Progression of pulmonary cysts in Birt-Hogg-Dubé syndrome: longitudinal thoracic computed tomography study with quantitative assessment

Abstract

Background: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, pulmonary cysts, and recurrent pneumothorax. Pulmonary cysts are the cause of recurrent pneumothorax, which is one of the most important factors influencing patient quality of life. It is unknown whether pulmonary cysts progress with time or influence pulmonary function in patients with BHD syndrome. This study investigated whether pulmonary cysts progress during long-term follow-up (FU) by using thoracic computed tomography (CT) and whether pulmonary function declines during FU. We also evaluated risk factors for pneumothorax in patients with BHD during FU.

Methods: Our retrospective cohort included 43 patients with BHD (25 women; mean age, 54.2 ± 11.7 years). We evaluated whether cysts progress by visual assessment and quantitative volume analysis using initial and serial thoracic CT. The visual assessment included the size, location, number, shape, distribution, presence of a visible wall, fissural or subpleural cysts, and air-cuff signs. In CT data obtained from a 1-mm section from 17 patients, the quantitative assessment was performed by measuring the volume of the low attenuation area using in-house software. We evaluated whether the pulmonary function declined with time on serial pulmonary function tests (PFT). Risk factors for pneumothorax were analyzed using multiple regression analysis.

Results: On visual assessment, the largest cyst in the right lung showed a significant interval increase in size (1.0 mm/year, p = 0.0015; 95% confidence interval [CI], 0.42-1.64) between the initial and final CT, and the largest cyst in the left lung also showed significant interval increase in size (0.8 mm/year, p < 0.001, 95% CI; -0.49-1.09). On quantitative assessment, cysts had a tendency to gradually increase in size. In 33 patients with available PFT data, FEV1pred%, FEV1/FVC, and VCpred% showed a statistically significant decrease with time (p < 0.0001 for each). A family history of pneumothorax was a risk factor for the development of pneumothorax.

Conclusions: The size of pulmonary cysts progressed over time in longitudinal follow-up thoracic CT in patients with BHD, and pulmonary function had slightly deteriorated by longitudinal follow-up PFT.

Keywords: Birt-Hogg-Dubé (BHD) syndrome; Computed tomography; Folliculin gene mutation; Pneumothorax; Pulmonary cyst; Pulmonary function test.

Fig. 1

Result of quantitative assessment. Dot plots for the evolution of the volume of cysts in serial thoracic CT for 17 patients who had available 1-mm thin section CT data with serial follow up for at least 6 months. Eleven patients showed an interval increase in the LAA % between the initial and last CT (shown as blue lines). Six patients showed no significant interval change in the LAA % (shown as gray lines)

Fig. 2

A representative case showing cyst progression in a 54-year-old male with BHD disease. a, b, e, f Baseline axial and coronal CT images and figures. c, d, g, h CT images obtained 6 years later. b, d, f, h Low attenuation area as a color map according to cyst size analyzed by in-house software. Black box in g indicates a cyst with “air-cuff signs”

Fig. 3

Results of the evolution of the PFT. Evolution of the parameters of the PFT during serial follow up in patients with BHD syndrome, left: raw data, right: linear mixed model, a) FEV1, b) FEV1/FVC, c) VC, d) DLCO, e) RV/TLC, and f) DLCO/VA. FEV1_pred %, FEV1/FVC, and VC pred_% among the PFT parameters showed a statistically significant decreasing trend with time (p < 0.0001 for each) and RV/TLC values showed a statistically significant increasing trend over time (p < 0.0001). DLCO and DLCO/VA values showed no significant change over time. FEV1 forced expiratory volume in one second, FVC forced vital capacity, TLC total lung capacity, RV residual volume, DLco carbon monoxide transfer factor, DLco/VA carbon monoxide transfer coefficient, %pred percentage of predicted value capacity