Epidermal growth factor receptor targeted fluorescence molecular imaging for postoperative lymph node assessment in patients with oral cancer

Abstract

Rationale: In most oral cancer patients, surgical treatment includes resection of the primary tumor combined with the excision of lymph nodes (LN)s, either for staging or treatment. All LNs harvested during surgery require tissue processing and subsequent microscopic histopathological assessment to determine the nodal stage. In this study, we investigated the use of the fluorescent tracer cetuximab-800CW to discriminate between tumor-positive and tumor-negative LNs before histopathological examination.Methods: Here, we report a retrospective ad hoc analysis of a clinical trial designed for resection margin evaluation of oral squamous cell carcinoma patients (NCT02415881). Two days prior to surgery, patients were intravenously administered with 75 mg cetuximab followed by 15 mg cetuximab-800CW, an Epidermal Growth Factor Receptor (EGFR)-targeting fluorescent tracer. Fluorescence images were obtained of excised, formalin-fixed LNs and correlated with histopathological assessment.Results: Fluorescence molecular imaging of 514 LNs (61 pathologically positive nodes) can detect tumorpositive LNs ex vivo with 100% sensitivity and 86.8% specificity (AUC 0.97). In this cohort, the number of LNs that require microscopic assessment was decreased by 77.4%, without missing any metastasis.Additionally, in 7.5% of the fluorescence false-positive LNs, we identified metastases missed by standard histopathological analysis. Conclusion:Our findings suggest that EGFR-targeted fluorescence molecular imaging can aid in the detection of LN metastases in the ex vivo setting in oral cancer patients. This image-guided concept can improve the efficacy of postoperative LN examination and identify additional metastases, which safeguards appropriate postoperative therapy and may improve patient prognosis.

Multispectral optoacoustic tomography for in vivo detection of lymph node metastases in oral cancer patients using an EGFR-targeted contrast agent and intrinsic tissue contrast: A proof-of-concept study

“…5 a shows the increased mean fluorescence intensity of 1.02 (IQR 0.61–1.73) x 10 -2 observed in malignant LNs (n = 9) compared to 0.16 (IQR 0.11–0.26) x 10 -2 in benign LNs (n = 140) (p < 0.0001). Furthermore, malignant LNs showed a maximum fluorescence intensity of 2.49 (IQR 1.72–3.89) x 10 -2 compared to 0.50 (IQR 0.37–0.74) x 10 -2 in benign LNs (p < 0.0001), as shown earlier [48] . Fig.…”

“…This cetuximab-800CW fluorescence largely co-localizes with EGFR-expression. Earlier, we showed the tumor-specificity of cetuximab-800CW fluorescence in LNs [48] . Abbreviations: LN+ , malignant lymph node; LN-, benign lymph node; H&E, hematoxylin and eosin; EGFR, epidermal growth factor receptor.…”

“…All LNs were imaged in a closed-field fluorescence imaging system (Pearl Trilogy®, LI-COR BioSciences) to ensure control of imaging parameters. The protocol for fluorescence imaging of LNs has been described previously [36] , [48] .…”

How Image-Guided Pathology Can Improve the Detection of Lymph Node Metastases in Prostate Cancer

“…[4][5][6] To improve sensitivity of histopathology, molecular imaging can guide the pathologist by identifying suspicious LNs that potentially require additional and/or deeper cuts, before histopathological evaluation. 7 This so-called image-guided pathology could both improve sensitivity and efficiency of the histopathological process and safeguard appropriate postoperative therapy for the patient. 8…”

“…This case illustrates that it is important to realize that histopathology, albeit the standard of reference, has its limitations due to sampling effects and could thus lead to false-negative results [4][5][6]. To improve sensitivity of histopathology, molecular imaging can guide the pathologist by identifying suspicious LNs that potentially require additional and/or deeper cuts, before histopathological evaluation 7. This so-called image-guided pathology could both improve sensitivity and efficiency of the histopathological process and safeguard appropriate postoperative therapy for the patient 8.…”