Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families

Abstract

Background: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD.

Methods: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families.

Results: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas.

Conclusion: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

Figure 1

(A) Estimate of the age-related penetrance function for renal cancer based on available data on both mutation carriers and their untested relatives till the age of 70: 16% (continuous line n=86 mutation carriers and 84 untested relatives), together with the Kaplan–Meier estimator based on the known mutation carriers only at age 70: 20% (n=86, red dashed line). (B) Estimate of the age-related penetrance function for renal cancer based on available data on both mutation carriers and their untested relatives together with a minimum 95% confidence interval. Estimated penetrance at age 70: 16%, 95% minimal confidence interval: (6-26%). (C) Estimation of the penetrance function of age at the first pneumothorax and a minimum 95% confidence interval based on available data on both mutation carriers and their untested relatives (n=85 mutation carriers and 84 untested relatives). Estimated penetrance at age 70: 29%, 95% minimal confidence interval: (9–49%).

Figure 2

Overview of the FLCN mutations identified in this study. Del: deletion, F: frameshift, M: missense, N: nonsense, SS: splice site. Exons are depicted as rectangles. The family numbers are shown after the mutations.

Figure 3

Illustration of the histological pictures of renal cell carcinomas in our series. (A) The most common pattern found, classified as clear cell/chromophobe. The tumour cells show eosinophilic cytoplasm, moderate nuclear pleiomorphism, vague perinuclear halos, no explicit cell borders and no vascular prominence. (B) Classical picture of clear cell carcinoma, as can be seen in many of the tumours in our series, but mostly only in part of the tumour cells. (C) A clear cell/chromophobe renal cell carcinoma with partially clear cytoplasm, more prominent cell borders, no thick-walled vessels. (D) Renal cell carcinoma with sarcomatoid changes (in the right part of the picture).