GPNMB immunohistochemistry distinguishes diagnostically challenging cases of lymphangioleiomyomatosis from other mesenchymal neoplasms presenting with cystic lung metastases.

Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm in the family of perivascular epithelioid cell (PEComa) tumors with myomelanocytic differentiation. Metastatic LAM causes cystic lung disease, but diagnosis may be hampered by low tumor burden, limited expression of melanocytic markers, and pathologic mimics that can also cause cystic lung metastases. Glycoprotein non-metastatic melanoma protein B (GPNMB) is an emerging marker for PEComas, but its diagnostic utility in distinguishing LAM from pathologic mimics remains incompletely understood. Biopsies of cystic lung metastases were retrieved including LAM (n = 17), gynecologic metastasizing leiomyoma or low-grade leiomyosarcoma (n = 10), endometrial stromal sarcoma (n = 6), cellular fibrous histiocytoma/dermatofibroma (n = 3), angiosarcoma (n = 3), and non-LAM PEComa (n = 1). GPNMB immunohistochemistry was performed on each case, quantified, and compared to melan-A, HMB45, MiTF, and cathepsin K. All 17 LAM cases and one non-LAM PEComa expressed GPNMB, with most LAM cases showing expression in >75% of tumor cells. GPNMB also highlighted alveolar macrophages and two metastatic dermatofibromas, representing potential diagnostic pitfalls. Cathepsin K also diffusely highlighted LAM and the non-LAM PEComa. In contrast, expression of other melanocytic markers in LAM varied and was often absent or minimal. Our data show that GPNMB is highly expressed by LAM in the lung, with immunohistochemistry performance similar to cathepsin K but superior to traditional melanocytic markers. GPNMB may be useful to confirm diagnostically challenging cases of LAM and to exclude most non-PEComatous mimics presenting with cystic lung metastases, but metastatic dermatofibromas can be a diagnostic pitfall.