Wall disruption and cystic dilatation of interlobular septa in Birt-Hogg-Dubé syndrome

Several hypotheses have been proposed to explain the mechanisms underlying pulmonary cyst formation in Birt-Hogg-Dubé syndrome (BHDS). We examined four patients with BHDS from two families and identified novel histopathological features potentially involved in cyst formation and pneumothorax. Genetic testing was performed in one patient from each family, and both harbored the same pathogenic variant of FLCN (c.1347_1353dup). Histological analysis revealed cystic dilatation and focal disruption of the interlobular septa, with communication between pulmonary cysts, alveoli, and septal structures. These findings suggest the possibility of air tracking into and along the interlobular septa and indicate that structural alterations of the interlobular septa may contribute to the development of pulmonary cysts and pneumothorax in BHDS.