be positive CD99 is not consistently expressed |
EWSR1::NFATC2, FUS::NFATC2, and EWSR1::PATZ1 | [22, 26, 27] |
| Alveolar Rhabdomyosarcoma |
Desmin, Myogenin, MyoD1, CD99 (cytoplasmic ±), Occ pos- AE1/AE3, synaptophysin, chromogranin, CD56 (pitfall) |
85% fusion; PAX3::FOXO1 (70–90%); PAX7::FOXO1 (10–30%) | [22, 28] |
| Desmoplastic small round cell tumor |
AE1/AE3, desmin, WT1 (C-terminus antibody), NSE, CD56, CD99 (v) Myogenin and MYOD1 are consistently negative |
EWSR1 gene rearrangement; EWSR1::WT1 fusion | [22, 29] |
| Non-Hodgkin Lymphoma/ Leukemia | LCA, B cell or T cell lineage markers, Tdt (leukemic blasts) | Lymphoma specific gene fusions | [22] |
| Poorly differentiated Synovial sarcoma | EMA, keratins, SS18-SSX fusion specific antibody, TLE1, bcl-2, CD99 (v), S100 (v, focal) | SS18::SSX1/2/4 | [22, 30] |
| Predominantly neuroendocrine/ neuroectodermal | |||
| Olfactory neuroblastoma |
Synaptophysin, chromogranin, SSTR2, calretinin, AE1/AE3 (-/ + , 1/3rd focal), S100 positive rim Negative- CD99 |
– | [31] |
| Sinonasal neuroendocrine carcinoma | AE1/AE3, Synaptophysin, chromogranin | [3, 4] | |
| Teratocarcinosarcoma (in a biopsy; sampling of the neuroectodermal components) |
Neuroectodermal component-CD99 (cytoplasmic), synaptophysin, INSM1, Chromogranin (v), GFAP (v) Squamous- p40/p63 + Epithelial- AE1/AE3, Ck7 (v) Mesenchymal- Vimentin, desmin (v), MyoD1 (v) |
SMARCA4 deletions (subset) | [32] |
| Melanoma | HMB45, S100, SOX10, Melan A, TIFF | KIT, RAS, BRAF mutations | [33] |
| Merkel cell carcinoma | Cytokeratins, synaptophysin, chromogranin, NSE, INSM1, CD56, NFP, CK20 (perinuclear dot), CM2B4 (anti-MCPyV) | MCPyV DNA | [3, 4, 34] |
| Predominantly carcinoma morphology | |||
| Basaloid squamous carcinoma | Cytokeratins, p40, p63, HMWCK | – | [3, 4] |
| NUT carcinoma | NUT, AE1/AE3, p63 > p40, HMWCK, synaptophysin and, chromogranin (occasional), CD34 (v) | NUT::BRD4; NUT::BRD3; NUT::NSD3; | [35] |
| SMARCB1-deficient carcinoma |
SMARCB1 loss, AE1/AE3, p40, p63, HMWCK, CK7 (v) Synaptophysin and chromogranin (v, 8–18%) |
Biallelic SMARCB1 deletions (2/3rds) | [4, 36] |
| SMARCA4-deficient carcinoma | SMARCA4 loss, AE1/AE3, CK7 (rare), synaptophysin (90%), chromogranin (40%), CD56 (60%) | Biallelic SMARCA4 inactivation | [4, 36] |
| Sinonasal undifferentiated carcinoma | AE1/AE3, CK7, p63 (v), p16 (v), IDH1/2 mutant specific (subset) | IDH2-mutations (33–85%) | [3, 4, 37] |
| Basal cell adenocarcinoma | Cytokeratins, p40, p63, S100, SOX10, beta-catenin | CYLD or CTNNB1 alterations (subset) | [7, 38] |
| Myoepithelial carcinoma | Cytokeratins, p40, p63, S100, SOX10, SMA, calponin |
EWSR1::POU5F1, PBX1, PBX3 or ZNF444 Clear cell MECA- EWSR1 rearrangements |
[7, 39] |
| Sialoblastoma | Cytokeratins (v), SOX10, p63, beta-catenin, S100 (v), SMA (v), CD117 (v), and calponin (v) | – | [40] |
| Solid Adenoid cystic carcinoma | Cytokeratins, CK7, SOX10, S100, SMA, p40, p63, Calponin | MYB/MYBL1 gene rearrangements or fusions | [4, 7, 41] |
| Ameloblastic Carcinoma | Cytokeratins, p40, p63, CK19, calretinin, SOX2 (v), SMA (v), abnormal p53 | BRAF V600E; TP53 | [42] |
| Sebaceous carcinoma | EMA, p40, p63, p16, AR, adipophylin, p53, perilipin | TP53/RB1 mutations; HER2 amplification (75%) | [43, 44] |
| Basal cell carcinoma/basosquamous carcinoma | BerEP4, p40, p63, bcl-2, synaptophysin (v), chromogranin (v) | – | [45] |
| Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) |
Synaptophysin, chromogranin, INSM1 in the NE component; Cytokeratins in non-NE, p40 if squamous component |
– | [46] |
| Medullary thyroid Carcinoma | Calcitonin, INSM1, Synaptophysin, Chromogranin, CEA, TTF1 (v) | RET gene rearrangements | [47] |
| Poorly differentiated thyroid carcinoma | AE1/AE3, TTF1, PAX8, Thyroglobulin positive | – | [3, 4] |
| CASTLE | CD5, p63, CD117, synaptophysin (v), chromogranin (v) | – | [3, 48] |
v variable positivity, pos positive, ITD Internal tandem duplication, occ occasional, NE neuroendocrine, CASTLE Carcinoma with thymus-like elements;