TSC gene-associated lesions of the lung

Pathogenetic alterations of tumor suppressor genes TSC1 and TSC2 are responsible for the development of tuberous sclerosis complex (TSC) and various sporadic diseases, including sporadic lymphangioleiomyomatosis (LAM). TSC can be inherited and non-inherited and is characterized by indolent tumor formation in multiple organs. The most important pulmonary manifestation of TSC is LAM. It affects the majority of female and a small subset of male patients, heavily impacting their quality of life and survival. It is a cystic lung disease, which is now considered a PEComa-type neoplasm. In addition to the TSC-associated form (TSC-LAM), LAM can also occur sporadically (S-LAM), almost exclusively in women. Both forms present with proliferation of immature smooth muscle cells, resulting in cystic destruction of the pulmonary parenchyma and emergence of respiratory symptoms, including dyspnea and pneumothorax. Currently, sirolimus is the only FDA-approved treatment option for LAM patients; however, a subgroup of patients either do not respond or tolerate therapy. Recently published data has shed light on the heterogeneity of LAM and the importance of the tumor microenvironment, which may serve as new aspects for future research. Other TSC gene-associated lesions of the lung include multifocal micronodular pneumocyte hyperplasia (MMPH) and non-LAM PEComa (clear cell sugar tumor). While MMPH may not be progressive or require clinical treatment, it might require differentiation from atypical adenomatous hyperplasia or lepidic adenocarcinoma of the lung.