title: Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families.
abstract: 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.
authors.affiliation: Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Furuya
authors.forename: Reiko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Koga
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Gotoda
authors.forename: Seiji
authors.initials: S
authors.lastname: Takagi
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujii
authors.forename: Akira
authors.initials: A
authors.lastname: Okada
authors.forename: Naoto
authors.initials: N
authors.lastname: Kuroda
authors.forename: Suzuko
authors.initials: S
authors.lastname: Moritani
authors.forename: Hideki
authors.initials: H
authors.lastname: Mizuno
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nagahama
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yoshino
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aoki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakatani
mesh_terms: D000328:Adult; D000368:Aged; D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058249:Birt-Hogg-Dube Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology*; D003560:Cysts / Q000150:complications / Q000235:genetics / Q000473:pathology*; D005192:Family Health; D005260:Female; D006222:Hamartoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000473:pathology*; D008171:Lung Diseases / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009378:Neoplasms, Multiple Primary; D011030:Pneumothorax / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D038601:Ribosomal Protein S6 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D038601:Ribosomal Protein S6; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases