Positron Lymphography: Multimodal, High-Resolution, Dynamic Mapping and Resection of Lymph Nodes After Intradermal Injection of 18F-FDG

The lymphatic system is a complex network of capillaries that collect and drain the interstitial fluid and macromolecules that extravasate at the intersection of the arterial and venous vasculature (1). Lymph nodes (LNs) are interspersed throughout this network to filter the fluid and provide a site for immunoregulatory lymphocytes to encounter antigen. Because LNs are important foci of the immune system, their status is an important indicator of many diseases (2). In oncology, metastatic cells have the capacity to spread through the lymphatic system. The sentinel LN hypothesis states that the closest draining LN to a tumor (the sentinel node) can be evaluated for tumor cell invasion and provide information on the extent of disease. LN involvement is a crucial prognostic marker for melanoma (3,4) and for cancers of the prostate (5), cervix (6,7), and breast (8). Sentinel LN involvement is the most important prognostic indicator for patients with primary breast cancer (9,10). General clinical practice is to remove these LNs and analyze them for the presence of tumor cells. Lymphatic mapping enables visualization of local LNs to guide sentinel LN resection in the clinical setting. It is also useful in the research space to study the biologic roles of the lymphatics. Tools for mapping have included MRI (11), scintigraphic (12,13) and tomographic nuclear imaging (14), and optically absorbing (15) and fluorescent dyes (16). This array of molecular modalities possesses a wide range of sensitivities, depths of penetration, resolution, throughput, and cost (17). Clinically, LNs are localized through injection of 99mTc-labeled sulfur colloid (99mTc-SC), often with the subsequent injection of isosulfan blue dye to guide resection. The technique affords a high identification rate (8). However, there is limited specificity and transport of the colloid, providing only 2-dimensional planar information. Tomographic imaging (SPECT) is possible, but it requires long imaging times and has limited resolution. The vital dye may also travel past the sentinel LN. In addition to questions concerning the global supply of 99Mo for generators, these limitations have spurred development of replacement (18) or alternative contrast agents exploiting various modalities (3,19). Here, we demonstrate dual-modality imaging using a single tracer for both lymphatic mapping and guided surgical resection with the ubiquitous PET radiotracer 18F-FDG. In place of LN accumulation of 18F-FDG after systemic delivery, injection is performed directly into the rich lymphatic bed of the dermis (20). Similar to 99mTc-SC, regional delivery localizes transport of 18F-FDG through the lymphatic vessels to draining nodes. 18F-FDG PET/CT clearly delineates the fine vessels and LNs in rodents. In addition to the low background, inherently quantitative nature, high sensitivity, and high temporal resolution of PET lymphography, the radiotracer itself enables optical guidance to localize nodes through emission of Cerenkov radiation (CR). Produced by high-energy charged particles emitted on radioactive decay (β+ for 18F), the visible-wavelength CR photons from PET isotopes can be acquired using highly sensitive camera equipment (21,22). PET lymphography also allows white-light imaging (standard photography) of the subject, providing anatomic localization for surgical investigations (23). Thus, through a single intradermal injection of 18F-FDG, a clinically approved and widely available agent, we achieved both exquisite nuclear tomographic lymphatic mapping for preclinical or preoperative investigation and an optical signal to lead intraoperative resection.