Pathology of Birt-Hogg-Dubé syndrome: A special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review

Pathol Int. 2019 Jan;69(1):1-12. doi: 10.1111/pin.12752. Epub 2019 Jan 11.


Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts and renal cell carcinomas. Affected individuals inherit germline mutations in the folliculin gene (FLCN). Approximately 150 pathogenic FLCN variants have been identified worldwide. Many Japanese probands of BHD syndrome were first identified by pulmonologists and/or radiologists during treatment of pneumothoraces. Lung specimens obtained through video-assisted thoracoscopic surgery (VATS) have characteristic features unique to BHD syndrome; however, pathologists often miss key findings and diagnose patients with "bullae/blebs". The pleural and subpleural cysts of BHD syndrome-associated lung diseases are often modified by tissue remodeling and can be difficult to distinguish from emphysematous bullae/blebs. Intraparenchymal unruptured cysts tend to retain distinctive features that are different from other cystic lung diseases. Here, we review the clinicopathological findings of BHD syndrome in a Japanese population based on data from 200 probands diagnosed by genetic testing and a total of 520 symptomatic family members identified through BHD-NET Japan ( Detailed morphology of pulmonary cysts obtained from VATS and autopsied lung specimens are described, and pathological clues for differentiating miscellaneous cystic lung disorders are discussed.

Keywords: Birt-Hogg-Dubé syndrome; FLCN; germline mutation; histopathology; lung; pulmonary cyst.

Publication types

  • Review

MeSH terms

  • Birt-Hogg-Dube Syndrome / genetics
  • Birt-Hogg-Dube Syndrome / pathology*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / pathology*
  • Cysts / genetics
  • Cysts / pathology*
  • Germ-Line Mutation
  • Humans
  • Japan
  • Lung / pathology
  • Lung Diseases / genetics
  • Lung Diseases / pathology*
  • Proto-Oncogene Proteins / genetics*
  • Skin / pathology
  • Tumor Suppressor Proteins / genetics*


  • FLCN protein, human
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins

Supplementary concepts

  • Cystic Disease Of Lung