title: Benign clear cell "sugar" tumor of the lung in a patient with Birt-Hogg-Dubé syndrome: a case report.
abstract: BACKGROUND
  Birt-Hogg-Dubé (BHD) syndrome is a rare inherited autosomal genodermatosis and caused by germline mutation of the folliculin (FLCN) gene, a tumor suppressor gene of which protein product is involved in mechanistic target of rapamycin (mTOR) signaling pathway regulating cell growth and metabolism. Clinical manifestations in BHD syndrome is characterized by fibrofolliculomas of the skin, pulmonary cysts with or without spontaneous pneumothorax, and renal neoplasms. There has been no pulmonary neoplasm reported in BHD syndrome, although the condition is due to deleterious sequence variants in a tumor suppressor gene. Here we report, for the first time to our knowledge, a patient with BHD syndrome who was complicated with a clear cell "sugar" tumor (CCST) of the lung, a benign tumor belonging to perivascular epithelioid cell tumors (PEComas) with frequent causative relation to tuberous sclerosis complex 1 (TSC1) or 2 (TSC2) gene.
  
  
  METHODS
  In a 38-year-old Asian woman, two well-circumscribed nodules in the left lung and multiple thin-walled, irregularly shaped cysts on the basal and medial area of the lungs were disclosed by chest roentgenogram and computer-assisted tomography (CT) during a preoperative survey for a bilateral faucial tonsillectomy. Analysis of the resected tumor showed large polygonal cells with clear cytoplasm proliferating in a solid pattern. Immunohistochemistry revealed that these tumor cells were positive for microphthalmia-transcription factor, S100, and CD1a but negative for HMB45, indicating that the tumor was a CCST. Genetic testing indicated that the patient had a germline mutation on exon 12 of the FLCN gene, i.e., insertion of 7 nucleotides (CCACCCT) (c.1347_1353dupCCACCCT). Direct sequencing of the FLCN exon 12 using genomic DNA obtained from her microdissected CCST cells clearly revealed loss of the wild-type FLCN sequence, which confirmed complete functional loss of the FLCN gene. On the other hand, no loss of heterozygosity around TCS1- or TSC2-associated genetic region was demonstrated.
  
  
  CONCLUSIONS
  To our knowledge, this is the first report of CCST of the lung in a patient with BHDS, indicating that CCST should be added to the spectrum of pulmonary manifestations of BHDS.
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, 4-8-1 Seta, Setagaya-Ku, Tokyo, 158-0095, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Gunji-Niitsu
authors.affiliation: Department of Pathology, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shibuya-Ku, Tokyo, 150-8935, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, 4-8-1 Seta, Setagaya-Ku, Tokyo, 158-0095, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kumasaka
authors.affiliation: Departments of Pathology, JCHO Tokyo Yamate Medical Center, 3-22-1 Hyakunin-cho, Shinjuku-Ku, Tokyo, 169-0073, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Kitamura
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, 4-8-1 Seta, Setagaya-Ku, Tokyo, 158-0095, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Hoshika
authors.affiliation: Human Pathology, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, 4-8-1 Seta, Setagaya-Ku, Tokyo, 158-0095, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Respiratory Medicine, JCHO Tokyo Yamate Medical Center, 3-22-1 Hyakunin-cho, Shinjuku-Ku, Tokyo, 169-0073, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tokuda
authors.affiliation: Thoracic Surgery, JCHO Tokyo Yamate Medical Center, 3-22-1 Hyakunin-cho, Shinjuku-Ku, Tokyo, 169-0073, Japan.
authors.forename: Riichiro
authors.initials: R
authors.lastname: Morita
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, 4-8-1 Seta, Setagaya-Ku, Tokyo, 158-0095, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Human Pathology, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, 4-8-1 Seta, Setagaya-Ku, Tokyo, 158-0095, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Mitani
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kikkawa
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3, Hongo, Bunkyo-Ku, Tokyo, 113-8431, Japan. kseyama@juntendo.ac.jp.|The Study Group of Pneumothorax and Cystic Lung Diseases, 4-8-1 Seta, Setagaya-Ku, Tokyo, 158-0095, Japan. kseyama@juntendo.ac.jp.
authors.forename: Kuniaki
authors.identifier: http://orcid.org/0000-0002-1374-2500
authors.initials: K
authors.lastname: Seyama
mesh_terms: D000328:Adult; D058249:Birt-Hogg-Dube Syndrome / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005091:Exons; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D016254:Mutagenesis, Insertional; D010375:Pedigree; D054973:Perivascular Epithelioid Cell Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014057:Tomography, X-Ray Computed; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA
keywords: Folliculin; Germline mutation; Loss of heterozygosity; Tumor suppressor gene syndrome