Examination of the histogenesis of epithelial cysts in angiomyolipoma with epithelial cysts (AMLEC) using GPNMB and TSC2 immunostains.

Angiomyolipoma with epithelial cysts (AMLECs) is an uncommon subtype of angiomyolipoma (AML), with both a classic AML component and a bland epithelial-lined cystic component. The histogenesis of the cysts in AMLECs is unclear. Two main hypotheses have been proposed: the cysts represent entrapped dilated native tubules versus the epithelial differentiation of AML. Mutations of tuberous sclerosis genes are frequently observed in AML. Glycoprotein non-metastatic melanoma protein B (GPNMB) exhibits a low expression in most normal tissues and is transcriptionally activated by TFE3 and TFEB. Loss of TSC1/2/mTOR function paradoxically activates TFE3 and TFEB, resulting in a strong diffuse GPNMB expression. We explored the histogenesis of epithelial cysts in five AMELC cases using HMB45, Cathepsin-K, GPNMB and TSC2 immunostains. GPNMB was strongly and diffusely positive in the classic spindle cell component in all five AMLECs, but not in the cystic epithelium and associated blood vessels. Correspondingly, loss of TSC2 labeling was only seen in the classic spindle cell AML but not in the cystic epithelium and vessels. HMB45 was positive in the classic spindle cell component and not in the cystic epithelium or blood vessels. Cathepsin-K stained both spindle and epithelial components but was weaker in the epithelium. Our study demonstrates that strong diffuse expression of GPNMB correlates with loss of TSC2 expression. The epithelial cysts and associated vessels in AMLECs do not harbor TSC pathway alteration, thus supporting the idea that they are entrapped native tubules and vasculatures, not part of the neoplasia.