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.

 

  • Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, Klein ME, Takikita S, Nagashima K, Schmidt LS, & Linehan WM (2012). Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN. Journal of the National Cancer Institute, 104 (22), 1750-64 PMID: 23150719
  • Juszczak A. Halliday D, Minhai R & Ali A (2011). A large adrenal tumour as a phenotypic manifestation of the Birt-Hogg-Dubé syndrome. European Congress of Endocrinology. Endocrine Abstracts, 26, 58
  • Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Lévy R, Ferlicot S, Wolkenstein P, Hammel P, Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjöld M & Richard S (2002). Clinical and genetic studies of Birt-Hogg-Dubé syndrome. Journal of Medical Genetics, 39 (12), 906-12 PMID: 12471204
  • Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, Sääf A, Zickert P, Aly M, Bergerheim U, Nordenskjöld M, Gad S, Giraud S, Denoux Y, Yonneau L, Méjean A, Vasiliu V, Richard S, MacKeigan JP, Teh BT, & Furge KA (2010). Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. BMC medical genomics, 3 PMID: 21162720
  • Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, Gunji Y, Kikkawa M, Iwakami S, Hino O, Takahashi K & Seyama K (2010). Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. Journal of Medical Genetics, 47 (4), 281-7 PMID: 20413710
  • Nahorski MS, Lim DH, Martin L, Gille JJ, McKay K, Rehal PK, Ploeger HM, van Steensel M, Tomlinson IP, Latif F, Menko FH & Maher ER (2010). Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. Journal of Medical Genetics, 47 (6), 385-90 PMID: 20522427
  • Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, & Merino MJ (2002). Renal tumors in the Birt-Hogg-Dubé syndrome. The American journal of surgical pathology, 26 (12), 1542-52 PMID: 12459621
  • Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, Mackay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG PMID: 23386036
  • Raymond VM, Long JM, Everett JN, Caoili EM, Gruber SB, Stoffel EM, Giordano TJ, Hammer GD, & Else T (2013). An Oncocytic Adrenal Tumor in a Patient with Birt-Hogg-Dubé Syndrome. Clinical endocrinology PMID: 23848572
  • Reese E, Sluzevich J, Kluijt I, Teertstra HJ, De Jong D, Horenblas S & Ryu J (2009). Birt-Hogg-Dubé Syndrome. Cancer Syndromes. Bethesda (MD): National Center for Biotechnology Information (US) PMID: 21249760
  • Tallini G (1998). Oncocytic tumours. Virchows Archiv: an international journal of pathology, 433 (1), 5-12 PMID: 9692819
  • Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J & Linehan WM (2002). Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer epidemiology, biomarkers & prevention, 11 (4), 393-400 PMID: 11927500

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

Leave a Comment

Share This