TY - JOUR
T1 - Pulmonary cysts of birt-hogg-dubé syndrome
T2 - A clinicopathologic and immunohistochemical study of 9 families
AU - Furuya, Mitsuko
AU - Tanaka, Reiko
AU - Koga, Shunsuke
AU - Yatabe, Yasushi
AU - Gotoda, Hiroko
AU - Takagi, Seiji
AU - Hsu, Yung Hsiang
AU - Fujii, Takeshi
AU - Okada, Akira
AU - Kuroda, Naoto
AU - Moritani, Suzuko
AU - Mizuno, Hideki
AU - Nagashima, Yoji
AU - Nagahama, Kiyotaka
AU - Hiroshima, Kenzo
AU - Yoshino, Ichiro
AU - Nomura, Fumio
AU - Aoki, Ichiro
AU - Nakatani, Yukio
PY - 2012/4
Y1 - 2012/4
N2 - Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling.
AB - Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling.
KW - Birt-Hogg-Dubé syndrome
KW - folliculin
KW - mTOR
KW - pulmonary cysts
KW - renal tumors
UR - http://www.scopus.com/inward/record.url?scp=84859066969&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859066969&partnerID=8YFLogxK
U2 - 10.1097/PAS.0b013e3182475240
DO - 10.1097/PAS.0b013e3182475240
M3 - Article
C2 - 22441547
AN - SCOPUS:84859066969
SN - 0147-5185
VL - 36
SP - 589
EP - 600
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
IS - 4
ER -