Lung cysts are a highly penetrant symptom of BHD Syndrome, affecting up to 90% of patients, yet the mechanism of how they develop remains unclear. The histology, appearance and location of lung cysts seem to be disease specific, allowing clinicians to distinguish BHD from other cystic lung diseases based on radiological findings, suggesting that the mechanism through which lung cysts develop may be different in BHD and other diseases. A recent study from a group of researchers in Japan may shed light on this question by comparing the lung pathologies of a cohort of BHD patients and primary spontaneous pneumothorax patients (PSP), in the biggest cohort study of this kind yet.
Kumasaka et al. analysed 229 lung cysts in resections from 50 BHD patients and compared them with 117 lung cysts from 34 PSP patients, comparing samples for number, size, location and presence of inflammation. They found that BHD lung cysts were found in both subpleural and intrapulmonary areas; often found at interlobular septa and 40% had venules; and only showed signs of inflammation if located in the subpleura. These results correspond well to those of Fabre et al. who showed that BHD-associated lung cysts were generally basally located, in the subpleura and did not show inflammatory changes.
Combining these observations with published data linking FLCN to cell-cell adhesion (Medvetz et al., 2012; Nahorski et al., 2012) and unpublished data from Kumasaka et al. showing that lung fibroblasts from BHD patients show diminished migration and decreased TGFβ expression, the authors have suggested a mechanism through which lung cysts might develop. They suggest that heterozygous loss of FLCN causes alveoli walls to become weak and vulnerable to disruption by lung expansion and retraction during breathing, causing cysts to form. This hypothesis may explain why BHD lung cysts are predominantly located in the lower regions of the lungs, which are subjected to greater mechanical force during breathing than upper regions.
The authors also noted that intrapulmonary cysts and uninflamed subpleural cysts were usually roughly the same size. However, cysts showing inflammatory markers were generally larger and there appeared to be an inverse correlation between cyst size and number. Pneumothorax is known to cause inflammation in the cells surrounding the collapsed region (Lichter and Gwynne, 1971). Thus the authors suggest that if a BHD patient experiences a pneumothorax, nearby cysts may get inflamed and start to grow, possibly subsuming nearby cysts and reducing the number of cysts overall. As all of the BHD patients in this study had experienced episodes of pneumothorax, it would be interesting to see whether the lung cysts in patients who have never had a pneumothorax show any signs of inflammation to test this hypothesis.
While these hypotheses are compelling, they are as yet unproven and a major limitation of this study is that, although the BHD cohort were all shown to have FLCN mutations, meaning that they are confirmed BHD Patients, it is unclear whether the control cohort were tested for FLCN mutation mutations or not. It has previously been shown that in an unselected series of 102 Chinese patients with PSP, nearly 10% were cryptic BHD cases (Johannesma et al., 2014, Ren et al., 2008), suggesting that 3 or 4 patients in this study’s control group may also be BHD patients, potentially confounding the analysis.
However, if lung cysts are caused by weakened alveolar walls, this may explain the efficacy of lower pleural covering with ROC mesh, which dissolves into the surface of the lung and strengthens the tissue. This treatment is currently being developed by Professor Kurihara in Japan, and as of June 2013 there had been no cases of recurrent pneumothorax in 45 BHD patients who had undergone this procedure, suggesting it could be a very effective treatment (5th BHD Symposium Abstracts).
-
5th BHD and 3rd HLRCC Symposium Abstracts. Familial Cancer, 12 (3), 405-448 DOI: 10.1007/s10689-013-9678-z
-
Fabre A, Borie R, Debray MP, Crestani B, & Danel C (2013). Distinguishing the histological and radiological features of cystic lung disease in Birt-Hogg-Dubé syndrome from those of tobacco-related spontaneous pneumothorax. Histopathology PMID: 24168179
-
Johannesma P, Thunnissen E, & Postmus P (2014). How reliable are clinical criteria to distinguish between BHD and smoking as a cause for pneumothorax? Histopathology PMID: 24383416
-
Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, & Seyama K (2014). Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathologic and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology PMID: 24393238
-
Lichter I, & Gwynne JF (1971). Spontaneous pneumothorax in young subjects. A clinical and pathological study. Thorax, 26 (4), 409-17 PMID: 5565786
-
Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PloS one, 7 (11) PMID: 23139756
-
Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878
-
Ren HZ, Zhu CC, Yang C, Chen SL, Xie J, Hou YY, Xu ZF, Wang DJ, Mu DK, Ma DH, Wang Y, Ye MH, Ye ZR, Chen BF, Wang CG, Lin J, Qiao D, & Yi L (2008). Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax. Clinical genetics, 74 (2), 178-83 PMID: 18505456
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.