title: Bronchial involvement in advanced stage lymphangioleiomyomatosis: histopathologic and molecular analyses.
abstract: Lymphangioleiomyomatosis (LAM), a rare progressive disease that almost exclusively affects women, is characterized by pulmonary cysts and neoplastic proliferation of smooth muscle-like cells (LAM cells). Airflow obstruction is a physiologic consequence that is commonly observed in LAM and has been attributed to narrowing of peripheral airways. However, histopathologic examinations of the entire airway have been precluded by the limited availability of such specimens. Here, we used explanted lung tissues from 30 LAM patients for a thorough histologic analysis with a special emphasis on the bronchi. We found bronchial involvement by LAM cells and lymphatics in all patients examined. Furthermore, a moderate to severe degree of chronic inflammation (73%), goblet cell hyperplasia (97%), squamous cell metaplasia (83%) of the epithelium, and thickening of basal lamina (93%) were identified in the bronchi. Because LAM cells are transformed by the functional loss of the TSC genes leading to a hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, we confirmed the expression of phospho-p70S6K, phospho-S6, phospho-4E-BP1, and vascular endothelial growth factor (VEGF)-D in LAM cells from all of the patients examined. In contrast, no protein expression of hypoxia-inducible factor 1α, a downstream molecule indicative of mTORC1 activation and leading to VEGF production, was detected in any patient. Our study indicates that late-stage LAM patients commonly have bronchi involved by the proliferation of both LAM cells and lymphatics and that chronic inflammation complicated their disease. Furthermore, the up-regulation of hypoxia-inducible factor 1α, a common event in mTORC1-driven tumor cells, does not occur in LAM cells and plays no role in VEGF-D expression in LAM cells.
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan. Electronic address: tkhyz@juntendo.ac.jp.
authors.forename: Takuo
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan; Department of Pathology, Japanese Red Cross Medical Center, Tokyo 150-0012, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kumasaka
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Mitani
authors.affiliation: Institute of Development, Aging and Cancer, Division of Cancer Control, Thoracic Surgery, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Institute of Development, Aging and Cancer, Division of Cancer Control, Thoracic Surgery, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Fengshi
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of General Thoracic Surgery, Okayama University, Okayama 700-8558, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oto
authors.affiliation: Department of General Thoracic Surgery, Okayama University, Okayama 700-8558, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
authors.affiliation: Department of General Thoracic, Breast and Pediatric Surgery, Faculty of Medicine, Fukuoka University, Fukuoka 814-0133, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiraishi
authors.affiliation: Department of General Thoracic, Breast and Pediatric Surgery, Faculty of Medicine, Fukuoka University, Fukuoka 814-0133, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Iwasaki
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Kieko
authors.initials: K
authors.lastname: Hara
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan; Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Ando
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan; Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan; Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Gunji-Niitsu
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan; Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kunogi
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo 158-0095, Japan; Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Seyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D015153:Blotting, Western; D001980:Bronchi / Q000737:chemistry* / Q000473:pathology* / Q000601:surgery; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D006965:Hyperplasia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D042601:Lymphatic Vessels / Q000737:chemistry* / Q000473:pathology* / Q000601:surgery; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000032:analysis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000032:analysis; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D010750:Phosphoproteins; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Airway obstruction; HIF-1α; Lung transplantation; Lymphangiogenesis; Lymphangioleiomyomatosis; VEGF-D; mTORC1