EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review
Abstract
:1. Introduction
2. Ewing Sarcoma
3. Round-Cell Sarcomas with EWSR1-Non-ETS Fusions
3.1. NFATc2-Rearranged Sarcoma
3.2. EWSR1-PATZ and EWSR1-VEZF1 Rearranged Sarcoma
- Low-grade appearing tumors: the spindled, epithelioid, ovoid, and round cells are set in a hyaline stroma reminiscent of solitary fibrous tumors and myoepithelioma.
- Intermediate and high-grade appearing neoplasms have a round and/or ovoid morphology with few spindle cells and slight stromal component. The tumors of this second subgroup resemble other small, blue round-cell tumors, e.g., ARMS, BCOR-, and CIC-rearranged sarcoma.
3.3. Small Blue Round-Cell Tumor with EWSR1-SMARCA5 Rearrangement
3.4. Desmoplastic Small Round-Cell Tumor (DSCRT)
4. Myxoid Liposarcoma (MLS)
5. Tumors with EWSR1/FUS Fused to the CREB-Family
5.1. Angiomatoid Fibrous Histiocytoma (AFH)
5.2. Primary Pulmonary Myxoid Sarcoma (PPMS)
5.3. EWSR1-CREM Undifferentiated Sarcoma
5.4. Clear-Cell Sarcoma (CCS)
5.5. Clear-Cell Sarcoma-Like Tumor of the Gastrointestinal Tract (Osteoclastrich Tumor of the Gastrointestinal Tract or Malignant Gastrointestinal Neuroectodermal Tumor)
5.6. Mesothelioma
6. Myoepithelial Tumors
7. Low-Grade Fibromyxoid Sarcoma (LGFMS)/Sclerosing Epithelioid Fibrosarcoma (SEF)
8. Extraskeletal Myxoid Chondrosarcoma (EMC)
9. EWSR1-SMAD3-Positive Fibroblastic Tumor (ESFT)
10. Epithelioid and Spindle Cell Rhabdomyosarcoma with EWSR1/FUS-TFCP2 Fusion
11. Retroperitoneal Leiomyoma
12. Simple (Unicameral) Bone Cyst (SBC)
13. Hemangioma of Bone with an EWSR1-NFATC1 Fusion
14. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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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 |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Solitary fibrous tumor | Patternless pattern of spindle cells or round cells; hyalinized stroma; collagen bundles; staghorn vessels; and possibly fat component | CD34, BCL2, CD99, and STAT6 | NAB2-STAT6 |
Myoepithelial tumor | Divers spectrum; reticular/trabecular pattern; variable spindle/epithelioid/plasmocytoid/clear cells; rarely ductal component (mixed tumors); and myxoid stroma | Pankeratins, S100, SOX10, EMA, GFAP, P63, SMA, calponin, and desmin (focal) | EWSR1 rearrangements (various fusion partners); PLAG1 rearrangements (mixed tumors) |
DSRCT | Sheets/nests/cords of uniform, bland, round cells; and desmoplastic stroma | Desmin (dot-like), keratin, EMA, and WT1 (C-terminus) | EWSR1-WT1 |
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 |
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 |
ARMS | Nests/sheets with central discohesion (pseudoalveolar) or solid nests; monomorphic, primitive round cells; and multinucleated wreath-like giant cells | Desmin, myogenin (strong, diffuse), MyoD1, keratin, and neuro-endocrine markers (CD56, synaptophysin, chromogranin) | PAX3/PAX7-FOXO1 |
Malignant peripheral nerve sheath tumor/Triton | Fascicles of spindle cells and/or sheets epithelioid cells with perivascular accentuation and alternating cellularity; staghorn vessels; geographic necrosis; and heterologous differentiation (rhabdomyoblasts, glandular structures) | S100, SOX10 (focally), and loss of H3K27me3 | Inactivating mutations of NF1, CDKN2A/B, EED, and SUZ2 |
Synovial sarcoma | Sheets-fascicles; cellular, monomorphic spindle cells; high N/C ratio; variable epithelial differentiation; staghorn vessels; variable amount of collagen; mast cells; and calcification/ossification; poorly differentiated areas may show round-epithelioid cells | CD99, BCL2, CD56, TLE1, S100 (focal), EMA, and keratins (variable) | SS18-SSX1/2/4 |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Neuroblastoma | Primitive cells; rosettes; neuropil; and ganglion cells | CD56, synaptophysin, and chromogranin | nMYC amplification; ATRK, ALK mutations; and chromosomal aberrations (1p, 17q, and 11q) |
Lymphoma | Variably sized hyperchromatic-blastoid cells with variable atypia; minimal cytoplasm | CD45, B/T-cell markers | Diverse |
Blastemic Wilms | Primitive, undifferentiated round-to-spindled cells | WT1 (N-terminus), CD56 | WT1, TP53 mutations; 11p15.5 deletion |
Small cell/neuroendocrine 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 |
Metastatic Merkel cell carcinoma | Round-oval nuclei; high N/C-ratio; salt and pepper chromatin; indistinct nucleoli; molding; and apoptosis | Broad spectrum keratins; CK20 (dot-like), CD56, chromogranin, and synaptophysin | Diverse; depends on polyomavirus (PyV) status; PyV- tumors: Rb1, TP53 mutations |
Small cell mesothelioma | Solid nests; high N/C-ratio; well defined membrane; fine chromatin; and indistinct nucleoli | Calretinin, CK5/6, WT1 (N-terminus), and D2-40 | Diverse; P16 loss; BAP1 mutation; NF2 deletion; and ALK/EWSR1/FUS rearrangments |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Lipoblastoma | Lobulated architecture with fibrous septa with often prominent vasculature; possibly myxoid stroma with possibly plexiform vasculature; resembling fetal fat with prelipoblasts, lipoblasts, and mature fat in variable portions | Not specific | PLAG1 rearrangements (various fusion partners) |
Myxoid pleomorphic liposarcoma | Progressive transition between areas resembling myxoid liposarcoma and pleomorphic liposarcoma; pleomorphic cells; and myxoid matrix | Not specific | RB1 deletion, TP53 mutations |
Chondroid lipoma | Myxohyaline chondroid matrix; lipoblasts intermingled with mature adipocytes and chondroid cells; and vascularized septa | S100 (mature adipocytes and lipoblasts); keratins (rare) | C110r95-MRTFB |
Soft tissue angiofibroma | Myxoid-collagenous stroma; prominent, branching vasculature; and bland spindle cells, possibly adipocytes | CD34, EMA, desmine (dendritic cells) | NCOA2 rearrangements (various fusion partners) |
Small, blue round-cell tumors (when round-cell liposarcoma) | Cells with small round-oval-spindle cells with little cytoplasm | See Table Ewing and Ewing-like sarcomas | See Table Ewing and Ewing-like sarcomas |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Histiocytic lesions | Diverse; histiocytes; and multinucleated giant cells | Diverse (depending on entity); CD68, CD163, and FXIIIA | Diverse (depending on entity); activating MAPK signaling mutations (BRAF, NRAS, KRAS, ARAF, and MAP2K1) |
Follicular dentritic sarcoma | Fascicles/whorls/storiform pattern; oval-spindle cells with small nucleoli and syncytial borders; nuclear pseudoinclusions; binucleate (often) or multinucleate (rare) forms; and admixed lymphocytic infiltrate with perivascular lymphocytic cuffs | CD21, CD23, CD35, and D2-40 | Highly diverse mutational profile |
Small, blue round-cell tumors See Table 1 and Table 2 | Cells with small round-oval-spindle cells with scant cytoplasm | Diverse (depending on entity) | Diverse (depending on entity) |
Epithelioid fibrous histiocytoma | Polypoid; epidermal collarette; epithelioid cells with vesicular nuclei, small nucleoli, and amphophilic cytoplasm | FXIIIA, EMA, and ALK | ALK rearrangements (various fusion partners) |
Aneurysmatic fibrous histiocytoma | Epidermal hyperplasia and basal layer pigmentation; circumscribed, dermal based proliferation; haphazard arrangement of ovoid spindle cells; admixed foam and giant cell; central blood-filled cystic space; and abundant hemosiderin deposition | FXIIIA, SMA | Not specific |
Rhabdomyosarcoma | Monomorphic primitive round cells with variable rhabdomyoblastic differentiation (depending on subtype) | Desmin, myogenin, and MyoD1 | Diverse (depending on subtype); PAX3/PAX7-FOXO1 fusions (ARMS); alterations of RAS signaling pathway (embryonal RMS) |
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 |
Inflammatory myofibroblastic tumor | Fascicular pattern (variable); plump-spindle cells with vesicular nuclei and small nucleoli; amphophilic cytoplasm; oedematous-myxoid-fibrous stroma; and mixed inflammatory infiltrate | SMA, calponin, desmin, keratin (focal), ALK, and ROS1 | ALK rearrangements (various fusion partners); ROS1, NTRK3, RET, or PDGFRB rearrangements |
Carcinoma | Sheets/nests/trabecula; round-oval-epithelioid cells with nuclear atypia and variable amount of cytoplasm | Pankeratins, lineage specific markers (depending on site of origine) | Diverse (depending on site of origin) |
Meningeoma | Highly diverse (according to subtype and grade): lobulated; whorled, fascicular pattern; spindle or plump syncytial cells; intranuclear pseudoinclusions; and psammoma bodies | EMA, S100, and PR | Monosomy 22; NF2 deletions |
Extraskeletal myxoid chondrosarcoma | Multinodular; lace-like/reticular pattern; round-spindle monomorphic cells; eosinophilic cytoplasm; and myxoid matrix | Non-specific; S100 (focal) | NR4A3-EWSR1-/TAF15/TCF12/TFG |
Myoepithelioma (syncytial) | Cutaneous; poorly marginated; syncytial growth; sheets of uniform ovoid-histiocytoid-epithelioid cells; and minimal stroma | S100, EMA, GFAP, SMA, and calponin | EWSR1-PBX3 |
Myxoid liposarcoma | Lobulated; primitive uniform round-ovoid cells; variable number of lipoblasts; myxoid stroma; and plexiform vasculature (chicken wire) | DDIT3 | FUS/EWSR1-DDIT3 |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Salivary gland myoepithelial tumors | Strands/nests/ductular structures of epithelial/myoepithelial cells; and chondromyxoid/hyalinised stroma | Epithelial cells: EMA, cytokeratins; Myoepithelial cells: GFAP, S100, SOX10, p40, p63, and SMA | PLAG1 or HMGA2 fusions |
Angiomatoid fibrous histiocytoma | Syncytial/whorling pattern (classic AFH); reticular/lace-like pattern (myxoid AFH); uniform histiocytoid cells; blood-filled pseudocysts; and inflammatory/lymphocytic reaction (lymph node-like) | Desmin, EMA, and ALK | EWSR1-ATF1 or EWSR1-CREB1 |
Extraskeletal myxoid chondrosarcoma | Multinodular; lace-like/reticular pattern; round-spindle monomorphic cells with eosinophilic cytoplasm; and myxoid stroma | Non-specific; S100 (focal) | NR4A3-EWSR1/TAF15/TCF12/TFG |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Melanoma | Diverse growth patterns; large, atypical spindle-epithelioid-bizarre cells with vesicular nuclei and prominent, eosinophilic nucleoli; nuclear pseudo-inclusions; abundant eosinophilic-clear cytoplasm; and melanin pigment | S100, SOX10, Melan-A, HMB45, and MITF | Diverse: ARID2, BAP1, BRAF, GNAQ, HRAS, KIT, NF1, NRAS, PTEN mutations; and chromosomal gains/losses |
Epithelioid Schwannoma | Multilobulated growth; encapsulated; nests or single cells; variableschwannoma epithelioid cells; and myxoid-hyalinized stroma | S100, SOX10, Loss of INI1 (~40%) | Loss of SMARCB1 (~40%) |
Myoepithelial tumors | Divers spectrum; reticular/trabecular pattern; variable spindle/epithelioid/clear/plasmocytoid/rhabdoid cells; rarely ductal component (mixed tumors); fibromyxoid stroma; and hyalinization | Pankeratins, S100, SOX10, EMA, GFAP, P63, SMA, calponin, and desmin (focal) | EWSR1 rearrangements (various fusion partners); PLAG1 rearrangements (mixed tumors) |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Clear-cell sarcoma | Nested-fascicular pattern; epithelioid-plump spindle cells with vesicular nuclei and macronucleoli; fibrous septa; and scattered wreath-like multinucleated giant cells | Melanocytic markers (S100, SOX10, Melan-A, HMB45, and MITF) | EWSR1-ATF1/CREB (most often); EWSR1-CREM (rare) |
Desmoplastic small round-cell tumor | Sheets/nests/cords of uniform, small round cells; and variable desmoplastic stroma | Desmin (dot-like), keratin, EMA, and WT1 (C-terminus) | EWSR1-WT1 |
Carcinoma | Sheets/nests/trabecules; round-oval-epithelioid cells with nuclear atypia and variable cytoplasm | Pankeratins, lineage-specific markers (depending on site of origin) | Diverse (depending on site of origin) |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Extraskeletal myxoid chondrosarcoma | Multinodular; lace-like/reticular pattern; round-spindle monomorphic cells with eosinophilic cytoplasm; and myxoid stroma | Non-specific; S100 (focal) | NR4A3-EWSR1/TAF15/TCF12/TFG |
Chordoma | Lobulated; fibrous septa; cords/nests of large epithelioid/polygonal cells, physaliphorous cells (bubbly cytoplasm); and variable myxoid stroma | Cytokeratin, EMA, S100, Brachyury | Germline tandem duplication of TBXT (rare); germline loss-of-function mutations of TSC1/2 (rare) |
Sclerosing epitheloid fibrosarcoma | Infiltrative; cords/nests of monomorphic epithelioid cells; and hyalinized/sclerotic/collagenous stroma; | MUC4, SMA, and EMA | EWSR1/FUS/PAX5-CREB3L1/CREB3L2/CREB3L3/CREM |
(Adeno)carcinoma | Sheets/nests/trabeculae, glands; round-oval-epithelioid cells with nuclear atypia and variable cytoplasm; and ductular structures (adenocarcinoma) | Pankeratins, lineage specific markers (depending on site of origin) | Diverse (depending on site of origin) |
Small, blue, round cell tumors | Cells with small round-oval-spindle cells with little cytoplasm | Diverse (depending on entity) | See Table 1, Table 2 and Table 3 |
Epitheloid sarcoma | Nodules of uniform epithelioid-spindled cells with eosinophilic cytoplasm; central geographic necrosis (classic type); multinodular/sheet-like growth; large-slightly pleomorphic epithelioid cells with eosinophilic cytoplasm (proximal type) | CD34, keratins, EMA, and loss of INI1 | Loss of SMARCB1 |
Melanoma | Diverse growth patterns; large, atypical spindle-epithelioid-bizarre cells with vesicular nuclei and prominent, eosinophilic nucleoli; nuclear pseudo-inclusions; abundant eosinophilic-clear cytoplasm; and melanin pigment | S100, SOX10, Melan-A, HMB45, and MITF | Diverse: ARID2, BAP1, BRAF, GNAQ, HRAS, KIT, NF1, NRAS, PTEN mutations; and chromosomal gains/losses |
Epithelioid schwannoma | Multilobulated growth; capsule; nests or singly cells; variable epithelioid cells; and myxoid-hyalinized stroma | S100, SOX10, and loss of INI1 (~40%) | Loss of SMARCB1 (~40%) |
Epitheloid malignant peripheral nerve sheath tumor | Lobulated growth; atypical epithelioid cells with enlarged nuclei; and prominent nucleoli and eosinophilic cytoplasm | S100, SOX10 (strong and diffuse), and loss in INI1 (~75%) | Loss of SMARCB1 (~75%) |
Ossifying fibromyxoid tumor (mostly benign, rarely malignant) | Multilobulated; nests/cords of uniform round-spindle cells; indistinct cytoplasm; no atypia (rarely high nuclear grade in malignant lesions); fibromyxoid stroma; partial rim of mature bone; and atypical osteoid in malignant tumors | S100, desmin, GFAP (focal), and pankeratin (rare) | PHF1 rearrangements (diverse fusion partners) |
Clear-cell sarcoma | Nested-fascicular pattern; epithelioid-plump spindle cells with vesicular nuclei and macronucleoli; fibrous septa; and scattered wreath-like multinucleated giant cells | Melanocytic markers (S100, SOX10, Melan-A, HMB45, and MITF) | EWSR1-ATF1/CREB (most often); EWSR1-CREM (rare) |
Malignant rhabdoid tumors | Solid pattern; uniform rounded-polygonal cells with vesicular nuclei and prominent nucleoli; and eosinophilic hyaline-like cytoplasmic inclusions | Diverse; keratins, EMA, CD99, synaptophysin, SALL4, glypican-3, and INI1 loss | SMARCB1 biallelic loss |
Epithelioid hemangio-endothelioma | Infiltrative, sometimes angiocentric growth; cords/nests of bland looking epithelioid and spindle cells; glassy cytoplasm; intracytoplasmic vacuoles (blister cells); and myxohyaline stroma | CD34, CD31, ERG, D2-40, keratins (subset), SMA, CAMTA1, and TFE3 | WWTR1-CAMTA1 (>90%); YAP1-TFE3 |
Pseudomyogenic (epitheloid sarcoma-like) hemangio-endothelioma | Multiple discontinuous nodules; possibly involvement of different tissue planes; sheets/fascicles of plump-spindle-epithelioid cells with abundant, brightly eosinophilic cytoplasm; vesicular nuclei with small nucleoli; mild nuclear atypia; not obvious vascular; and prominent stromal neutrophils (50%) | Keratins (AE1/AE3 but not MNF116), FLI, ERG, CD31 (50%), SMA (focal), and FOSB | SERPINE1/ACTB-FOSB |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Desmoid-type fibromatosis | Long, sweeping fascicles; slender uniform spindle cells; pale cytoplasm; and parallel to fascicles thin-walled blood vessels with perivascular edema | Beta-catenin (nuclear), SMA, and desmin (focal) | CTNNB1 or APC mutations |
Nodular fasciitis | Plump spindle cells; tissue-culture aspect; extravasated erythrocytes; lymphocytes; and sometimes osteoclast-like giant cells | Non-specific: SMA, CD68, and desmin (focal) | USP6 rearrangements (diverse fusion partners) |
Ossifying fibromyxoid tumor (mostly benign, rarely malignant) | Multilobulated; nests/cords of uniform round-spindle cells; indistinct cytoplasm; no atypia (rarely high nuclear grade in malignant lesions); fibromyxoid stroma; partial rim of mature bone; and atypical osteoid in malignant tumors | S100, desmin, GFAP (focal), and pankeratin (rare) | PHF1 rearrangements (diverse fusion partners) |
Neurofibroma | Nodular or diffuse growth; variable admixture of perineurial cells, schwann cells and fibroblasts; hyperchromasia; usually no atypia or mitoses; and myxoid-collagenous stroma with “shredded-carrot” collagen | S100, SOX10, CD34, and EMA | NF1 deletions |
Perineurioma | Nodular; non-encapsulated; circumscribed or infiltrative; whorled/storiform/fascicular pattern; and slender spindle cells with bipolar cytoplasmic extensions and uniform oval or elongated nuclei | EMA, GLUT1, CD34, and Claudin 1 | TRAF7 mutations (intraneural perineurioma); NF1/2 deletions |
Desmoplastic fibroblastoma | Paucicellular; bland stellate-spindle cells; and abundant collagenous-myxocollagenous stroma | FOSL1, SMA (focal) | t(2;11) |
Malignant peripheral nerve sheath tumor | Fascicles of monomorphic atypical spindle cells with perivascular accentuation and alternating cellularity; pleomorphism is possible; staghorn vessels; geographic necrosis; and heterologous differentiation | S100, SOX10 (focal), and loss of H3K27me3 | Inactivating mutations of NF1, CDKN2A/B, EED, and SUZ2 |
Fibroma nuchae | Paucicellular; bland spindle cells; thick collagen bundles; and entrapped adipose tissue and/or small nerves | CD34 | Not relevant |
Intramuscular (cellular) myxoma | Myxoid stroma; hypocellular; uniform spindle-stellate cells; inconspicuous vessels; and infiltration into skeletal muscle | CD34 | GNAS mutations |
Dermatofibrosarcoma protuberans | Dermal based; cellular, storiform pattern of uniform spindle cells; encasement of skin appendages; and infiltration in subcutaneous fat with honeycombing | CD34 | COL1A1-PDGFB (most often); COL6A3-PDGFD or EMILIN2-PDGFD (rare) |
NTRK-rearranged spindle cell neoplasm (emerging) | Wide spectrum of morphologies and histological grades; most often haphazardly arranged monomorphic spindle cells; variable stromal/perivascular hyalinization; and infiltrative growth into fat | S100, CD34 (co-expression), and NTRK | NTRK1-3 rearrangements (diverse fusion partners); RAF1 or BRAF fusions (rare) |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Ossifying fibromyxoid tumor | Multilobulated; nests/cords of uniform round-spindle cells; indistinct cytoplasm; no atypia (rarely high nuclear grade in malignant lesions); fibromyxoid stroma; partial rim of mature bone; and atypical osteoid in malignant tumors | S100, desmin, GFAP (focal), and pankeratin (rare) | PHF1 rearrangements (diverse fusion partners) |
Carcinoma (lobular, signet ring cell) | Files-small nests; round-oval cells with variable cytoplasm and nuclear atypia; and intracytoplasmic mucin vacuole | Pankeratins, lineage specific markers (depending on site of origine) | Diverse (depending on site of origin) |
Sclerosing lymphoma | Variably sized hyperchromatic-blastoid cells with variable atypia; scant cytoplasm; and sclerotic stroma | CD45, B/T-cell markers | Diverse |
Synovial sarcoma | Sheets-fascicles; cellular, monomorphic spindle cells; high N/C ratio, variable epithelial differentiation; staghorn vessels; variable amount of collagen; mast cells; and calcification/ossification; poorly differentiated areas may show round-epithelioid cells | CD99, BCL2, CD56, TLE1, S100 (focal), EMA, and keratins (variable) | SS18-SSX1/2/4 |
Clear-cell sarcoma | Nested-fascicular pattern; epithelioid-plump spindle cells with vesicular nuclei and macronucleoli; fibrous septa; and scattered wreath-like multinucleated giant cells | Melanocytic markers (S100, SOX10, Melan-A, HMB45, and MITF) | EWSR1-ATF1/CREB (most often); EWSR1-CREM (rare) |
Osteosarcoma | Highly diverse; infiltrative growth; severely anaplastic and pleiomorphic cells; monomorphic small cell appearance is rare; and atypical neoplastic bone formation (essential) | SATB2, osteocalcin (BGLAP), osteonectin (SPARC), osteoprotegerin (TNFRSF11B), RUNX2, S100, actins, CD99, keratin, and EMA | Highly complex chromosomal aneuploidy |
Myoepithelioma | Divers spectrum; reticular/trabecular pattern; variable spindle/epithelioid/clear/plasmocytoid/rhabdoid cells; rarely ductal component (mixed tumors); fibromyxoid stroma; and hyalinization | Pankeratins, S100, EMA, GFAP, SOX10, P63, SMA, calponin, and desmin (focal) | EWSR1 rearrangements (various fusion partners); PLAG1 rearrangements (mixed tumors) |
Diagnosis | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Cellular schwannoma | Encapsulation; predominantly Antoni A areas; variable neuroid spindle cells; possibly hyperchromasia and frequent mitoses; rarely Verocay bodies or schwannian whorls; and hyalinized vessels subcapsular lymphocytes | S100, SOX10 | NF2 deletion; LATS1/2, ARID1A/1B, and DDR1 mutations; SH3PXD2A-HTRA1 |
Perineurioma | Whorled/storiform pattern; slender spindle cell with bipolar cytoplasmic extensions and oval/elongated uniform nuclei | EMA, GLUT1, CD34, Claudin 1 | TRAF7 mutations (intraneural perineurioma); NF/2 deletions |
Myofibroma/myopericytoma | Myofibroma: nodular; biphasic pattern: immature plump-spindle cells around staghorn vessels; and nodules/fascicles of hyalinized-myoid-chondroid appearing cells. Myopericytoma: lobular; variably cellular; bland oval-spindle-myoid cells; and perivascular growth | SMA (myofibroma/myopericytoma), caldesmon (myopericytoma) | PDGFRB, NOTCH3 mutations; SRF-RELA |
Angioleiomyoma | Bundles of bland leiomyocytes around numerous vessels | SMA, calponin, caldesmon, and desmin (variable) | Not relevant |
Cellular digital fibroma | Whorls/short fascicles; bland spindle cells with slightly eosinophilic cytoplasm; pale pink-red, paranuclear inclusions; and collagenous stroma | Actin, calponin, and caldesmon | Not relevant |
Calcifying aponeurotic fibroma | Fibromatosis-like, infiltrative component of bland spindle cells; nodular calcified component with hyalinized-chondroid matrix encircled by rounded-chondrocyte like cells; and osteoclast-type giant cells | SMA, CD99, S100 (chondroid areas) | FN1-EGF |
Acral fibromyxoma | Nodular or diffuse; infiltrative growth of bland spindle-stellate cells; and variably myxoid-collagenous stroma | CD34, EMA, SMA, and RB1 (loss) | RB1 deletions |
Superficial fibromatosis | Plexiform or multinodular; moderately cellular bland spindle cells; and collagenous stroma | SMA, desmin, beta-catenin (nuclear) positive in a subset of cases despite absence of CTNNB1 or APC mutation | Not relevant |
Cellular dermatofibroma | Radiar configuration; storiform/short fascicular pattern; cellular center of fibrohistiocytic cells; and peripheral collagen entrapment | SMA, FXIIA, and CD68 | PRKCB/PRKCD-PDPN/CD63/LAMTOR1 |
Lipofibromatosis | Admixture of mature fat, fascicles of bland myofibroblastic spindle cells (fibromatosis-like) and lipoblast-like cells at the interface | CD34, SMA | EGFR/HER1/ROS/RET/PDGFRB-EGF/HBEGF/TGF-α |
Smooth muscle neoplams | Intersecting fascicles of smooth muscle cells; blunt-ended, cigar-shaped nuclei; and eosinophilic cytoplasm | SMA, desmin, and caldesmon | Not relevant; |
Synovial sarcoma | Sheets-fascicles; cellular, monomorphic spindle cells; high N/C ratio; variable epithelial differentiation; staghorn vessels; variable amount of collagen; mast cells; calcification/ossification; and poorly differentiated areas may show round-epithelioid cells | CD99, BCL2, CD56, TLE1, S100 (focal), EMA, and keratins (variable) | SS18-SSX1/2/4 fusion |
Malignant peripheral nerve sheath tumor | Fascicles of spindle cells with perivascular accentuation and alternating cellularity; staghorn vessels; georgraphic necrosis; and heterologous differentiation | S100, SOX10 (focal), and loss of H3K27me3 | Inactivating mutations of NF1, CDKN2A/B, EED, and SUZ2 |
Acral dermatofibrosarcoma protuberans | Dermal-based; cellular, storiform pattern of uniform spindle cells; encasement of skin appendages; and infiltration in subcutaneous fat with honeycombing | CD34 | COL1A1-PDGFB fusion (most often); COL6A3-PDGFD or EMILIN2-PDGFD (rare) |
Low-grade fibromyxoid sarcoma | Alternating myxoid-fibrous areas; whorling/fascicular pattern of bland spindle cells; arcades of small vessels; and sometimes hyaline rosettes, which sometimes overlap with sclerosing epitheloid fibrosarcoma | MUC4 (highly sensitive and specific); EMA, S100, CD34, and SMA (variable) | EWSR1/FUS-CREB3L1/2 |
Pseudomyogenic (epitheloid sarcoma-like) hemangioendothelioma | Multiple discontinuous nodules; possible involvement of different tissue planes; sheets/fascicles of plump-spindle-epithelioid cells with abundant, brightly eosinophilic cytoplasm; vesicular nuclei with small nucleoli; mild nuclear atypia; not obvious vascular; and prominent stromal neutrophils (50%) | Keratins (AE1/AE3 but not MNF116), FLI, ERG, CD31 (50%), SMA (focal), and FOSB | SERPINE1/ACTB-FOSB |
NTRK-rearranged spindle cell neoplasms | Wide spectrum of morphologies and histological grades; most often haphazardly arranged monomorphic spindle cells; variable stromal/perivascular hyalinization; and infiltrative growth into fat | S100, CD34 (co-expression), and NTRK | NTRK1-3 rearrangements (diverse fusion partners); RAF1 or BRAF fusions (rare) |
Entity | Morphology | IHC | Common Genetic Alterations |
---|---|---|---|
Inflammatory myofibroblastic tumor | Fascicular pattern (variable); plump-spindle cells with vesicular nuclei and small nucleoli and amphophilic cytoplasm; oedematous-myxoid-fibrous stroma; and mixed inflammatory infiltrate | SMA, calponin, desmin, keratin (focal), ALK, and ROS1 | ALK rearrangements (various fusion partners); ROS1, NTRK3, RET, or PDGFRB rearrangements |
Carcinoma | Sheets/nests/trabecules; round-oval-epithelioid cells with variable cytoplasm and nuclear atypia | Pankeratins, lineage-specific markers (depending on site of origine) | Diverse (depending on site of origin) |
Myoepithelial carcinoma | Solid sheets/nests of variable myoepithelial cells (epitheloid, spindled, plasmocytoid, rhabdoid, and clear) with high nuclear grade or undifferentiated round-cell morphology; necrosis; and high mitotic count | Pankeratins, EMA, S100, SOX10, GFAP, P63, SMA, calponin, desmin (focal); and INI1 loss (subset) | EWSR1 rearrangements (various fusion partners); PLAG1 rearrangements (mixed tumors) |
EWSR1-PATZ1 sarcoma | Diverse morphology: round-spindle cells; fibrous stroma | Co-expression of myogenic markers (desmin/myogenin/MyoD1) and neurogenic markers (S100/SOX10/MITF/GFAP) | EWSR1-PATZ1 |
Dedifferentiated chondrosarcoma | Conventional chondrosarcoma with abrupt transition to a high-grade non-cartilaginous sarcoma (undifferentiated sarcoma, osteosarcoma, angiosarcoma, leiomyosarcoma, and rhabdomyosarcoma) | Diverse (according to line of differentiation); loss of H3K27me3, MDM2 overexpression, p53 overexpression, and PDL1 | Complex karyotype; IDH1/2, TP53 mutations |
Pseudomyogenic (epitheloid sarcoma-like) hemangioendothelioma | Multiple discontinuous nodules; possibly involvement of different tissue planes; sheets/fascicles of plump-spindle-epithelioid cells with abundant, brightly eosinophilic cytoplasm; vesicular nuclei with small nucleoli; mild nuclear atypia; not obvious vascular; and prominent stromal neutrophils (50%) | Keratins (AE1/AE3 but not MNF116), FLI, ERG, CD31 (50%), SMA (focal), and FOSB | SERPINE1/ACTB-FOSB |
Rhabdomyosarcoma (spindle cell) | Cellular fascicles with intersecting/herringbone pattern; atypical uniform spindle cells with pale eosinophilic cytoplasm; primitive round cells may be present; and tadpole/strap cells (sometimes) | Desmin, MyoD1 (focal or diffuse), myogenin (focal) | SRF/VGLL2/TEAD1-NCOA2, VGLL2-CITED2 (congenital spindle cell RMS); and MYOD1 mutation |
Leiomyosarcoma | Intersecting fascicles of smooth muscle cells; blunt-ended, cigar-shaped nuclei; variable atypia and pleomorphism (depending on grade); eosinophilic cytoplasm; mitoses; necrosis | SMA, desmin, and caldesmon | Extensive genomic instability (leiomyosarcoma); diverse gene involvement with p53 mutations; deleterious ATRX alterations; ALK rearrangement (small subset); and NF1 mutations (subset of inflammatory leiomyosarcoma); |
Melanoma | Diverse growth patterns; large, atypical spindle-epithelioid-bizarre cells with vesicular nuclei and prominent, eosinophilic nucleoli; nuclear pseudo-inclusions; abundant eosinophilic-clear cytoplasm; and melanin pigment | S100, SOX10, Melan-A, HMB45, and MITF | Diverse: ARID2, BAP1, BRAF, GNAQ, HRAS, KIT, NF1, NRAS, and PTEN mutations; chromosomal gains/losses |
Malignant peripheral nerve sheath tumor | Fascicles of spindle cells with perivascular accentuation and alternating cellularity; staghorn vessels; necrosis; and heterologous differentiation | S100, SOX10 (focal), and loss of H3K27me3 | Inactivating mutations of NF1, CDKN2A/B, EED, and SUZ2 |
Diagnosis | Morphology | Common Genetic Alterations |
---|---|---|
Fibrous dysplasia | Irregular, curvilinear trabeculae of woven (or rarely lamellar) bone without osteoblast rimming; inconspicuous osteoblasts; sharpey fibers; and osteoclasts bland fibroblastic stroma | GNAS mutations (50–70%) |
Intraosseous ganglion | Cavity without lining; filled with mucoid viscous material | None (probably degenerative) |
Lipoma | Nodules of mature adipose tissue, often fibrotic | Unknown |
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Flucke, U.; van Noesel, M.M.; Siozopoulou, V.; Creytens, D.; Tops, B.B.J.; van Gorp, J.M.; Hiemcke-Jiwa, L.S. EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review. Diagnostics 2021, 11, 1093. https://doi.org/10.3390/diagnostics11061093
Flucke U, van Noesel MM, Siozopoulou V, Creytens D, Tops BBJ, van Gorp JM, Hiemcke-Jiwa LS. EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review. Diagnostics. 2021; 11(6):1093. https://doi.org/10.3390/diagnostics11061093
Chicago/Turabian StyleFlucke, Uta, Max M. van Noesel, Vasiliki Siozopoulou, David Creytens, Bastiaan B. J. Tops, Joost M. van Gorp, and Laura S. Hiemcke-Jiwa. 2021. "EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review" Diagnostics 11, no. 6: 1093. https://doi.org/10.3390/diagnostics11061093
APA StyleFlucke, U., van Noesel, M. M., Siozopoulou, V., Creytens, D., Tops, B. B. J., van Gorp, J. M., & Hiemcke-Jiwa, L. S. (2021). EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review. Diagnostics, 11(6), 1093. https://doi.org/10.3390/diagnostics11061093