Bronchial involvement in advanced stage lymphangioleiomyomatosis: Histopathologic and molecular analyses

Takuo Hayashi, Toshio Kumasaka, Keiko Mitani, Yoshinori Okada, Takashi Kondo, Hiroshi Date, Fengshi Chen, Takahiro Oto, Shinichiro Miyoshi, Takeshi Shiraishi, Akinori Iwasaki, Kieko Hara, Tsuyoshi Saito, Katsutoshi Ando, Etsuko Kobayashi, Yoko Gunji-Niitsu, Makiko Kunogi, Kazuhisa Takahashi, Takashi Yao, Kuniaki Seyama

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Summary 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.

Original languageEnglish
Pages (from-to)34-42
Number of pages9
JournalHuman Pathology
Publication statusPublished - Apr 1 2016


  • Airway obstruction
  • HIF-1α
  • Lung transplantation
  • Lymphangiogenesis
  • Lymphangioleiomyomatosis
  • VEGF-D
  • mTORC1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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