In order to determine the characteristics of renal cell carcinomas (RCC) in BHD patients, Benusiglio et al. (2014) recruited 124 French BHD patients from Hôpital Bicêtre near Paris, and the Edouard Herriot University Hospital in Lyon.
Of the patients recruited, 33 had had kidney cancer. The median age at the diagnosis of the first tumour was 46, with an age range of 20 – 83. Whilst the majority of patients had a solitary tumour at diagnosis, four patients (12%) had two tumours, and nine patients (27%) presented with multifocal disease. Pathology reports were available for all but five patients, and, as expected, the majority of tumours (23/33, or 70%) were of oncocytic or hybrid oncocytic/ choromophobe histology. However, one patient had a papillary RCC, one had an undifferentiated RCC, and 3 patients (9%) had clear cell RCC.
Four patients had metastatic disease at diagnosis. One patient was found to have a lung metastasis 23 years after his initial diagnosis. The metastatic tumour was removed, and the patient showed no sign of cancer relapse upon his death four years later due to an unrelated condition. Another patient received nephrectomy and adjuvant radiotherapy for multiple metastatic retroperitoneal lymph-nodes, and is alive and well seven years later with no signs of disease progression.
Two patients in this cohort received systemic treatment for metastatic disease. One patient presented with multifocal kidney tumours and liver metastases, and disease stability was achieved following three years of systemic treatment with sunitinib, everolimus and temsirolimus. Eight years after ceasing treatment, this patient is still alive and well, and her tumours are stable. Another patient has survived for 5 years following diagnosis, and has received multiple systemic treatments to control slow growing liver and lung metastases.
The survival time following a diagnosis of metastatic renal cancer is usually between 4 months and 2 years (Manola et al., 2011), and all four of these BHD patients have survived with metastatic kidney cancer for more than five years. This suggests that even when BHD renal cancers do metastasise, they are clinically benign compared to more common metastatic renal cancers. Interestingly, mTOR inhibitors achieved long-term disease stability in one patient, which is consistent with the observation that tumours with somatic FLCN mutations respond well to mTOR inhibitors, and suggest that this class of drug may be particularly effective to control metastatic disease in BHD patients.
The results of this study correspond well with previous cohort studies (Schmidt et al., 2005, Toro et al., 2008), and together suggest that roughly 30% of BHD patients are at risk of developing renal cell carcinoma. Although the median age of diagnosis with kidney cancer was 46, the range was 20 – 83 years, suggesting that abdominal screening should commence at a young age – the current recommendation is to commence screening at 20 – 21 years old (Menko et al., 2009, Stamatakis et al., 2013) – and should continue throughout the patient’s lifetime. Furthermore, while the majority of BHD patients who develop RCC will have oncocytic, chromophobe or hybrid tumours, 10% of patients are at risk of developing clear cell RCC, which is more aggressive. Finally, BHD patients who present with metastatic disease seem to have a significantly better prognosis than patients who present with sporadic forms of metastatic RCC.
- Benusiglio, P., Giraud, S., Deveaux, S., Méjean, A., Correas, J., Joly, D., Timsit, M., Ferlicot, S., Verkarre, V., Abadie, C., Chauveau, D., Leroux, D., Avril, M., Cordier, J., & Richard, S. (2014). Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study Orphanet Journal of Rare Diseases, 9 (1) DOI: 10.1186/s13023-014-0163-z
- Manola J, Royston P, Elson P, McCormack JB, Mazumdar M, Négrier S, Escudier B, Eisen T, Dutcher J, Atkins M, Heng DY, Choueiri TK, Motzer R, Bukowski R, & International Kidney Cancer Working Group (2011). Prognostic model for survival in patients with metastatic renal cell carcinoma: results from the international kidney cancer working group. Clinical cancer research : an official journal of the American Association for Cancer Research, 17 (16), 5443-50 PMID: 21828239
- Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER, & European BHD Consortium (2009). Birt-Hogg-Dubé syndrome: diagnosis and management. The Lancet. Oncology, 10 (12), 1199-206 PMID: 19959076
- Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, & Linehan WM (2005). Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. American journal of human genetics, 76 (6), 1023-33 PMID: 15852235
- Stamatakis L, Metwalli AR, Middelton LA, & Marston Linehan W (2013). Diagnosis and management of BHD-associated kidney cancer. Familial cancer, 12 (3), 397-402 PMID: 23703644
- Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, & Linehan WM (2008). BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Journal of medical genetics, 45 (6), 321-31 PMID: 18234728
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.