Lung Cysts in Birt-Hogg-Dube Syndrome: Unique Histopathological Features and Accelerated mTOR-Mediated Signaling
Mitsuko Furuya, Reiko Tanaka, Shunsuke Koga, Yasushi Yatabe, Hiroko Gotoda, Seiji Takagi, Yung-Hsiang Hsu, Takeshi Fujii, Yoji Nagashima, Kiyotaka Nagahama, Kenzo Hiroshima, Ichiro Yoshino, Ichiro Aoki, Osamu Matsubara, Akira Oka, Suzuko Moritani, Yukio Nakatani. Yokohama City University Graduate School of Medicine, Yokohama, Japan; Chiba University Graduate School of Medicine, Chiba, Japan; Aichi Cancer Center, Nagoya, Japan; Sapporo Kosei Hospital, Sapporo, Japan; Kucchan Kosei Hospital, Kucchan, Japan; Buddhist TzuChi General Hospital, Hualien, Taiwan; Toranomon Hospital, Tokyo, Japan; Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan; National Defense Medical College, Tokorozawa, Japan; Nishi Niigata Chuo Hospital, Niigata, Japan; Nagoya Medical Center, Nagoya, Japan
Background: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, renal cell tumors and pulmonary cysts with recurrent pneumothoraces. Pulmonary manifestations often constitute the initial clinical presentation, and the correct diagnosis is mandatory for proper patients' care. Histopathology of the BHD lung cysts, however, is poorly understood. BHD is caused by mutations in the BHD gene, which encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor, regulating cellular activity through the mammalian target of rapamycin (mTOR) pathway.
Design: We investigated the histopathology of BHD lung cysts, using specimens resected for pneumothoraces in 12 patients of 9 BHD families. The patients were in their late 30s to 60s with a female predominance. Conventional and immuonohistochemical stainings were performed with special reference to FLCN and related proteins involved in the mTOR pathway. Genetic analysis of the germ line BHD gene mutation was also performed.
Results: Genetic tests confirmed all the patients examined had heterozygous BHD gene mutations. Histopathologically, the BHD lung cysts showed unique features: 1) part of the cyst wall is often abutting or incorporated within the the pleura, interlobular septa or bronchovascular bundles; 2) the cyst is lined by alveolar pneumocytes, attenuated or with a predominance of type II pneumocyte-like cuboidal cells; and 3) some cysts show internal septation by alveolar walls, or a complex alveolar pattern. Nonspecific blebs and bullae were also seen, but were thought to be secondary changes due to pneumothoraces or intrapulmonary rupture. Immunohistochemically, the lining cells of the cysts expressed pneumocyte markers and FLCN. These cells also expressed phospho-S6 strongly, suggesting activation of the mTOR pathway.
Conclusions: The BHD lung cysts have unique histopathological features that help render the correct diagnosis. They may be regarded as hamartoma-like aberrant cystic alveolar formation, possibly under activation of mTOR pathway due to haploinsufficiency of FLCN.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 304, Wednesday Morning