Sentinel lymph node biopsy (SLNB) has been implemented in most Dutch Head and Neck Cancer institutions as a standard oncological care for staging the clinically negative neck in early-stage (cT1/2N0) oral squamous cell carcinoma (OSCC) [1]. As SLNB has shown to accurately stage the clinically negative neck in these patients, with a pooled sensitivity of 87% and negative predictive value of 94%, SLNB offers a reliable, less invasive alternative for elective neck dissection with overall lower morbidity rates, better quality-of-life, and lower healthcare costs [1,2,3,4,5,6,7,8,9,10].

Nevertheless, SLNB with conventional peritumorally administered 99mTc-labeled radiotracers has its predicaments in OSCC, arising from the limited resolution of conventional scintigraphy and SPECT/CT imaging. Especially in cases where sentinel lymph nodes (SLNs) are located in proximity of the primary tumor, the activity residing at the radiotracer injection site can conceal these adjacent SLNs and impede distinction between SLN and injection site. This so-called shine-through phenomenon is notably manifest in floor-of-mouth OSCC, resulting in a significant lower accuracy of SLNB in floor-of-mouth tumors (sensitivity 63%; NPV 90%) compared to other OSCC subsites (sensitivity 86%; NPV 95%) [1]. Such decline in diagnostic accuracy increases the risk of neglecting occult lymph node metastasis that will inevitably develop into clinical manifestation of disease and consequently induce a poor oncological prognosis [11, 12].

Furthermore, on conventional scintigraphy and SPECT/CT imaging, distinguishing hotspots as either real SLN or higher echelon node (HEN) can pose a challenge. Consequently, in clinical practice, presumably an excessive amount of lymph nodes is harvested, as some will actually represent HENs. Extirpation of HENs may lead to unnecessary morbidity and risk of complications and may even hamper a complementary surgical treatment in case of metastatic involvement of SLNs [13].

In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, we present a promising novel imaging technique that may solve the clinical issues addressed: [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy [14]. The superior spatial resolution of PET/CT lymphoscintigraphy, when compared to SPECT/CT using 99mTc-labeled radiotracers, enables identification of SLNs located close to the radiotracer injection site and improves anatomic localization of SLNs, which is of particular importance in the complex anatomy of the neck and its abundant lymph nodes. Hence, PET/CT lymphoscintigraphy using [68Ga]Ga-tilmanocept might lead to a reduction of false-negative SLNB outcomes by diminishing the shine-through phenomenon. In addition, its high temporal resolution and ability to visualize lymphatic vessels could improve differentiation between true SLNs and HENs, thereby decreasing unnecessary HEN extirpation and reducing the risk of surgical complications and morbidity [14, 15].

Further merits of [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy, relative to SPECT/CT with [99mTc]Tc radiotracers, include its potential to considerably shorten acquisition time with similar signal-to-noise ratios, as well as the concomitant opportunities provided by using a tri-modal agent (IRD-800CW-[68Ga]Ga-[99mTc]Tc-tilmanocept) [16,17,18,19]. This tri-modal agent should facilitate high-resolution PET/CT lymphoscintigraphic images for preoperative SLN mapping and, the following day, intraoperative localization of SLNs with both the conventional portable gamma probe and fluorescence imaging, without interference from 68Ga’s positron emission due to its short half-life (68 min). Although high-energy handheld PET probes are available, designed for intraoperative localization of SLNs containing a positron-emitting isotope–labeled radiotracer (e.g., [89Zr]Zr-nanocolloid), their use is not recommended due to their large size and limited sensitivity [20]. Therefore, intraoperative localization of SLNs should still depend on at least conventional gamma probe guidance, which remains feasible when combining [68Ga]Ga and [99mTc]Tc radiotracers [14].

Finally, in contrast to other commonly used positron emitting isotopes (e.g., 11C, 18F, 89Zr), production of 68Ga does not require a nearby cyclotron, but can be obtained from a portable 68Ge/68Ga generator, allowing on-demand preparation of [68Ga]Ga-tilmanocept in a standard hospital radiopharmacy [21,22,23].

Yet, the materialistic costs associated with [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy may remain a hindrance for the global spread of this innovative technique. First of all, as labeling of 68Ga with nanocolloids is unfeasible due to instability of their bond at physiological pH, this technique relies on using the more expensive tracer tilmanocept. Secondly, the additional costs for labeling tilmanocept with 68Ga should be taken into account. The necessary commercial automated synthesis units are relatively expensive, although more economical options with minimal operator radiation exposure are available [23]. In addition, 68Ge/68Ga generators typically cost in excess of €50.000 and expire after 1 year. However, it should be emphasized that the interest in 68Ga-labeled tracers (e.g., [68Ga]Ga-DOTATOC, [68Ga]Ga-PSMA) continues to increase. Accordingly, the costs per preparation decrease, while 68Ge/68Ga generators have already proven to provide a cost-effective alternative to radionuclides obtained from reactors and cyclotrons [23,24,25]. Finally, the operating costs for PET acquisition are still higher than scintigraphy and SPECT acquisition, despite the fact that the costs of purchasing and operating PET scanners have been halved over the past 10 years [25]. All considered, the costs for performing [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy in our institution are estimated at €1.700 per patient, not including expenses for additional 99mTc and fluorescent labeling in light of future perspectives. In contrast, in our institution, costs for conventional lymphoscintigraphy including SPECT/CT using [99mTc]Tc nanocolloid are estimated at €1.200 per patient, when performed in a research setting.

In spite of these higher materialistic costs, [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy may even be cost-effective, apart from its potential to raise the standard of care, especially when enabling a depletion of false-negative SLNB outcomes, considering that patients with regional failure (i.e., false negative) generally require comprehensive healthcare, including more extensive surgery and adjuvant radiotherapy, compared to patients who are correctly staged positive for disease by SLNB [9, 11, 26]. Furthermore, the potential of [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy to significantly decrease acquisition times for SLN imaging may substantially decline relative personnel costs [25]. Since [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy may diminish unnecessary HEN extirpation, expenses for meticulous histopathological assessment (i.e., step-serial-sectioning, immunohistochemistry) of irrelevant HENs might also be avoided [27].

For now, [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy for SLN mapping in early-stage OSCC is both promising and encouraging, although the number of studied patients requires a considerable increase before any definite conclusions can be drawn. Still, the first results are inspiring for future prospects, including adoption of a tri-modal agent for SLNB (IRD-800CW-[68Ga]Ga-[99mTc]Tc-tilmanocept), implementation in other malignancies, and employing highly accurate targeted radiotherapy by PET/CT lymphoscintigraphic–guided nodal irradiation.