title: Pulmonary Neoplasms in Patients with Birt-Hogg-Dubé Syndrome: Histopathological Features and Genetic and Somatic Events.
abstract: Birt-Hogg-Dubé syndrome (BHD) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene. Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas (RCCs). Currently, little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms. Herein, we describe 14 pulmonary neoplastic lesions in 7 patients with BHD. All patients were confirmed to have germline FLCN mutations. Neoplasm histologies included adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), atypical adenomatous hyperplasia (n = 8), and micronodular pneumocyte hyperplasia (MPH)-like lesion (n = 1). Five of the six adenocarcinoma/MPH-like lesions (83.3%) demonstrated a loss of heterozygosity (LOH) of FLCN. All of these lesions lacked mutant alleles and preserved wild-type alleles. Three invasive adenocarcinomas possessed additional somatic events: 2 had a somatic mutation in the epidermal growth factor receptor gene (EGFR) and another had a somatic mutation in KRAS. Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin (p-mTOR) and phospho-S6. Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling. Additional driver gene mutations were detected only in invasive cases, suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients.
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.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okudela
authors.affiliation: Department of Pathology, Kagawa Prefectural Central Hospital, Kagawa, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Thoracic Surgery, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Yoshioka
authors.affiliation: Department of Pathology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Toyonori
authors.initials: T
authors.lastname: Tsuzuki
authors.affiliation: Pathology and Oncology, University of Occupational and Environmental Health, Japan, Kita-Kyushu, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Shibuya
authors.affiliation: Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kita-Kyushu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yatera
authors.affiliation: Department of Internal Medicine, Saiseikai Fukui Hospital, Fukui, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shirasaki
authors.affiliation: Department of Pathology, Saiseikai Fukui Hospital, Fukui, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sudo
authors.affiliation: Department of Thoracic Surgery, National Disaster Medicine Center, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kimura
authors.affiliation: Department of Pathology, National Disaster Medicine Center, Tokyo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Thoracic Surgery, Showa University Northern Yokohama Hospital, Yokohama, Japan.
authors.forename: Shugo
authors.initials: S
authors.lastname: Uematsu
authors.affiliation: Department Pathology, Showa University Northern Yokohama Hospital, Yokohama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kunimura
authors.affiliation: Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ikuma
authors.initials: I
authors.lastname: Kato
authors.affiliation: Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakatani
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D056809:Alveolar Epithelial Cells / Q000473:pathology; D001483:Base Sequence; D058249:Birt-Hogg-Dube Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D058570:TOR Serine-Threonine Kinases