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We present the case of a 73-year-old male with Neurofibromatosis Type 1, chronic myelogenous leukemia in remission, prostate cancer, and basal cell carcinoma. He had recurrent hospitalizations for shortness of breath, seizures, and stroke-like episodes with aphasia and left-sided weakness. On exam, he was alert, oriented, and following commands, with diffuse cutaneous neurofibromas, left-sided hypertonia, pronator drift, brisk reflexes, palmar grasp reflex, diminished sensation, dysmetria, and visual hallucinations. Brain imaging showed multiple metastases with vasogenic edema. Further evaluation revealed pulmonary nodules and a pancreatic head mass. Bronchoscopy with biopsy demonstrated tumor cells in single cells and aggregates, with vacuolated cytoplasm and enlarged, spindle-shaped nuclei. Immunohistochemistry was positive for HMB45, SOX-10, and MART-1, and negative for S100, pancytokeratin, TTF-1, chromogranin, and CD56. H3K27me3 expression was retained. Genomic profiling identified mutations in BRAF (N581T), CD22 (G375E), and NF1 (R1276). The differential diagnosis included metastatic melanoma versus malignant peripheral nerve sheath tumor. Given the patient’s NF1 history and no known primary melanoma, MPNST was more likely, though the primary lesion was not identified. The management was palliative. Prognosis remained poor.

Malignant Peripheral Nerve Sheath Tumors are rare and diagnostically challenging, particularly due to overlap with melanoma. While no single definitive marker exists, immunohistochemical stains such as S100, SOX10, and H3K27me3 can aid in differentiation. Clinical correlation is critical, especially in patients with NF1 and no cutaneous melanoma, highlighting the importance of integrating molecular, histopathological, and clinical data for accurate diagnosis and management.