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1 Enterprise Interest Nothing to declare
2 Pulmonary Pathology of Birt-Hogg-Dubé (BHD) Syndrome Mitsuko FURUYA, Ikuma KATO, Reiko TANAKA, Yukio NAKATANI. Yokohama City University, Japan Chiba University, Japan
3 COI Disclosure Information Mitsuko Furuya I have no financial relationships to disclose.
4 Birt-Hogg-Dubé (BHD) Syndrome <Autosomal dominant disorder> Germline mutation of FLCN (17p.11.2) Skin :Fibrofolliculomas Lung:Pulmonary cysts, Pneumothorax Kidney:RCCs Prognosis determining disease
5 Pulmonary cysts in BHD
6 Skin Manifestations in BHD Fibrofolliculomas/ Fibrous papules Kamada T et al. J Dermatol, 2015, 42:
7 Multiple RCCs in BHD <Prognosis-determining disease> Furuya M et al. Cancer Sci. 2015;106:315-23
8 165 Japanese BHD Families (N=421) FLCN mutation hot spots of Japanese BHD families Histopathology of BHD Pulmonary cysts Neoplasms in BHD lungs
9 165 Japanese BHD Families (N=421) FLCN mutation hot spots of Japanese BHD families Histopathology of BHD Pulmonary cysts Neoplasms in BHD lungs
10 FLCN Mutation Hot Spots in BHD families 39 patterns (exon 4~14) exon 14 exon 4 (N = 165) exon 13 c.1533_1536del (18%) exon 12 c.1347_1353dup (16%) exon 11 c.1285dupc (30%) exon 10 Furuya M, et al. Clin Genet 2016; 90:
11 165 Japanese BHD Families (N=421) FLCN mutation hot spots of Japanese BHD families Histopathology of BHD Lung (97 tissues) Neoplasms in BHD lungs
12 Pneumothorax (PTX): Major Symptom to be Suspected of BHD Lung cysts w/o PTX 8 (5 %) Unknown 3 Others 2 RCC 42 (25.5 %) PTX 110 (67%) 165 probands Furuya M, et al. Clin Genet 2016; 90:
13 Number of patients Number of patients Most RCC Patients Have Episodes of Pneumothorax (26/43, 60.5%) Age of initial pneumothorax Age of initial diagnosis of RCC 15 Peak 10 Peak (Age) 0 (Age) Furuya M, et al. Clin Genet 2016; 90:
14 Subpleural Cysts Preferentially Localize in Lower Lobes, Easily Rupture. Furuya M, et al. Am J Surg Pathol. 2012; 66:
15 Pulmonary Cysts ( ) Abut on Bronchovascular Bundles Br PV Br PV PV B B Br Br: bronchus, bronchiole PV: pulmonary vein Furuya M, Nakatani Y. J Clin Pathol. 2013; 66:
16 Pulmonary Cysts ( ) Abut on Each Cyst B PV Br PV B: bronchus, bronchiole, PV: pulmonary vein Furuya M, Nakatani Y. J Clin Pathol. 2013; 66:
17 Pulmonary Cysts ( ) Abut on Each Cyst B PV Br PV B: bronchus, bronchiole, PV: pulmonary vein Furuya M, Nakatani Y. J Clin Pathol. 2013; 66:
18 Pulmonary Cysts ( ) Abut on Each Cyst B PV Br PV B: bronchus, bronchiole, PV: pulmonary vein Furuya M, Nakatani Y. J Clin Pathol. 2013; 66:
19 Pulmonary Cysts ( ) Abut on Each Cyst B PV Br PV B: bronchus, bronchiole, PV: pulmonary vein Furuya M, Nakatani Y. J Clin Pathol. 2013; 66:
![Bullae]](/docs-images/86/93315164/images/20-3.jpg "Pro-SPC CAM5.")
20 Cyst Walls Lined by Alveolar Epithelium [ Epithelial Cysts = Bullae] Pro-SPC CAM5.2 Koga et al. Pathol Int 2009; 59:
21 Activated mtor Signaling in BHD Lung N N N BHD lung FLCN mtor p-mtor (Ser2448) p-s6 (Ser 235/236) p-mtor p-akt p-akt (Ser 473) HIF-1α VEGF p-s6 HIF-1 VEGF β-actin Nishii T et al. Pathol Int. 63:45-55, 2013
22 How BHD Cysts Develop and Rupture? Hamartomas formation of giant alveoluslike structure Abut on bronchovascular bundles Abnormal epithelial/mesenchymal interaction Localize in mechanical stress-prone areas (diaphragm/mediastinum) Furuya M, Nakatani Y. J Clin Pathol. 2013; 66:
23 165 Japanese BHD Families (N=421) FLCN mutation hot spots of Japanese BHD families Histopathology of BHD Pulmonary cysts Neoplasms in BHD lungs
24 Miscellaneous Neoplasms in BHD Colorectal cancer or polyp 16 Liver cyst or hemanigoma 15 Lung neoplasms (including Adenoca) 15 Thyroid carcinoma or cyst 12 Salivary gland tumor or cyst 4 Furuya M, et al. Clin Genet 2016; 90:
25 Neoplasms of Pneumocyte Lineage Papillary adenocarcinoma Micronodular pulmonary hyperplasia-like lesion Furuya M, et al. PLoS One. 2016;11:e
26 A Case (LP-5) with Multiple AAHs V Br Furuya M, et al. PLoS One. 2016;11:e
27 Lung Neoplasms (n= 15) in 8 BHD Patients Patient s No Sex Age Histology LP-1 (proband) Female 65 PAC and AAH LP-2 (brother) Male 59 MPAC LP-3 Female 62 AIS LP-4 Female 71 MPH-like lesion LP-5 Female 54 AAHx7 LP-6 Female 72 AIS LP-7 Male 68 MIA LP-8 Female 66 IMT Furuya M, et al. PLoS One. 2016;11:e
28 Somatic Event of FLCN in Lung Neoplasms Germline Neoplasm (LCM) PAC, MPAC, MIA ATCCCCCCCCACGT CACG ATCCCCCCCCACGT Mono allelic FLCN + EGFR mutation or KRAS mutation MPH-like lesion AIS C TCTGAGGCTG TGAGGCT C TCTGAGGCTG Mono allelic FLCN No mutation was found in EGFR, KRAS, ALK, ROS1 CACACCTCCTTT GCC TTGCCTGG CACACCTCCTT TGCC Furuya M, et al. PLoS One. 2016;11:e
29 Summary 165 BHD families (421 individuals) were investigated. Characteristic histology of the lung help pathologists to suggest BHD. 60% of kidney cancer patients had episodes of pneumothorax, and initial oonset age of pneumothorax is younger than that of kidney cancer. Correct diagnosis of pulmonary cysts and appropriate medical surveillance wwill improve patients prognoses.
30 <Japan> BHD-Net Japan <USA> BHD Foundation <EU> BHD Consortium
31 Special Thanks to Pulmonary Pathology Working Group Prof. Dr. Nakatani
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