Beyond Nerve Tumors: Differential Diagnoses in Suspected Peripheral Nerve Sheath Tumors

A subset of patients with suspected peripheral nerve sheath tumors (PNSTs) are ultimately found to have non-neurogenic pathologies mimicking PNSTs. This study analyzed such “drop-out” cases from the German Peripheral Nerve Tumor Registry (PNTR) to identify diagnostic pitfalls, assess imaging value, and clarify the role of intraoperative and histological findings. This retrospective PNTR sub-study reviewed patients initially registered with suspected PNST who were later reclassified as “drop-out” cases due to intraoperative or histopathological findings inconsistent with PNST. Patients were treated at two high-volume nerve centers (University Hospital Essen and BKH Günzburg). Clinical data, imaging, surgical notes, and histopathology were analyzed descriptively, focusing on presentation, diagnostic discrepancies, nerve involvement, and surgical strategy. Of 590 registered patients, 50 (8.5%) were reclassified. The mean age was 50.8 years (range 19–90); 29 were men and 21 women. Most lesions were in the upper extremity (68%). Final diagnoses included benign soft tissue tumors (32%), malignant tumors (14%), inflammatory/immune-mediated (10%), non-neoplastic/reactive (10%), traumatic/regenerative neuromas (10%), cystic (10%), misdiagnoses/non-tumorous (10%), and vascular lesions (4%). Pain was the most frequent symptom (n = 33). Intraneural growth occurred mainly in inflammatory, reactive, and traumatic lesions, whereas non-PNSTs typically showed nerve contact only. Surgery ranged from fascicle biopsy to gross total resection. About one in twelve suspected PNSTs represented alternative pathologies. Red flags included absent intraneural growth, nonspecific pain, cubital tunnel clustering, and frequent biopsy need. Awareness of PNST mimics and meticulous imaging review are crucial to prevent misclassification and preserve function. • One in twelve presumed PNSTs showed a non-PNST final diagnosis. • PNST mimics commonly affected the upper extremity and ulnar nerve. • Soft-tissue, cystic, reactive, and malignant lesions frequently mimicked PNSTs. • High-resolution ultrasound adds key value in identifying PNST mimics. • Targeted biopsy, not resection, is essential when nerve involvement is unclear.