A case of adrenal carcinoma in a BHD patient

Birt-Hogg-Dubé syndrome (BHD) is caused by mutations in the FLCN gene and characterised by fibrofolliculomas; lung cysts and increased predisposition to pneumothorax; and increased predisposition to kidney cancer. Other symptoms have been reported to be associated with BHD Syndrome, such as parotid tumours and colorectal cancer, however, the numbers of these cases are so small that it is difficult to determine whether these symptoms are truly associated with BHD, or if they are coincidental. A recent report by Raymond et al. suggests that adrenal tumours may be associated with BHD.

Raymond et al. describe the case of a 62 year old woman with histologically confirmed trichodiscomas indicative of BHD. Further screening revealed the presence of two small lung cysts and an adrenal mass. Resection of the mass confirmed it to be an oncocytic adrenal tumour which was likely to be malignant. Genetic testing confirmed a diagnosis of BHD.

The authors subsequently analysed the prevalence of adrenal masses in confirmed cases of BHD. In a cohort of 14 confirmed BHD patients from 11 families, one patient was found to have an adrenal nodule. Retrospective analysis of the literature yielded three additional reports of adrenal tumours in BHD patients (Juszczak et al., 2011; Kunogi et al., 2010; Reese et al., 2009). However, in 359 cases of sporadic adrenocortical carcinomas, no patient fulfilled the clinical criteria for BHD, suggesting that although adrenal cortical carcinomas may be a rare symptom of BHD syndrome, it is unlikely that sporadic cases of this cancer represent undiagnosed cases of BHD.

The adrenal tumour reported by Raymond et al. was of oncocytic histology. Oncocytic tumours are of epithelial origin and are characterised by an accumulation of defective mitochondria (Tallini, 1998). Analysis of 130 tumours from 30 BHD patients showed that 50% of BHD-associated renal tumours are of mixed oncocytic/ chromophobe histology, while oncocytic histology is only seen in 3 – 5% of sporadic renal cell carcinomas (Pavlovich et al., 2002), indicating that BHD patients are more likely to develop this type of tumour. Indeed, BHD renal tumours (Klomp et al., 2010) and FLCN-null murine muscle tissues (Hasumi et al., 2012) show increased expression of PPARGC1A, which stimulates mitogenesis, thus providing a mechanism through which FLCN mutation may lead to oncocytic transformation.

Interestingly, Pradella et al. recently found that compound heterozygosity of FLCN and PTEN was the cause of a BHD-associated parotid oncocytoma and a Cowden-associated thyroid oncocytoma. This lead Pradella et al. to suggest that such double heterozygosity, where a germline mutation followed by somatic mutation of a different gene leads to tumour development, may underlie the development of oncocytic tumours specifically in the context of genetic syndromes.

Adrenocortical carcinoma is associated with a number of genetic syndromes, including Li Fraumeni Syndrome, Beckwith Wiedeman Syndrome, Multiple Endocrine Neoplasia type 1 and Familial Adenomatous Polyposis. While a lack of tumour tissue precluded genetic analysis, it would be interesting to determine whether the adrenal tumour reported by Raymond et al. showed either loss of heterozygosity of FLCN, or compound heterozygosity with one of the genes associated with the above syndromes.

Indeed, Familial Adenomatous Polyposis predisposes mutation carriers to colorectal cancers, which has been previously reported to be associated with BHD (Khoo et al., 2002; Nahorski et al., 2010), although this is the subject of some debate as other studies have found no association (Zbar et al., 2002). Therefore, it is possible that rare tumours which have been reported in cases of BHD may be caused by compound heterozygosity. However, it is also possible that these tumours are not associated with BHD syndrome and have arisen by coincidence.

While Raymond et al. suggest that adrenal tumours may be a very rare symptom of BHD, it is important to remember that at present skin lesions, lung cysts and pneumothorax, and kidney cancer are the only confirmed symptoms of BHD. As previously discussed, the founding of an international registry for all BHD patients would allow for more rigorous statistical studies to be performed and the full spectrum of symptoms determined. In turn, this could lead to improved risk prediction and modified screening and treatment pathways for BHD patients.


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