Table 2.
Differential diagnoses for acral MYH10::ALK fusion superficial mesenchymal neoplasm.
| Differential diagnosis | Acral/plantar site predilection | Histological overlap | Key distinguishing features |
|---|---|---|---|
| Epithelioid fibrous histiocytoma (EFH) / SAMS | Predominantly lower extremity (~71%); uncommon at acral sites | ALK+, CD34-/+, S100-/+; epithelioid or spindle cell morphology, sparse fibrous or myxoid stroma | Typically dermal, cytologically bland, low mitotic activity, no necrosis; benign behavior; lacks high-grade features |
| Inflammatory myofibroblastic tumor (IMT) | Rare in skin, even rarer at acral sites | ALK+ (~75%); spindle cells in fibromyxoid stroma with inflammatory infiltrate | Desmin-/+, SMA+; prominent lymphoplasmacytic infiltrate; CD34−, S100−; characteristic fusion partners (e.g., TPM3) |
| NTRK-rearranged spindle cell neoplasm | Occurs in extremities, including acral sites | Co-expression of S100 and CD34; perivascular hyalinization | SOX10− NTRK1/2/3; ALK− by IHC; requires molecular confirmation |
| Clear cell sarcoma | Predilection for tendons/aponeuroses of foot and ankle in young adults | S100+; epithelioid & spindle cells in nests within fibrous septa. | HMB-45+, Melan-A+, SOX10+; EWSR1::ATF1 or EWSR1::CREB1/CREM fusion; CD34−; melanocytic differentiation |
| Synovial sarcoma | Common malignant soft tissue tumor of the foot | Spindle and/or round cells; rarely biphasic | EMA+, cytokeratin+/-; SS18::SSX fusion; CD34−; biphasic or monophasic architecture; SS18 IHC+; SS18::SSX1/2 fusions |
| Superficial CD34-positive fibroblastic tumor | Predominantly lower extremity (~73%) | CD34+; spindle pleomorphic cells in superficial soft tissue |
Glassy cytoplasm, nuclear inclusions; PRDM10 rearrangement; S100−; CADM3+, WT1+; ALK− |
| Extraskeletal myxoid chondrosarcoma | Rare in acral/plantar sites; case reports in plantar fascia | Myxoid stroma with cords/nests of round-to-spindled cells; variable S100 | S100+, CD117+/-, synaptophysin+/-, INSM1+, p63+/-; NR4A3 rearrangement (e.g., EWSR1::NR4A3; rarely TAF15 & others); CD34−; lobulated architecture; indolent but metastatic potential |