Primary malignant melanoma of the lung with C-KIT mutation and SRD5A3-KIT fusion

Primary pulmonary malignant melanoma (PMML), an exceedingly rare aggressive neoplasm originating from bronchial mucosal melanocytes, is characterized by early metastatic dissemination and high mortality. While over 95% of malignant melanomas are cutaneous in origin, fewer than 80 PMML cases have been documented globally. The molecular pathogenesis of PMML remains poorly defined, with less prior genomic studies utilizing Next-generation sequencing (NGS) reported to date.

A 68-year-old asymptomatic woman was referred to our institution in June 2022 after a routine health screening revealed a solitary pulmonary nodule. Chest CT demonstrated a 1.2 cm × 0.8 cm hypodense nodular opacity nodule in the posterior segment of the left upper lobe. The lesion remained stable during a 2-month observation period. Despite the absence of respiratory symptoms (e.g., cough, hemoptysis) or constitutional signs (e.g., weight loss), the patient elected surgical resection due to persistent malignancy concerns.

Histopathological examination revealed tumor cells exhibiting epithelioid to spindle-shaped morphology, characterized by prominent nucleoli and intracytoplasmic melanin deposition (hematoxylin and eosin staining). Immunohistochemical analysis demonstrated diffuse and strong positivity for S-100, HMB-45, and Melan-A. Based on the histomorphological features and immunohistochemical profile, a diagnosis of malignant melanoma was established. NGS detected a somatic KIT exon 11 mutation (c.1727 T > C, p. Leu576Pro; variant allele frequency: 20.1%) and identified an SRD5A3-KIT gene fusion involving transcript variants NM_024592.4 (SRD5A3) and NM_000222.2 (KIT), with breakpoints in Exon 5 of SRD5A3 and Exon 6 of KIT. The fusion variant showed a somatic mutation frequency of 24.8%. These findings not only expand the molecular landscape of PMML but also suggest therapeutic opportunities through targeted kinase inhibition. This case underscores the critical role of integrated multimodal analysis (radiological-pathological-molecular) in characterizing rare malignancies.