Study screening and enrollment are presented in Figure 1. A search of the EMR from January 2000 to October 2023 using ICD code Q87.89 (‘other congenital malformation syndromes’) and search term ‘birt hogg dube’ identified 189 potential cases. Individual records were reviewed, with 149 meeting one major or two minor diagnostic criteria for BHD syndrome.(6)
Baseline characteristics in patients with (n=39) and without renal tumor (n=110) are presented in Table 1. Those with renal tumor were older at the time of BHD diagnosis (56 vs. 46.7, P = 0.002), male (64% vs. 41%, P=0.01), had greater smoking history (44% vs. 24%, P=0.02), lower FEV1% at presentation (82.7% vs 93.8%, P=0.02), and increased dermatological findings (46% vs 27%, P=0.04). Incidental renal tumors seen on imaging as a first clinical sign of BHD occurred in 59% of the tumor group (59%), while fibrofolliculoma (62%), pneumothorax (32%), and family history (32%) were common initial clinical findings in those without subsequent tumor. As initial tumor findings on imaging often pre-dated formal BHD diagnosis, mean age at tumor detection was 53.6 years. Forty-five unique tumors were diagnosed among 39 patients (10 patients had more than one tumor per kidney), with a median size of 2 cm (range 0.5 to 12 cm) at first radiologic detection. Microscopic hematuria was observed in four patients (21% of tested patients) at the time of tumor diagnosis.
Characteristics, staging, and management of renal cancer in 28 patients with pathologically confirmed disease are presented in Table 2. Among these, 16 patients were found to have renal tumors larger than 3 cm, six less than 3 cm, and six without data on tumor size at the time of resection. Twenty-six had urological procedures at the time of initial radiologic presentation. Only two had renal tumors measuring initially 0.5 centimeters and 3 centimeters, followed for 4 and 2 years, respectively. They were later measured at 1.8 centimeters and 4 centimeters, respectively. One was followed with a yearly MRI noting renal tumor size increase ranging between 0.1 to 0.3 centimeters per year.
Clear-cell renal cell carcinoma was the most common histopathologic subtype (54%) on biopsy or resection. Three patients had other histology including papillary cell carcinoma, low-grade BHD-associated renal cell neoplasm, and mucinous tubular and spindle cell carcinoma. Stage 1 (pT1NanyM0) cancer was present in the majority (79%) at diagnosis. Nephrectomy was the most common treatment approach (79%). One patient, who initially underwent partial nephrectomy for papillary cell-type renal cell carcinoma experienced recurrence at the same site and required additional surgical resection, radiation, and pazopanib-targeted therapy. Another patient was diagnosed with oncocytoma on biopsy and is being followed with annual imaging. All remaining treated patients are currently undergoing follow-up imaging with no signs of tumor recurrence.
Eleven patients had suspected renal tumors measuring less than 3 centimeters, currently under surveillance. The shortest duration of follow-up was one year, with the longest being 24 years. The maximum growth rate of renal tumors among this group was 0.23 centimeters per year.
Univariable and multivariable logistic regression models assessing risk factors for the development of renal tumors are presented in Table 3. Age at BHD diagnosis (OR 1.04 (1.01-1.07), P = 0.003), male sex (OR 2.58 (1.21-5.50), P = 0.01), smoking history (OR 2.6 (1.19-5.63), P = 0.02), presence of fibrofolliculomas (OR 2.33 (1.09-4.99), P = 0.03), presence of pneumothorax (OR 3.56 (1.10-11.46), P = 0.03), and lower baseline %FEV1 (OR 0.95 (0.91-1.0), P = 0.02) were predictive of renal tumor development on univariable analysis. After adjustment for a priori covariables (age at BHD diagnosis, sex, and smoking history), only age and male sex were predictive (OR 1.05 (1.01-1.08, P=0.002) and 2.59 (1.17-5.73, P=0.02), respectively).
Kaplan-Meier survival analysis is presented in Figure 2, stratified by the presence of renal tumor. Log-rank testing suggested decreased time to all-cause mortality in those with renal tumors (P = 0.02). There were five observed deaths in the tumor group, none of whom died from documented renal cancer, and two in the non-tumor group. Causes of death included pneumonia, acute respiratory failure, acute renal failure, and septic shock in four, and was unspecified in the remainder.
Most patients with renal tumors in our cohort were diagnosed with BHD after tumors were already present on radiologic assessment. This was often the initial radiologic abnormality prompting workup leading to BHD diagnosis. Only two patients in our cohort were diagnosed with BHD before the development of renal tumors. Patient 1 was diagnosed with BHD in April of 2012 at the age of 55. An initial screening MRI conducted in August of 2016 was unremarkable. A second MRI in November of 2019, a little over three years later, detected a renal mass measuring 3.5 centimeters. Nephrectomy was pursued and confirmed clear cell renal cell carcinoma on histopathology. Patient 2 was diagnosed with BHD in June of 2018 at the age of 47. After initial annual MRI screening studies, a renal tumor was identified on abdominal CT approximately two and a half years later, in December 2020, measuring 1.5 centimeters. MRI of the abdomen in April of 2020, eight months earlier, revealed no abnormalities. A Follow-up MRI in October of 2022 showed an increase to 1.8 centimeters, with the patient continuing observation based on the last available follow-up.