[Birt-Hogg-Dubé syndrome-associated renal tumors: a clinicopathological and molecular genetic analysis of ten cases].

Objective: To investigate the clinicopathological features, immunophenotypic characteristics, molecular genetic profiles for an accurate diagnosis of renal tumors associated with Birt-Hogg-Dubé (BHD) syndrome. Methods: Clinicopathological data from 10 patients with BHD syndrome-associated renal tumors were collected from Ningbo Clinical Pathology Diagnosis Center (4 cases) and Ruijin Hospital, Shanghai Jiaotong University School of Medicine (5 in-house cases and 1 consultation case) from January 2015 to December 2025. Their clinical characteristics and histological features were studied and analyzed. Immunohistochemical staining and next-generation sequencing (NGS) were performed. Follow-up data were obtained and relevant literature was reviewed. Results: All 10 patients were adults, including 6 males and 4 females, with an age 57 (54, 67) years old. Seven patients had pulmonary bullae/pneumothorax and one patient had a right anterior chest wall fibroma. For the patients with renal tumor, 6 cases presented with a unilateral single tumor, 1 case with unilateral multiple tumors and 3 cases with bilateral multiple tumors (totaling 16 renal tumors). Four cases of the renal tumor were associated with multiple renal cysts. Histologically, among the 16 tumors, 10 were hybrid oncocytic/chromophobe tumors (HOCT) with the typical "mosaic" pattern, 4 with chromophobe renal cell carcinoma-like morphology, 1 with predominantly sarcomatoid morphology and focal areas of low-grade oncocytic renal tumor, and 1 renal angiomyolipoma. The immunophenotype of BHD-associated renal tumors was not specific. Immunohistochemistry revealed diffuse positive for GPNMB in all epithelial-derived renal tumors (15/15). CK7 and CD117 were focally expressed in 7/15 cases each, CD10 was focally expressed in 6/15 cases, and carbonic anhydrase Ⅸ (CAⅨ) was negative in all tumors (0/15). ALK, TFE3 and TFEB were negative. No loss of SDHB or FH expression was identified. DNA next-generation sequencing identified FLCN mutations in all cases, including 7 cases with germline FLCN mutations and 3 cases with somatic FLCN mutations. During a 9-120 months follow-up, the patient with sarcomatoid differentiation passed away 6 months after renal tumor identified, and another patient experienced relapse in the left kidney 6 years after bilateral nephron-sparing surgery. No relapse or metastasis was identified in the remaining 8 patients. Conclusions: Morphologically, BHD syndrome-associated renal tumors can mimic various low-grade oncocytic renal tumors. In addition to the classic HOCT morphology, they may also present with high-grade sarcomatoid differentiation. GPNMB is a highly sensitive marker for BHD-associated renal tumors. Molecular genetic analysis to detect FLCN mutation is the gold standard for definitive diagnosis. BHD syndrome-associated renal tumors typically show indolent biological behavior, with sarcomatoid differentiation as a morphological feature of poor prognosis.