**1. Introduction**

The global incidence of thyroid cancer has continuously increased over the past decades [1]. This upward trend has been attributed to improved diagnostic acumen owing to the availability of advanced technology, as well as to lifestyle and environmental changes. Thyroid cancer is currently the most common endocrine cancer worldwide [2,3]. Despite increases in incidence, mortality from thyroid cancer has remained stable over the past decades [1]. The life expectancy of many thyroid cancer patients, especially those younger than 45 years, is not reduced when compared with that of the general population [4]. The prevention of treatment-related morbidity is essential, including minimization of postoperative hypoparathyroidism rates, particularly for young patients with an overall excellent long-term prognosis. The majority of the thyroid cancer burden affects women [3], and the prevention of complications with repercussions on pregnancies is crucial for those of reproductive age.

The treatment of choice for thyroid cancer is surgical resection. Depending on the tumor extent, a total or near-total thyroidectomy with therapeutic or prophylactic lymph node dissection is indicated. Despite the significant benefits of total resection, including increased survival and reduced recurrence rates, extensive resections are typically accompanied by substantially increased complication rates [5]. Thus, the risks and benefits of thyroid cancer surgery must be balanced, targeting complete excision of malignant lesions while preserving critical structures such as the laryngeal nerves and parathyroid glands (PGs), particularly in thyroidectomy with lymphadenectomy. As these challenges are continuously encountered in thyroid cancer surgery, surgical innovations are targeted at minimizing procedure-related morbidity while maintaining therapeutic benefits.

One such innovation is intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN). Over the last two decades, IONM has gained popularity and has become the gold standard for thyroid surgeries in order to prevent injury to the RLN [6], despite initial controversial discussions regarding its benefit [7]. Another emerging technology is fluorescence image-guided surgery (FIGS), a real-time navigation modality based on optical imaging. The use of fluorescence imaging is relatively new in surgery, although it is a widely known method used in biomedical sciences for visualizing cells and tissues in vitro and in vivo [8]. The intraoperative use of light sources in the near-infrared (NIR) excitation range induces the emission of a fluorescent signal via a wavelength shift during tissue interaction [9].

In more detail, fluorescence is based on the property of certain substances to absorb external light at a given excitation wavelength and subsequently emit light at a different, longer wavelength with lower energy [10]. As a result, fluorescence imaging involves a sequence in which the tissue of interest is illuminated by a filtered light source at a specific excitation wavelength, light is absorbed by the target tissue, a longer wavelength is emitted, and the fluorescent band is detected by a specifically designed camera [11,12]. The advantage of light in the NIR range is a deeper tissue penetration (<1 cm, with a limited depth resolution beyond 5 mm) [13,14]; thus, NIR imaging devices enable the surgeon to see behind the tissue surface [15]. Other wavelengths (ultraviolet: 200–400 nm or visible: 400–650 nm) are limited for in vivo real-time imaging due to low light penetration into the tissues and autofluorescence from endogenous fluorophores in the body [16,17]. Current in vivo fluorescence imaging systems are thus optimized for the NIR range. This imaging modality provides the surgeon with real-time feedback during the surgical procedure to identify and differentiate surgical targets from normal tissue [12]. Two different modalities of detection of near-infrared autofluorescence (NIRAF) are actually used: a probe-based modality such as the PTeye (by AiBiomed, Santa Barbara, CA, USA) that provides a

quantitative, and auditory feedback when the handheld fiber probe touches parathyroid tissue, and the imaging-based modality that uses an NIR light source in conjunction with a filtered camera to identify the autofluorescence of the tissue on a display monitor such as the Fluobeam-800/Fluobeam-LX (Fluoptics, France), PDE Neo II (Hamamatsu, Shizuoka Pref. Japan), and EleVision™ IR Platform (Medtronic, Minnesota, MN, USA), among others.

FIGS is gaining popularity and is being increasingly used in endocrine surgery, including adrenal [15,18], parathyroid, and thyroid surgery [19,20]. With the integration of specific contrast agents and advanced imaging systems, fluorescence guidance has the ability to bring about significant positive change in surgery, leading to better outcomes by improving the visualization of tissues for resection, such as tumors, or those to be preserved, such as nerves, blood vessels, and neighboring organs [12,21].

Two fluorescence imaging approaches are important in thyroid and parathyroid surgery, namely, contrast-enhanced fluorescence and autofluorescence imaging. The first technique is based on either intravascular or local administration of an exogenous contrast agent, whereas the second technique uses the intrinsic florescent properties of the target tissue via specific optical modalities [10,22].
