Background Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor of intermediate malignancy exhibiting a broad anatomical distribution. Herein, we characterize primary AFH across various typical and highly unusual anatomical locations. As an enigmatic entity, AFH presents significant diagnostic challenges due to its variable morphology and propensity to mimic other benign and malignant lesions, thereby hindering accurate early recognition. Methods We retrospectively analyzed seven cases of primary AFH diagnosed at our center. All seven cases were systematically evaluated for clinicopathological features, morphological variations, immunophenotypes, molecular profiles, treatment modalities, and clinical follow-up outcomes. Results The cohort (age range, 9–74 years; predominantly female) presented with localized tumors in diverse sites, including the lower extremities, adrenal gland, retroperitoneum, rib, scalp, and spinal canal. Notably, over half of the cases (4/7) were initially misdiagnosed in outside institutions. Histologically, all tumors exhibited classic nodular architecture and pseudoangiomatous spaces, alongside significant morphological variations such as myxoid stroma, marked collagen sclerosis, and intratumoral lymphoid tissue. Immunohistochemically, these tumors demonstrated positivity for Desmin (6/7), ALK (2/5), and EMA (2/6). Crucially, partial to diffuse CDK4 expression was observed in all tested patients (3/3) without evidence of CDK4 or MDM2 amplification. Molecular testing was performed in five patients, revealing EWSR1 rearrangements in all cases (5/5), including EWSR1::ATF1 (n = 2) and EWSR1::CREB1 (n = 1) fusions. No recurrence or metastasis was documented during 8–31 months of follow-up (median, 23 months). Conclusion AFH is a clinically and morphologically diverse mesenchymal tumor with an excellent prognosis but substantial diagnostic pitfalls. Our findings highlight the critical value of recognizing variant morphologic features and the novel non-amplification-dependent CDK4 expression to differentiate AFH from MDM2/CDK4-amplified lipomatous tumors. Definitive diagnosis necessitates the integration of histomorphology, targeted immunoprofiling, and molecular confirmation. Greater awareness of these atypical clinicopathological presentations can prevent misdiagnosis and ensure appropriate management.
