Folate receptor overexpression can be visualized in real time during pituitary adenoma endoscopic transsphenoidal surgery with near-infrared imaging

Abstract

OBJECTIVE Pituitary adenomas account for approximately 10% of intracranial tumors and have an estimated prevalence of 15%-20% in the general US population. Resection is the primary treatment for pituitary adenomas, and the transsphenoidal approach remains the most common. The greatest challenge with pituitary adenomas is that 20% of patients develop tumor recurrence. Current approaches to reduce recurrence, such as intraoperative MRI, are costly, associated with high false-positive rates, and not recommended. Pituitary adenomas are known to overexpress folate receptor alpha (FRα), and it was hypothesized that OTL38, a folate analog conjugated to a near-infrared (NIR) fluorescent dye, could provide real-time intraoperative visual contrast of the tumor versus the surrounding nonneoplastic tissues. The preliminary results of this novel clinical trial are presented. METHODS Nineteen adult patients who presented with pituitary adenoma were enrolled. Patients were infused with OTL38 2-4 hours prior to surgery. A 4-mm endoscope with both visible and NIR light capabilities was used to visualize the pituitary adenoma and its margins in real time during surgery. The signal-to-background ratio (SBR) was recorded for each tumor and surrounding tissues at various endoscope-to-sella distances. Immunohistochemical analysis was performed to assess the FRα expression levels in all specimens and classify patients as having either high or low FRα expression. RESULTS Data from 15 patients (4 with null cell adenomas, 1 clinically silent gonadotroph, 1 totally silent somatotroph, 5 with a corticotroph, 3 with somatotrophs, and 1 somatocorticotroph) were analyzed in this preliminary analysis. Four patients were excluded for technical considerations. Intraoperative NIR imaging delineated the main tumors in all 15 patients with an average SBR of 1.9 ± 0.70. The FRα expression level of the adenomas and endoscope-to-sella distance had statistically significant impacts on the fluorescent SBRs. Additional considerations included adenoma functional status and time from OTL38 injection. SBRs were 3.0 ± 0.29 for tumors with high FRα expression (n = 3) and 1.6 ± 0.43 for tumors with low FRα expression (n = 12; p < 0.05). In 3 patients with immunohistochemistry-confirmed FRα overexpression (2 patients with null cell adenoma and 1 patient with clinically silent gonadotroph), intraoperative NIR imaging demonstrated perfect classification of the tumor margins with 100% sensitivity and 100% specificity. In addition, for these 3 patients, intraoperative residual fluorescence predicted postoperative MRI results with perfect concordance. CONCLUSIONS Pituitary adenomas and their margins can be intraoperatively visualized with the preoperative injection of OTL38, a folate analog conjugated to NIR dye. Tumor-to-background contrast is most pronounced in adenomas that overexpress FRα. Intraoperative SBR at the appropriate endoscope-to-sella distance can predict adenoma FRα expression status in real time. This work suggests that for adenomas with high FRα exp...

ICAR: endoscopic skull‐base surgery

“…Preliminary work with OTL38, a folate analog conjugated to an analog of ICG, for pituitary adenomas suggests that it may be possible to delineate tumor margins with a high degree of sensitivity and specificity, specifically in adenomas with high folate receptor α expression . OTL38 functions in the NIR spectrum because of its conjugation with an ICG analog, and has the additional advantage of being a tumor‐specific dye, like 5‐ALA.…”

Targeted Optical Imaging Agents in Cancer: Focus on Clinical Applications

“…Use of fluorescence did not interfere with the surgeon's ability to perform the procedure. This “first-in-human” study demonstrates potential for use of small molecules to target ovarian cancer, guide radical cytoreductive surgery, and improve methods for intraoperative staging [ 62 – 69 ].…”

Clinicopathological analysis of 250�cases of pituitary adenoma under the new WHO classification

“…In conclusion, the new 2017 classification is practical and reasonable from both a molecular and clinical pathology perspective, as this classification is based on IHC studies of transcription factors, which are intuitively understandable and are technically and diagnostically helpful (26). The present study is not the first clinicopathological analysis of pituitary adenomas based on the new classification (26,(47)(48)(49)(50), however previous studies have also showed that the new WHO 2017 classification categorizes less null cell adenomas compared with previous classifications (26,47). In the present study, patients with pituitary tumour diagnosed after 2017 were systematically classified according to the 2017 classification criteria and provides a theoretical basis for the accurate diagnosis of PAs.…”