Higher ARNT expression is associated with the sparsely granulated phenotype in somatotroph pituitary adenomas: An immunohistochemical study

PURPOSE: Somatotroph pituitary adenomas are a heterogeneous group comprising distinct histopathological subtypes, including the well-defined densely granulated (DG) and sparsely granulated (SG) phenotypes. While the aryl hydrocarbon receptor-interacting protein (AIP) pathway has been implicated in pituitary tumorigenesis, the role of aryl hydrocarbon receptor nuclear translocator (ARNT) in somatotroph tumors remains poorly characterized. METHODS: We retrospectively analyzed 71 surgically treated somatotroph pituitary adenomas, clinically managed in a tertiary endocrinology center between 2020 and 2025. Immunohistochemical expression of AIP, AHR and ARNT was evaluated and correlated with clinicopathological characteristics, including cytokeratin pattern, hormonal expression and Ki-67 index. RESULTS: Moderate/strong ARNT expression was more frequent in SG than in DG adenomas (60% vs. 17.6%, p = 0.002). Patients with moderate/strong ARNT expression were younger than those with absent/weak expression (median 39 vs. 46 years, p = 0.044). In multivariable analysis, ARNT expression remained associated with the SG phenotype after adjustment for age and sex (adjusted OR 6.84, 95% CI 2.05-22.84; p = 0.002). No significant associations were observed between ARNT expression and Ki-67 index, baseline GH or IGF1 levels, AIP/AHR immunoexpression or the evaluated clinical outcomes, including biochemical control during first-generation somatostatin receptor ligand therapy. CONCLUSIONS: Increased ARNT expression is associated with the sparsely granulated phenotype in somatotroph pituitary adenomas, suggesting that ARNT expression may reflect tumor differentiation rather than proliferative activity. However, the present findings do not demonstrate additional prognostic or therapeutic utility beyond granulation pattern. Further molecular and transcriptomic studies are warranted to clarify the biological role of ARNT.