Introduction:

Birt-Hoge-Dube (BHD) syndrome is an underdiagnosed autosomal dominant inherited condition caused by mutations in the folliculin (FLCN) gene. Renal masses associated with BHD have been described to have an indolent course with the common pathologies being chromophobe renal cell carcinoma (chRCC), oncocytoma, or hybrid oncocytic tumor with features of both. The purpose of this study is to expand the literature on this rare disorder by reporting our center’s experience of the renal mass manifestations of BHD.

Methods:

A retrospective single center study of a cohort of patients with BHD was conducted. Patients were identified through either clinical care via clinical cancer geneticist or through the Penn Medicine BioBank (PMBB). The PMBB has been enrolling any patient in the Penn Medicine system older than 18 years who consent to storage and analysis of tissue samples. The medical record was evaluated for medical and imaging histories corresponding to phenotypes associated with BHD renal masses. For patients with history of at least one renal mass the age of onset, imaging modality at diagnosis, imaging indication at diagnosis, number of tumors, size of tumors, growth rate, pathology, and any interventions were noted. Genetic mutations from germline testing are reported. Quantitative results reported as median with inter-quartile range (IQR).

Results:

Eighty-one BHD patients were identified, 67 (80.2%) through clinical care and 14 (19.8%) via the PMBB. Median age at BHD diagnosis was 38 (28-57) years. Ten (12.3%) patients developed a total of 15 masses. Age at first tumor diagnosis was 58 (50.8-60.2) years. Median lesion size was 1.5 (1-2.1) cm at diagnosis. Indications for imaging include abdominal pain, non-renal malignancy BHD surveillance, flank pain, and abnormal liver function tests. Six (60%) of tumor patients were managed non-operatively, and four (40%) underwent resection. Per tumor, 9 (60%) were not resected, 3 were chRCC (20%), and 1 (6.7%) each were clear cell RCC, papillary RCC, or angiomyolipoma. Surveilled tumor growth rate was 0 (-0.02 – 0) cm/yr during a median 2.3 (2.3-5.6) year follow-up. A partial deletion in FLCN exon 1 occurred in 2 (20%) patients with both requiring surgery. The other tumor patients had unique mutations. 

Conclusion:

Renal tumors were found to affect 12.3% of BHD patients in this clinical cohort, consistent with prior reports of 12-34% of BHD patients developing renal tumors. These BHD-associated tumors were mostly small and indolent with a static growth rate. chRCC was the most common pathologic type although clear cell RCC and papillary RCC were also seen. The age of onset of the tumors was older than as compared to other hereditary renal cancer syndromes. Forty percent of our cohort required operative management. Limitations of this study include its retrospective nature, small sample size of BHD patients with renal lesions, and low follow-up time. Overall, these results support the current understanding of BHD-associated renal tumors as most often small, indolent lesions for which a conservative approach may be appropriate. Additionally, we report genetic mutation status to bring a precision medicine approach to this cohort of patients. 

Funding: N/A