Integrin αvβ6 Expression in the Human Pituitary Gland and Pituitary Neuroendocrine Tumors: Immunohistochemical Characterization with Potential Relevance to αvβ6 PET/CT Pituitary Uptake and Theranostic Implications

Integrins are heterodimeric transmembrane receptors that mediate bidirectional signaling and regulate cell–cell and cell–extracellular matrix interactions. Integrin αvβ6 is an epithelial-associated integrin that has emerged as a promising molecular target for PET/CT imaging using integrin αvβ6-directed radiotracers such as 68Ga-Trivehexin, and, most recently, for antibody–drug conjugate therapy in epithelial malignancies. Unexpected physiological and incidental uptake within the pituitary gland has been reported in integrin αvβ6-targeted PET studies, including uptake in morphologically normal pituitary glands and pituitary neuroendocrine tumors (PitNETs). However, the histological basis of integrin αvβ6 expression in the human pituitary gland remains poorly understood. The aim of this study is to characterize the immunohistochemical expression of integrin αvβ6 in normal human pituitary tissue and PitNETs and to evaluate its potential implications for integrin αvβ6-targeted imaging and theranostic applications. Five complete adult pituitary glands obtained at autopsy and 28 PitNETs were examined by immunohistochemistry for integrin αvβ6. Staining distribution, intensity, and cellular localization were assessed in the adenohypophysis, neurohypophysis, and Rathke’s cleft remnants. PitNETs were classified according to transcription factor expression (PIT1, TPIT, and SF1). Among the 28 PitNETs, 17 were SF1-lineage (60.7%), three were PIT1-lineage (10.7), two were TPIT-lineage (7.1%), three lacked a dominant transcription factor (10.7%), and three showed plurilineage expression (10.7%). Integrin αvβ6 expression was evaluated semiquantitatively according to staining intensity and the percentage of positive tumor cells. In normal pituitary glands, integrin αvβ6 immunoreactivity was predominantly membranous and localized to larger adenohypophyseal cells irrespective of transcription factor lineage or hormone phenotype. Strong expression was also observed in the epithelial lining cells of Rathke’s cleft remnants, whereas the neurohypophysis lacked detectable integrin αvβ6 expression. Among the 28 PitNETs, integrin αvβ6 expression was detected in 20 cases (71.4%). Positive tumors demonstrated variable staining intensity and extent, ranging from 20% to 100% positive tumor cells. By lineage, integrin αvβ6 expression was detected in 13 of 17 SF1-lineage tumors (76.5%), one of three PIT1-lineage tumors (33.3%), and zero of two TPIT-lineage tumors (0%). Additionally, all three tumors lacking a dominant transcription factor (100%) and all three plurilineage tumors (100%) demonstrated integrin αvβ6 expression. Eleven integrin αvβ6-positive tumors showed expression in ≥50% of tumor cells, and six exhibited strong or diffuse immunoreactivity. Integrin αvβ6 expression in adenohypophyseal cells and Rathke’s cleft remnants provides a histological explanation for physiological pituitary uptake observed on αvβ6-targeted PET/CT imaging. The high prevalence of integrin αvβ6 expression in PitNETs, particularly in a subset demonstrating strong and diffuse immunoreactivity, suggests potential applicability of integrin αvβ6-targeted molecular imaging and theranostic approaches, including both radioligand- and antibody-based strategies. However, these applications remain investigational and require further validation in preclinical and clinical studies. At the same time, physiological integrin αvβ6 expression in normal anterior pituitary tissue may limit imaging specificity and should be considered when developing integrin αvβ6-targeted radioligand therapies. Further clinicopathological and imaging correlation studies are warranted to define the diagnostic and therapeutic role of integrin αvβ6-targeted approaches in PitNETs.