Characterisation of renal tumours in patients with Birt-Hogg-Dubé Syndrome

Due to mutations in their folliculin (FLCN) gene Birt-Hogg-Dubé (BHD) syndrome patients have a greater risk of developing renal cell carcinomas (RCC) than others (Zbar et al., 2002, Houweling et al., 2011). Unlike sporadic cases of RCC, where the majority are classified as clear cell RCC (ccRCC), studies of FLCN-related tumours have found that the majority are either chromophobe RCCs (34%) or hybrid oncocytoma/chromophobe tumours (HOCTs, 50%) with fewer cases of ccRCC (9%) and only rare occurrences of renal oncocytomas or papillary RCCs (Pavlovich et al., 2002). It is also common for multiple tumours of different subtypes to develop on the same kidney. Using current histology methods diagnosing a tumour as being related to BHD rather than sporadic can be difficult, especially in undiagnosed BHD cases where the genetic background will be unknown.

A new paper by Iribe et al., (2015) has investigated if the immunohistochemical profile of BHD-related tumours is sufficiently distinct from sporadic RCC tumours to be of help in classification. They suggest that a panel of markers including Carbonic Anhydrase IX (CA-IX), Kidney specific cadherin (Ksp-cadherin), Cytokeratin 7 (CK7) and CD82 could help in the screening for FLCN-related RCCs and enable the correct classification of some different subtypes.

In total 32 tumours, from 17 BHD patients, were analysed by in situ hybridisation. The tumours had already been classified as chromophobe RCCs (n=14), HOCTs (n=15) or ccRCC (n=3). Expression of the markers in these samples was compared to sporadic chromophobe RCC, ccRCCs and oncocytomas – the presence of FLCN mutations in these controls was not excluded but, based on a lack of other BHD pathologies, was assumed.

Most of the FLCN-related chromophobe RCC and HOCTs analysed were Ksp-cadherin+, CD82+ and CA-IX, a profile similar to sporadic chromophobe RCCs. Unfortunately the results reported in this paper indicate that it would be difficult to distinguish between sporadic and FLCN-associated chromophobe RCC using this marker panel. However sporadic chromophobe RCC samples showed significantly higher expression of CK7 than FLCN-associated HOCTs. Additionally FLCN-associated HOCTs showed significantly greater expression of Ksp-cadherin and CD82 compared to sporadic oncocytomas. These differences indicate that the suggested panel of markers would be useful for distinguishing FLCN-associated HOCTs from sporadic chromophobe RCCs and oncocytomas.

All of the studied ccRCC samples, both BHD-associated and sporadic, stained positive for CA-IX but negative for the other markers. Therefore the panel suggested would be unsuitable for distinguishing FLCN-associated ccRCC from sporadic ccRCC. It would however be useful in determining if the clear cell-looking foci seen in some FLCN-associated RCCs are true ccRCC based on CA-IX+ expression or in fact Ksp-cadherin+, CK7+ and CD82+ HOCT or chromophobe cells.

Although the presence of HOCTs is more classically related to BHD, ccRCC and chromophobe RCC tumours also develop in BHD patients and therefore it is important to be able to distinguish between sporadic cases and those associated with FLCN mutations. A FLCN mutation will increase the likelihood of more tumours developing and the need for continual monitoring. The markers suggested by Iribe et al., are suitable for distinguishing FLCN-associated HOCTs from sporadic tumours but are insufficient to make this distinction for other RCC subtypes. Additional work from the group (Fuyura et al., 2015) will be able to add to the screening protocol and will be the topic of this blog in a few weeks.

The presence of germline FLCN mutations was confirmed in the Iribe et al., cohort however there was no identified pattern between mutation and tumour subtypes. Based on the Knudson two-hit hypothesis, tumourgenesis only occurs if both alleles of a tumour suppressor gene are mutated. Previous work by Vocke et al., (2005) identified such second-hit mutation in 70% of BHD-RCC tumours analysed. Such analysis was not completed in this study but it could be that larger analysis of such secondary mutations could provide clues to RCC subtype development in different patients. This could help with our understanding of tumourgenesis in BHD but also impact on the development of more targeted treatments.


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