Birt-Hogg-Dubé syndrome-associated renal cell carcinoma: Histopathological features and diagnostic conundrum

Abstract

Birt-Hogg-Dubé (BHD) syndrome is associated with the development of hereditary renal cell carcinoma (RCC) and is caused by a germline mutation in the folliculin gene. Most cases of BHD syndrome-associated RCC (BHD-RCC) are less aggressive than sporadic clear cell RCC 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 for as long as possible. The World Health Organization/International Society of Urological Pathology consensus classification defined distinct entities for certain hereditary RCC; 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-RCC 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 epidemiological studies of Japanese families and a literature review. Pathological diagnostic clues and differential diagnosis of BHD-RCC from other hereditary RCC are also briefly discussed.

Keywords: Birt-Hogg-Dubé syndrome; folliculin; hereditary cancer; histopathology; renal cell carcinoma.

Figure 1

Macro‐ and microscopic features of Birt‐Hogg‐Dubé (BHD) syndrome‐associated renal cell carcinoma (RCC). A, Surface section of a sporadic oncocytoma. A mahogany‐brown nodule is observed. B, Gross section of a sporadic chromophobe RCC. A beige nodule is observed. C, Gross section of hybrid oncocytic/chromophobe tumors from a 34‐year‐old woman with BHD syndrome. In the vicinity of the main tumor, an independent tumor is detected (arrowheads). Both tumors are a yellowish color and clearly demarcated. D, Hybrid oncocytic/chromophobe tumor with a tubular and cord‐like structure developed in a 44‐year‐old man with BHD syndrome. E, Higher magnification of (D). The tumor cells have round nuclei with perinuclear halo and oncocytoma‐like granular cytoplasm with cell‐cell boundaries. Inset: immunostaining of cytokeratin 7 (CK7) in a serial section. F, Clear cell RCC developed in a 58‐year‐old man with BHD syndrome. Histological features are indistinguishable from those of its sporadic counterparts. Inset: immunostaining of carbonic anhydrase IX (CA‐IX) in a serial section. G, Papillary RCC developed in a 56‐year‐old man with BHD syndrome. Tumor cells show eosinophilic granular cytoplasm. Inset: immunostaining of α‐methylacyl‐CoA racemase (AMACR) in a serial section

Figure 2

Macro‐ and microscopic features of cystic tumors. A, Gross section of a cystic tumor in a 61‐year‐old man. B, Microscopic features of (A). Tumor cells composed of oncocytic and clear cells are present along the cyst walls. The cysts are filled with eosinophilic exudate. C, Abdominal computed tomography scan of a 65‐year‐old man with chronic renal failure and dialysis. Polycystic lesions are present in both kidneys. D‐F, Microscopic features of the resected kidneys in (C). Tumors are composed of hybrid (D), papillary adenomatous (E) and chromophobe‐like morphology with raisinoid nuclei and/or binucleation (F)

Figure 3

Differential diagnosis between Birt‐Hogg‐Dubé (BHD) syndrome and other hereditary diseases. A, Gross section of the lung of a 28‐year‐old woman with tuberous sclerosis complex. Numerous round cysts are observed in a diffuse arrangement. B, Gross section of the lung of an 81‐year‐old man with BHD syndrome. Two oval cysts extend along the interstitial tissue in a back to back way, compressing the alveolar structures between them. C, Histology of the skin tumor of a 75‐year‐old woman with hereditary leiomyomatosis and renal cell cancer (HLRCC). Proliferation of piloleiomyoma cells is observed in the dermic layer. Inset: immunostaining of α‐smooth muscle actin (α‐SMA). Tumor cells show diffuse staining. D, Histology of the skin tumor of a 54‐year‐old man with BHD syndrome. Proliferation of basaloid epithelial cells around a hair follicle and surrounding fibrous tissue is observed, which is consistent with fibrofolliculoma. Inset: immunostaining of α‐SMA. Fibrous tissue is negative. E, Histology of HLRCC‐associated RCC in a 49‐year‐old man. Type 2 papillary RCC with a high nuclear grade is observed. Inset: immunostaining of fumarate hydratase (FH). Capillary endothelial cells show FH staining (arrows), but the tumor cells are negative. F, G, Histology of HLRCC‐associated RCC in a 57‐year‐old man (F) and SDH‐deficient RCC in a 40‐year‐old man (G). Both patients were diagnosed by genetic testing. Oncocytic tumor cells are arranged in a solid sheet‐like pattern. They were indistinguishable from oncocytomas by H&E staining alone