A Gain-of-Function Mutation in Mechanistic Target of Rapamycin Results in a Tuberous Sclerosis Complex-Like Manifestation of Parenchymal Lung Disease.

Abstract

Dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway rarely results in parenchymal lung disease, prototypically multifocal multinodular pneumocyte hyperplasia (MMPH) and lymphangioleiomyomatosis (LAM). Although LAM can occur sporadically, to our knowledge, MMPH has not previously been described independent of tuberous sclerosis complex (TSC), a syndrome caused by germline mutations in the tumor suppressor genes TSC1 or TSC2. We report the case of a man with a history of multiple malignancies who presented with incidental chest imaging findings of innumerable ground-glass nodules and several air-filled cysts, offering a diagnostic challenge. Histopathologic findings on lung biopsy identified nodular foci of pneumocyte hyperplasia with negative Human Melanoma Black-45 staining. Next-generation DNA sequencing of the tissue showed a previously described gain-of-function mutation in MTOR. We propose that this patient's TSC-like pulmonary disease is a direct result of this mutation, a novel finding that underscores the role of Next-generation DNA sequencing in cryptic histopathology.