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Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families.
Am J Surg Pathol. 2012 Apr; 36(4):589-600.AJ

Abstract

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling.

Authors+Show Affiliations

Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22441547

Citation

Furuya, Mitsuko, et al. "Pulmonary Cysts of Birt-Hogg-Dubé Syndrome: a Clinicopathologic and Immunohistochemical Study of 9 Families." The American Journal of Surgical Pathology, vol. 36, no. 4, 2012, pp. 589-600.
Furuya M, Tanaka R, Koga S, et al. Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol. 2012;36(4):589-600.
Furuya, M., Tanaka, R., Koga, S., Yatabe, Y., Gotoda, H., Takagi, S., Hsu, Y. H., Fujii, T., Okada, A., Kuroda, N., Moritani, S., Mizuno, H., Nagashima, Y., Nagahama, K., Hiroshima, K., Yoshino, I., Nomura, F., Aoki, I., & Nakatani, Y. (2012). Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. The American Journal of Surgical Pathology, 36(4), 589-600. https://doi.org/10.1097/PAS.0b013e3182475240
Furuya M, et al. Pulmonary Cysts of Birt-Hogg-Dubé Syndrome: a Clinicopathologic and Immunohistochemical Study of 9 Families. Am J Surg Pathol. 2012;36(4):589-600. PubMed PMID: 22441547.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. AU - Furuya,Mitsuko, AU - Tanaka,Reiko, AU - Koga,Shunsuke, AU - Yatabe,Yasushi, AU - Gotoda,Hiroko, AU - Takagi,Seiji, AU - Hsu,Yung-Hsiang, AU - Fujii,Takeshi, AU - Okada,Akira, AU - Kuroda,Naoto, AU - Moritani,Suzuko, AU - Mizuno,Hideki, AU - Nagashima,Yoji, AU - Nagahama,Kiyotaka, AU - Hiroshima,Kenzo, AU - Yoshino,Ichiro, AU - Nomura,Fumio, AU - Aoki,Ichiro, AU - Nakatani,Yukio, PY - 2012/3/24/entrez PY - 2012/3/24/pubmed PY - 2012/5/16/medline SP - 589 EP - 600 JF - The American journal of surgical pathology JO - Am J Surg Pathol VL - 36 IS - 4 N2 - Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling. SN - 1532-0979 UR - https://www.unboundmedicine.com/medline/citation/22441547/Pulmonary_cysts_of_Birt_Hogg_Dubé_syndrome:_a_clinicopathologic_and_immunohistochemical_study_of_9_families_ L2 - https://doi.org/10.1097/PAS.0b013e3182475240 DB - PRIME DP - Unbound Medicine ER -