Novel Pathogenesis of Pulmonary Lymphangioleiomyomatosis: A State of Neoplastic Senescence

Abstract

A novel pathogenesis of pulmonary lymphangioleiomyomatosis (PLAM) is presented incorporating a review of clinical and pathology research on the disease together with a review of research in the field of senescence. The clinical and radiographic progression of PLAM more closely resembles a progressive chronic interstitial pneumonia rather than a metastatic neoplasm.  In this model of pathogenesis it is proposed that: 1) the primary site of origin for this disease is the Mullerian smooth muscle found in the female reproductive tract and this accounts for the striking female predominance of the disease; 2) the tumor spreads to the lungs via a mechanism similar to lymphangitic carcinomatosis and this accounts for its universal symmetric and bilateral distribution; 3) there is a mutational basis for a senescence-associated growth arrest which helps explain the absence of enlarging tumor masses in the lung despite years of disease duration; and 4) PLAM cells have a senescence-associated secretory phenotype with implications for the pathogenesis of the cystic transformation of the lungs. The secretory phenotype of PLAM cells is reviewed and the overlap with the senescence associated secretory phenotype products of known senescent cells is documented. The role of the switch to glycolytic metabolism (Warburg state) by PLAM cells is described. Finally, the “contradictory signals” hypothesis for the induction of the senescent state is explored and its role in PLAM described.