Near Infrared Folate-Targeted, Intraoperative Visualization of Pituitary Adenoma

Introduction: Pituitary adenomas account for ~10% of intracranial tumors and have an estimated prevalence of 15–20% in the general US population. Surgical resection is the primary treatment for pituitary adenomas and the trans-sphenoidal approach remains the most common route. However, recurrence of tumor is seen in up to 20% of surgical cases and intraoperative magnetic resonance imaging is expensive and not readily available. Because some pituitary adenomas are known to overexpress folate receptor α (FRα), we hypothesized that a folate analog conjugated to a near infrared (NIR) fluorescent dye could provide increased optical contrast for margin detection. We present preliminary results of this novel clinical trial.

Methods: Nineteen adult patients presenting with pituitary adenoma were enrolled in the study. Patients were infused with OTL38 (On Target Laboratories, Indiana) 2 to 4 hours prior to surgery. A VisionSense 4-mm endoscope with both visible light and NIR light sensor was used to visualize pituitary adenoma and margins in real time during surgery. Signal-to-background-ratio (SBR) was calculated for each tumor and margin specimens at different endoscope-to-tissue distances. Immunohistochemistry was performed to assess FRα expression levels in all specimens.

Results: Data from 14 patients (4 null-cell, 1 totally-silent gonadotroph, 3 somatotroph, 5 corticotroph, 1 corticosomatotroph) were analyzed for this preliminary analysis. Five patients were excluded for technical considerations. Intraoperative NIR imaging delineated the main tumor with SBR of 2.8 ± 0.44 for tumors with high FRα expression (n = 3) and SBR of 1.6 ± 0.54 for low FRα expressing tumors (n = 11). The distance from the excitation source to the tissue affects SBR as well, with SBR increasing as the endoscope gets closer to the tumor. In the three patients with IHC-confirmed FRα overexpression (2 null-cell adenomas and 1 totally-silent gonadotroph), intraoperative NIR imaging demonstrated perfect classification of tumor with 100% sensitivity and 100% specificity of margin specimens.

Conclusion: Pituitary adenomas and their margins can be visualized in real time inside the operating room with preoperative injection of OTL38, a folate analog conjugated to NIR dye. Optical contrast is stronger for tumors that overexpress folate receptors, which is primarily seen in non-secretory adenomas. Its value at the time of surgery is promising but remains investigational. Future work will focus on non-functional adenomas, which are the only subset that overexpress folate receptor α.

No conflict of interest has been declared by the author(s).