Lymphangioleiomyomatosis: Calling It What It Is: A Low-Grade, Destructive, Metastasizing Neoplasm
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease primarily affecting women that has historically been classified and clinically managed as a nonneoplastic interstitial lung disease.The purpose of this document is to outline the accumulating data that support reclassification of LAM as a low-grade, destructive, metastasizing neoplasm.This major conceptual shift actually began more than 10 years ago in the pathology community.The 1999 World Health Organization classification of lung tumors regarded LAM as a "tumour-like" lesion, and in the 2004 classification, it was codified as a mesenchymal neoplasm (1, 2).The pulmonary community seems to have been slower to adopt this viewpoint, however, and continues to consider LAM one of the "other" idiopathic interstitial pneumonias.LAM occurs in patients with tuberous sclerosis complex (TSC) and also as a sporadic illness in patients without heritable disease.In either case, the smooth muscle-like "LAM cells" that diffusely infiltrate the lungs, lymphatics, and angiomyolipomas of patients with LAM have a low proliferative index and little or no evidence of cellular atypia, suggestive of a benign process.However, mounting genetic and cellular evidence has shown that, despite their innocent appearance, LAM cells exhibit the features and behaviors of a neoplasm.The finding of loss of heterozygosity for tuberous sclerosis complex genes in the lung, kidney, and lymphatic lesions of patients with LAM is consistent with clonal origins for these tumors.In the handful of patients who have had multiple tissues available for sequencing, identical TSC mutations found in the angiomyolipomas, lymph nodes, and lungs are indicative of seeding from a common, most likely extrapulmonary source (3).Angiomyolipomas have been proposed as a potential primary tumor, but they are present in a minority of patients with sporadic LAM (4).The expression of smooth muscle markers (5) and steroid hormone (estrogen and progesterone) receptors ( 6), variation of symptoms with the menstrual cycle (7), and report of LAM lesions in 9 of 10 resected uterine specimens from patients with LAM in a small series (8) are potentially consistent with a uterine primary tumor, at least in some patients.The TSC mutations that occur in LAM result in inappropriate, constitutive signaling through the