Birt-Hogg-Dubé Syndrome-associated Renal Cell Carcinoma: Histopathological Features and Diagnostic Conundrum.
Birt-Hogg-Dubé (BHD) syndrome is associated with the development of hereditary renal cell carcinoma and is caused by a germline mutation in the folliculin gene. Most cases of BHD syndrome-associated RCC (BHD-RCC) are less aggressive and multifocal. Therefore, it is critical to distinguish BHD-RCC from its sporadic counterparts to identify and monitor affected families and to preserve renal function as long as possible. The World Health Organization/International Society of Urological Pathology consensus classification defined distinct entities for certain hereditary RCCs; however, BHD-RCC was not included in this classification. Although the clinical features and molecular mechanisms of BHD-RCC have been investigated intensively over the last two decades, pathologists and urologists occasionally face difficulties in the diagnosis of BHD-RCCs that require genetic testing. Affected patients usually have miscellaneous benign disorders that often precede renal carcinogenesis. In the present review, we summarize the current understanding of the histopathological features of BHD-RCC based on our epidemiologic studies of Japanese families and a literature review. The pathological diagnostic clues and differential diagnosis of BHD-RCC from other hereditary RCCs are also briefly discussed.