Parotid Oncocytomas Express the Glycoprotein Non-metastatic Melanoma Protein B (GPNMB): A Potential Link with...

Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant disorder caused by germline pathogenic variations in the FLCN gene. It is characterized by cutaneous fibrofolliculomas, pulmonary cysts with risk of pneumothorax, and an increased risk of renal neoplasms. Salivary gland involvement, particularly parotid oncocytomas, is uncommon and may represent an underrecognized manifestation. This study evaluates the immunohistochemical (IHC) expression of folliculin (FLCN) and glycoprotein non-metastatic melanoma protein B (GPNMB) in parotid oncocytomas to assess their potential utility in identifying BHDS-associated lesions.

A multicenter retrospective study was performed on formalin-fixed, paraffin-embedded specimens, including BHDS-associated parotid oncocytomas, non-syndromic parotid oncocytomas, and BHDS-associated hybrid oncocytic/chromophobe renal tumors (HOCTs) as controls. IHC staining for FLCN and GPNMB was analyzed based on intensity, localization, and distribution. Statistical analysis was performed using chi-square testing.

BHDS-associated parotid oncocytomas occurred in younger patients (n = 4, mean age: 53.7 years) compared to non-syndromic oncocytomas (n = 10; mean age: 72.5 years). Histologically, all syndromic cases demonstrated prominent cytoplasmic clearing and vacuolization on hematoxylin-eosin (H&E) staining, a feature not observed in non-syndromic counterparts (p ≤ 0.05). FLCN expression was variable in BHDS-associated parotid oncocytomas, showing patchy nuclear and cytoplasmic staining without statistically significant differences between syndromic and non-syndromic groups (p ≥ 0.077). In contrast, GPNMB exhibited strong, diffuse granular cytoplasmic expression in both BHDS-associated renal tumor controls, and parotid oncocytomas, while non-syndromic parotid oncocytomas lacked this pattern (p ≤ 0.05).

Parotid oncocytomas in BHDS demonstrate distinctive clinicopathologic features, including younger patient age, cytoplasmic clearing, and a characteristic GPNMB-positive immunophenotype. These findings distinguish them from sporadic parotid oncocytomas and support the use of GPNMB as a potential adjunct marker to raise suspicion for BHDS. Recognition of this association is clinically significant, as patients with BHDS have an estimated 15-30% risk of developing renal malignancies, including chromophobe renal cell carcinoma and clear cell renal cell carcinoma, underscoring the importance of early diagnosis and appropriate surveillance.