Table 12.
Differential diagnoses of EWSR1-SMAD3-positive fibroblastic tumor.
| 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) |