For a very long time, treatment of differentiated thyroid cancer has constituted largely of thyroidectomy, later amended by the addition of molecular imaging and therapy with the sodium-iodine-symporter-targeted agent radioiodine, the isotope of which was chosen depending on the purpose of the procedure. However, except for the incidental identification of metastatic lymph nodes using probe-guided surgery, these two treatment modalities did not overlap.

In recent years, fluorescence-based imaging of tracers has emerged as an alternative to the use of radioisotopes. The wavelength used in fluorescence certainly is associated with drawbacks where it comes to whole-body imaging in the diagnostic and post-radioiodine-therapy setting, as fluorescent radiation does not penetrate more than skin deep [1]. For intraoperative use, however, it has emerged as a valuable adjuvant method in, e.g., parathyroid surgery [2] as well as a promising technique for improving surgical assessments in a host of different oncological surgery settings [3].

Although perioperative care has greatly improved, the techniques used in thyroid cancer surgery have not essentially changed since the days of Kocher. The one notable exception to this being the introduction of recurrent laryngeal nerve monitoring over the past decades to reduce the rate of post-thyroidectomy vocal chord palsy [4].

The paper by Metman et al. elsewhere in the issue of the European Journal of Nuclear Medicine and Molecular Imaging [5] shows that considerable advances, combining the best of both worlds in surgery and molecular imaging, may be right around the corner. In a newly reported phase 1 trial, the authors carried out a dose escalation study of a fluorescent molecular imaging agent targeted specifically at MET expressed in papillary thyroid cancer (PTC). After administration, patients subsequently underwent thyroid cancer surgery.

First of all, the authors showed that this agent was safe, with only one CTC grade I event occurring in a single patient out of a total 14 patients treated. Secondly, the authors reported that the agent was potentially effective, clearly differentiating PTC from healthy thyroid tissue and identifying PTC foci as small as 1.4 mm through optical fluorescent imaging. Thirdly, the authors have to be commended on translating all essential principles of molecular imaging from radioisotopes to an optical tracer—using specific targeting of a tracer, imaging, as well as quantification of the signal to arrive at their results.

The concept of employing the combination of molecular imaging and surgery as shown in this paper holds great promise for the future: for the first time, the surgeon will have additional tools readily available within the OR to aid in identifying previously unknown multifocal disease. In PTC, an optical scan showing multifocal disease will result in the immediate intraoperative decision to perform a total thyroidectomy instead of a hemithyroidectomy, thus obviating the need for a second surgery for completion thyroidectomy in these patients. This will increase patient safety, comfort, and eventually most likely also quality of life.

With a PTC foci-specific sensitivity of 66.66%, a specificity of 33.33%, and a positive predictive value of 50%, the current approach leaves some room for improvement, as these results still fall somewhat short of levels which in an ideal world would be desirable for clinical use. As the authors rightfully indicate in their discussion, the emission wavelength of the tracer used might not be optimal and further research could (and perhaps should) be done on optimization in this respect. Despite this, in some clinical applications with deeper located target lesions, a higher penetration depth is required for which optical tracers may not be able ideally suitable, and a radioactive tracer might still prove to be a valuable alternative.

It should therefore be noted that the reported method relies on ex vivo assessment, after surgical resection of the specimen, rather than direct in vivo assessment of the local status. When the aim of intraoperative imaging is to identify the need for a change in surgical management, the ex vivo approach is not always optimal. As an example, the authors refer to their recent study that reports on the use of the fluorescent-labeled tracer EMI-137 for identification of a true negative nodal compartment with the aim of avoiding a negative prophylactic central compartment dissection [6]. Although the data are very encouraging, this approach will only be effective when optical imaging techniques would be able to truly assess this negative nodal status in vivo. Given the issues with optical tissue properties [1], the risk of false negative results seems considerable.

The study by Metman et al. illustrates other limitations that the field of intraoperative fluorescence imaging is still facing. The authors could not use the same machine for all cases, thus limiting the cohort of patients available for quantitative analysis as there currently is no standard for quantification of fluorescent imaging—much unlike, e.g., positron emission tomography where the European Association of Nuclear Medicine Research Limited (EARL) standard is well established [7]. Perhaps a similar standard could in the future be developed for fluorescence-based imaging, thus enabling reliable quantification of fluorescence imaging, independent of the machine used.

For future clinical practice, the study presented by Metman et al. certainly shows that thyroid cancer surgery potentially stands to benefit from combining the best of both worlds of surgery and molecular imaging. Thus, after further due studies, perhaps thyroid surgery will be a novel environment and hitherto unsuspected context for the age-old Latin sentence: “fiat lux.”