Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-015-3049-y

REVIEW ARTICLE

Sentinel lymph node biopsy in oral and oropharyngeal squamous cell carcinoma: current status and unresolved challenges Christina Bluemel 1 & Domenico Rubello 2 & Patrick M. Colletti 3 & Remco de Bree 4 & Ken Herrmann 1

Received: 27 January 2015 / Accepted: 15 March 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Because imaging with ultrasound, computed tomography, magnetic resonance imaging or positron emission tomography is unreliable for preoperative lymph node staging of early-stage oral and oropharyngeal squamous cell carcinoma (OSCC), elective neck dissection has been typically performed. The targeted sampling of sentinel lymph nodes (SLN) identified by lymphoscintigraphy and detected by gamma probe has become an effective alternative for the selection of patients for regional nodal resection. With careful consideration to technique, high SLN detection rates have been reported. Advanced techniques including intraoperative handheld gamma camera imaging and freehand single photon emission computed tomography (SPECT) are expected to increase surgical confidence in these procedures. This review gives an update on SLN biopsy in patients with OSCC including clinical standards and controversial aspects.

Electronic supplementary material The online version of this article (doi:10.1007/s00259-015-3049-y) contains supplementary material, which is available to authorized users. * Christina Bluemel [email protected] 1

Department of Nuclear Medicine, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany

2

Department of Nuclear Medicine-PET/CT Oncologic & Endocrine Sections, Rovigo Hospital, Rovigo, Italy

3

Department of Radiology, University of Southern California, Los Angeles, CA, USA

4

Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, Utrecht, The Netherlands

Keywords Sentinel lymph node . Oral cancer . Neck dissection . Squamous cell carcinoma . Intraoperative imaging . Radioguided

Introduction Squamous cell carcinoma (SCC) constitutes the most common head and neck malignancy. SCC of the oral and oropharyngeal (OSCC) tract are frequently related to alcohol or tobacco use or human papillomavirus infection [1, 2]. In the USA, 45,780 new cases are estimated in 2015 [3]. In Europe, the incidence is about 11 cases per 100,000 people per year and the mortality rate 43,700 cases per year [4]. As one of the most important prognostic factors, lymph node status has to be determined in patients with newly diagnosed OSCC [5, 6]. Routine staging includes physical examination, ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI), whereas fluorodeoxyglucose (FDG) positron emission tomography (PET) is not standard of care in many institutes. US-guided fine-needle aspiration cytology (USgFNAC) appears to have a higher sensitivity for the detection of occult lymph node metastases, but reported sensitivities vary largely around 50 % [7, 8]. In any event, these staging procedures are not accurate enough for the final determination of the nodal status, mainly due to their reduced sensitivity for small (occult) metastases [9]. As the overall rate of occult lymph node metastases is 24.8 % in OSCC patients, histopathological assessment of the nodal status is mandatory and therefore elective neck dissection is widely performed [10]. The incidence of the N positivity correlates with the size of the primary tumour and ranges from 20.5 % in T1 carcinoma to 31.4 % in T4 carcinoma [11]. This also means that overall up to 75 % of patients are exposed to the risks of an elective neck dissection without

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any clinical benefit [12]. Therefore, sentinel lymph node biopsy (SLNB), as a less invasive alternative staging procedure, was investigated and emerged for the identification of occult lymph node metastases [13–15]. The SLN defined as the first draining node is identified by either an injection of blue dye or a radiopharmaceutical. In contrast to OSCC, SLNB is standard of care in patients with early-stage breast cancer or melanoma [16, 17]. In 1996 Alex and Krag confirmed the feasibility of the SLN concept in SCC of the head and neck [18]. In first validation studies, the sensitivity of SLNB was 90 % [19]. Typically, resection of only three nodes at maximum [14] is necessary for selecting patients for additional neck dissection. This is associated with reduced side effects (e.g. shoulder morbidity due to spinal accessory nerve injury) and superior cosmetic outcome compared to patients undergoing neck dissections [20–22]. Lymphoscintigraphy can also detect aberrant lymphatic drainage, as for example to the contralateral side or to more inferior neck levels than would be expected based on large retrospective studies on neck dissection specimens [23–25]. Therefore, SLNB allows for personalized management of the neck. Moreover, an SLNB strategy including neck dissections only in node-positive patients has been shown to be costeffective compared to elective neck dissections in all patients [26, 27]. Currently, SLNB has been introduced in a number of centres as the standard of care in clinically N0 OSCC patients. An SLNB strategy has also been integrated in the OSCC tumour guidelines of the National Comprehensive Cancer Network (NCCN Guideline 02.2014) [28]. As the last revision of SLNB in OSCC tumours by a nuclear medicine association dates back to 2009 [29], this review presents an update on SLN procedures in OSCC patients, including controversial aspects and clinical standards. A literature search was performed on PubMed using the following keywords: Boral cancer AND sentinel^ and Bhead neck AND sentinel^. Studies reporting only on cutaneous malignancies were excluded. We also reviewed the references of the corresponding articles. Focus laid on original studies published after the most recent review of 2009 [29]. Studies without any novel information compared to the practice guidelines (e.g. [30, 31]) or without relevance for daily clinical routine of radioguided procedures (e.g. [32]) were excluded. Prospective studies were favoured over retrospective studies and multicentre over single-centre studies. Papers reporting only on preclinical investigation of new methodologies (e.g. [33]) or histopathological work-up (e.g. [34, 35]) were excluded. Studies involving only small patient cohorts compared to larger available studies were excluded. Book chapters or reviews addressing key points of SLNB in OSCC were also included.

Clinical indications for SLNB in OSCC Patients with a clinical N0 neck and T1 or T2 OSCC are potential candidates for SLNB to stage the ipsilateral neck in unilateral tumours or the ipsi- and contralateral neck in patients with tumours close to the midline or even crossing the midline [29]. Gross lymphatic involvement potentially blocks and may alter the lymphatic drainage and reduce the accuracy of SLNB [36]. Therefore, in the case of any clinical suspicion for lymph node metastases, a neck dissection should be preferred and SLNB might only be an option to evaluate the contralateral clinical N0 neck [29]. SLNB is not recommended in T3 and T4 tumours due to its variable accuracy [29]. The performance of SLNB in previously treated neck has to be investigated in larger patient cohorts [37]. In the most recent NCCN guidelines (02.2014), SLN sampling was included [38]. If the primary tumour will be resected in patients with T1–2 cancer of the oral cavity, SLNB potentially followed by a neck dissection in case of a positive SLN is considered a valuable alternative to performing neck dissections in every patient. Since identification of SLN in floor of the mouth tumours is more difficult than at other sites in the oral cavity, SLNB is not advised in patients with a tumour at this site. It should be emphasized that centres starting to perform SLNB should have demonstrated expertise with this procedure by validation studies in which after SLNB a neck dissection is always performed [38]. If SLN identification is not possible, ipsilateral or bilateral neck dissection may be required according to the location of primary cancer. Interestingly, it is not explicitly specified in the practice guidelines regarding which diagnostic procedures are required to confirm a clinical N0 neck [29]. This lack of standardization is also reflected in the previously published studies with varying selection criteria for SLNB ranging from palpation only to USgFNAC. Several reviews and meta-analyses compared different imaging modalities for definition of clinical N0 necks [8, 39, 40] and as non-invasive alternatives to SLNB [7, 9]. For US alone, a pooled sensitivity of 66 % and specificity of 78 % was reported in a meta-analysis [39]. A meta-analysis by de Bondt et al. reported the best accuracy for USgFNAC being superior to CT, MRI and US [8]. However, USgFNAC is controversial because of the wide range of the reported sensitivities ranging from 14 to 73 % depending on the patient selection criteria and the physicians’ experience [7, 9]. Furthermore, isolated tumour cells and micrometastases cannot be detected, but have an impact on survival [25]. CT and MRI are the most common and accepted methods for the evaluation of the primary tumour and the neck region [14, 41–44]. A recently published study by Liao et al. proposed the best negative predictive value (NPV) for final LN staging is for CT/ MRI in combination with SLNB, when compared in combination with US, USgFNAC or PET [45]. Unfortunately, the combination of USgFNAC and SNLB only when USgFNAC

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is negative or inconclusive was not investigated, although USgFNAC was the second best diagnostic technique after SLNB. Since SLNB is a more complex and invasive procedure, it can be anticipated that the combination of USgFNAC and SLNB is the most sensitive combination for the detection of occult lymph node metastases with less burden to the patients compared to SLNB only. Although MRI techniques have recently advanced to include dynamic contrast imaging and apparent diffusion coefficient imaging, not every novelty is available everywhere; therefore, no recommendation for dedicated MR protocols was given [9]. FDG PET/CT including a low-dose or contrast-enhanced CT has not entered many OSCC clinical protocols. Metabolic imaging has demonstrated at least similar accuracies as reported for CT or conventional MRI, whereas other studies showed incremental value of FDG PET/CT in patients with N0 neck defined by physical examination, CT or MRI [9]. However, FDG PET especially in combination with contrast-enhanced CT might be useful for preoperative assessment of the neck status and has therefore been incorporated as an optional imaging method in some national guidelines [46]. However, given the limited resolution of PET it can be anticipated that the value of FDG PET for the detection of occult disease is limited [47]. The role of novel techniques like gene expression profiling [48] or PET/ MRI to select patients for neck dissection and SLNB requires further investigation [49, 50]. Which of all the available staging modalities should be performed before SLNB has not been consistently determined yet. The pre-SLNB staging has to be regarded as a confounding factor when comparing results of different studies. The preoperative staging procedure is strongly influenced by costs, reimbursement and availability, often defined in the recommendations of national guidelines. At least physical examination and any kind of high-resolution imaging (CT or MRI) or USgFNAC of the neck should be performed before SLNB to assess the primary tumour and lymph nodes.

Definition of SLNs SLNs receive the lymphatic drainage directly from the primary tumour and are not necessarily the most adjacent lymph nodes to the primary [51, 52]. Especially in OSCC, there is often more than one SLN [29, 53]. In OSCC, the SLN procedure mainly employs radiopharmaceuticals and therefore lymphoscintigraphy has a central role for the identification of SLNs. Criteria for image interpretation to identify SLNs have been published in practice guidelines [29]. However, definitions for the identification of SLNs vary among previously published studies. Flach et al. recently reported substantial interobserver variability for lymphoscintigraphy-derived SLN identification [54]. Sixteen observers interpreted nine lymphoscintigrams with three to nine hot spots with only

moderate agreement. A multidisciplinary interpretation (nuclear medicine physician and head and neck surgeons) or higher levels of experience resulted in an increased agreement [54]. Additional factors complicating the SLN definition include close proximity between the injection site and the first draining nodes as well as the complex drainage pattern in the head and neck region. To improve interobserver agreement, Flach and colleagues emphasize the need for dedicated guidelines for lymphoscintigraphy interpretation [54]. While there is no doubt that lymph nodes directly draining from the injection site are SLNs, the intensity of uptake, time of appearance and relevance of neck side and level were interpreted differently [54]. It has to be determined if only the first appearing node in dynamic imaging is the SLN or if every node appearing during lymphoscintigraphy without clear signs of second echelon nodes should be sampled. The maximum number of SLNs to be resected should be agreed upon. Civantos et al. reported that removing the three hottest nodes is generally sufficient [14]. Good agreement in the interpretation of lymphoscintigrams is also required for the comparability of studies in this field.

Diagnostic performance of SLNB in OSCC In 2002, Ross et al. summarized the discussion of the first international conference of SLNB in OSCC [19]. Two years later, the second international conference in Zurich defined methodological requirements for the success of SLNB and summarized the pooled data on 379 patients from 22 centres. A detection rate of 97 % using a combination of preoperative lymphoscintigraphy and intraoperative gamma probe was demonstrated [52]. In 2007 a meta-analysis by Alvarez Amézaga et al. pooled available data and reported an overall sensitivity of 93.4 % and a specificity of 100 % [55]. Besides tumour size, the location of the primary tumour is a factor for the failure of SLNB [14, 36]. Reduced detection rates were observed in tumours of the floor of the mouth because of the close proximity of the SLN and the injection site [13, 56, 57]. This was also reflected in the practice guidelines published in 2009 [29]. In 2010, the final results of the multicentre American College of Surgeons Oncology Group (ACOSOG) validation trial were published [14]. In 25 institutions, 106 SLNB biopsies were performed within a 3-year period by surgeons with different experience levels. The NPV of SLNB using additional step-serial sectioning and immunohistochemistry (IHC) was higher (96 %) compared with haematoxylin and eosin staining only (94 %). Not surprisingly, the more experienced surgeons perform better [14]. The high accuracy of SLNB was shown in long-term experience studies [13, 41, 42, 58, 59]. In the European multicentre trial (n=134 patients, 6 centres) including a follow-up of at least 5 years, the sensitivity and NPV were 91 and 95 %, respectively, whereas 55

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patients in this cohort received a SLNB-assisted elective neck dissection and 79 patients SLNB alone [13]. In a more recent meta-analysis (21 studies, 847 patients), a sensitivity of 93 % and NPV ranging from 88 to 100 % were shown [15]. The accuracy of SLNB was not only influenced by the histopathological work-up of SLNs, but also by the chosen reference standard [60]. The sensitivity in studies using elective neck dissection as reference standard was higher (94 %) than in those using clinical follow-up (91 %) [15]. A second metaanalysis in 2013 showed similar results with sensitivities and NPVs >90 % [61]. Unfortunately, only validation studies, i.e. studies in which an SLNB was followed by a neck dissection in all patients, were included. Recently, the results of a Dutch single-centre study [62] and of the Dutch multicentre trial were published, in which a neck dissection was only performed after positive SLN [63]. The sensitivity in the singlecentre study was much better than in the multicentre study, probably due to more experience in the single centre. These Dutch studies confirmed results of former studies that patients with a negative SLNB had a longer disease-specific survival compared with those with a positive SLNB treated with additional neck dissection, radiotherapy or both [25, 41, 44]. In a patient cohort of 109 patients from 15 European centres the negative impact of positive additional non-SLNs on outcome has been shown [64]. The predictive role of even small metastases was emphasized by Broglie et al. [25]. SLNB allows for a valuable neck node tumour control rate [13, 42, 63, 65, 66], and overall SLNB reduces occult lymph node metastases from 40 to 8 % [63]. The final results of the Sentinel European Node Trial (SENT), which recruited over 400 patients, have not yet been published [63].

experienced in SLNB [63]. The radiation exposure of SLNB is low [29]. Because lymphatic drainage is rapid and complex, with unpredictable drainage, for example to the contralateral side, but particularly to solve the problems of the ‘shinethrough’ phenomenon from the injection site hampering preoperative visualization and intraoperative detection of SLNs close to the primary tumour and the differentiation between real SLNs and second echelon nodes, novel tracers have been developed addressing these issues to solve logistical challenges and challenges in detection of SLNs. 99m Tc-tilmanocept (99mTc-diethylenetriaminepentaacetic acid-mannosyl-dextran), a dedicated tracer for SLNB, binds specifically to mannose receptors (CD206) expressed within lymph nodes [68]. Promising results, including fast drainage from the injection site, no drainage to second echelons and specific binding over 30 h, were shown in phase III trials in patients with melanoma and breast cancer [68, 69]. Due to the complex drainage and close proximity of the injection site and SLNs, these characteristics of 99mTc-tilmanocept are of great interest in OSCC patients. 99mTc-tilmanocept has been examined in 20 patients with oral cancer using elective neck dissection as reference standard [70]. The NPV in this cohort including five patients with tumours of the floor of the mouth was 100 % [70]. Using histopathological examination of the neck specimen as reference standard, a recent study of 85 head and neck cancers (93 % OSCC) showed a detection rate of 97.6 %, a sensitivity of 97.4 % and an NPV of 97.8 %. [71]. This tracer has recently been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in OSCC.

Radiopharmaceuticals

Technical requirements and preoperative lymphoscintigraphy

Basically blue dye or radiopharmaceuticals can be used for SLN procedures. In OSCC, mainly radionuclide tracers dominate, as blue dye can only be seen if no overlying tissue is present; moreover, the drainage of it is very fast in the head and neck region [9, 29]. Results of radiopharmaceuticals alone and in combination with blue dye are similar. Govers et al. reported a pooled sensitivity of 93 % for lymphoscintigraphy and gamma probe and 92 % for the combination procedure also including blue dye [15]. In Europe, most frequently 99mTc-nanocolloids are used [13], whereas in the USA filtered 99mTc-sulphur colloids are common [14]. The injected activity recommended by the practice guidelines ranges from 15 to 120 MBq in 0.4–1.0 ml depending on the intended time interval between injection and surgery. Lower activities might be sufficient [67]. A topical application of a local anaesthetic should be given to reduce pain. The injection should be performed peritumourally in at least four aliquots [29], as is typically done at centres

According to the second international conference, preoperative lymphoscintigraphy and intraoperative use of a gamma probe are recommended as minimal requirements to guarantee a reliable identification rate of SLNs [52]. Characteristics of gamma probes for intraoperative use and their quality control were summarized in previously published practice guidelines [29]. An intraoperative injection without the possibility for imaging might confound the identification and definition of SLNs and should be a voide d [ 54]. Preope rative lymphoscintigraphy or intraoperative imaging can be used as a road map and also for planning the incision site. A 1- or 2day protocol is possible [29]. Possibly, with introduction of intraoperative imaging some limitations could be overcome and the time needed for the whole procedure may be reduced. Intraoperative imaging may preclude preoperative lymphoscintigraphy although there are limited data supporting this premise.

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Lymphatic drainage in the head and neck is hardly predictable. Therefore, lymphoscintigraphy starts immediately after radiopharmaceutical injection. Because of the difficulties in the definition of true SLNs, a dynamic series is essential. Anterior and lateral or oblique early static images are required. Late static images might be performed if necessary [29]. Heuveling et al. compared early and late static imaging (2– 4 h after injection) in 60 patients [72]. In 15 % of the patients, only late images demonstrated SLNs. In 27 % of the patients, additional nodes were found with late imaging. These late appearing nodes had no impact on the nodal status, but did result in extended surgery. The authors conclude that late imaging is generally only needed in patients with midline tumours and tumours in the oral cavity other than mobile tongue or lateral floor of mouth tumours [72]. Technical details for image acquisition can be found in the practice guidelines [29]. Adequate gamma camera collimation is required in order to avoid septal penetration and star artefacts, which can affect the interpretation of both lymphoscintigraphy and single photon emission computed tomography (SPECT)/CT. This is especially crucial in OSCC due to the high number of SLNs near the injection site [29]. Due to the anatomical complexity of the head and neck region, SPECT/CT might be useful in localization of SLNs, identification of additional SLNs near the injection site and planning of surgery in patients with OSCC [73, 74]. SPECT/ CT provides functional information from SPECT, which can be combined with the morphological information of CT. CTderived attenuation information allows for correction of the SPECT signal for tissue attenuation and scattering, enabling also the visualization of poorly detectable nodes on planar images [73, 75]. In 2009 practice guidelines did not give a recommendation for SPECT/CT as Bthe true role of SPECT imaging in OSCC SNB has yet to be determined^ [29]. In 2013 Wagner et al. summarized the potential advantages reported in studies from 2004 to 2009 [76]. The advantages of SPECT/CT might be the identification of additional hidden nodes compared with planar images [11, 77, 78], reduction of the misinterpretation rate (e.g. skin contamination, injection site) [79, 80] and better anatomical localization [77, 80]. As already mentioned in the practice guidelines in the beginning of the SPECT/CT era, only low-end slow CT scanners were available [81]. Since the integration of modern high-end CT in hybrid scanners, the acquisition of high-resolution scans with or without contrast enhancement provides a precise anatomical setting of the SLNs displayed in 5-mm or even 2-mm slices on axial, coronal, sagittal views and maximum intensity projection, respectively [73, 75]. Additional volume rendering for 3-D display visualization of complex anatomy and their 3-D relationships might be improved [75]. Valdés-Olmos et al. summarized these improvements in SLN imaging leading to a Bnew paradigm of see and open in contraposition to former open and see^ [73]. A combination of full-dose diagnostic CT

with the SLNB procedure is not necessary, because only anatomical localization of SLNs including the differentiation of single nodes versus cluster of lymph nodes is necessary [75]. Furthermore, most of the patients have already undergone a diagnostic CT before SLNB as part of their diagnostic workup. Additionally, the clinical impact and cost-effectiveness of SPECT/CT lymphoscintigraphy in patients with OSCC has not been evaluated yet. Additionally, no definitive studies have addressed the clinical impact and cost-effectiveness of SPECT/CT lymphoscintigraphy in patients with OSCC.

A procedure suitable for everyone? Close collaboration between nuclear medicine physicians, head and neck surgeons and pathologists is mandatory to secure high detection rates and good reproducibility. Such collaboration should lead to increased agreement regarding the definition of true SLNs [54]. Clinicians and imaging specialists have to be aware of the limitations of SLNB. Nonvisualization of SLNs may be attributed to incorrect injection, shine-through phenomenon or gross tumour involvement of lymph nodes [14]. The success rate of SLNB is also related to the experience of the surgical centres. Therefore, the procedure is rated as ‘demanding’ by the NCCN guidelines and should only be performed in centres with expertise in this technique [38]. In centres with an experience of ten or less cases, a sensitivity of only 57 % could be obtained compared with centres with an experience of more than ten cases where sensitivity is 94 % [19]. Civantos et al. reported a reduction of NPV from 100 to 95 % in less experienced centres [14]. Therefore, perhaps the first ten procedures should be combined with subsequent elective neck dissections in all patients [19]. To allow an unexperienced centre to include the SLNB in their daily clinical routine, clear guidelines including the latest results of research are warranted. In these centres a limited number (one or two) surgeons should start performing SLNB to get experience as fast and good as possible. Regular checks of the success rates in each centre should be performed, followed by a discussion of these results by the responsible physicians, especially if the team participants change.

Overcoming limitations: tracers and intraoperative imaging One of the most relevant limitations of this approach in OSCC is the reduced detection rate in tumours of the floor of the mouth. Alkureishi et al. reported in their multicentre study an identification rate of 88 vs 96 % and corresponding sensitivity of 80 vs 97 % for floor of mouth tumours compared to other OSCC, respectively [13]. As reported by Civantos et al.,

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the false-negative rate in tumours of the floor of the mouth was significantly higher (25 %) than of tongue cancers (10 %) or other oral malignancies (0 %) [14]. The SLNs in close vicinity to the primary tumour are often masked because of the high tracer accumulation in the injection depots (shinethrough phenomenon). Therefore, dividing the radiocolloid dosage into smaller tracer depots may be advantageous. Additionally, novel tracers were investigated and intraoperative imaging of radionuclides was implemented into the operating room to overcome the shine-through phenomenon. Whereas blue dye is a routinely used non-radioactive tracer for SLNB, more recently superparamagnetic iron oxides have been introduced as an alternative to isotopic methods [82, 83]. Magnetic nanoparticles have a dimension similar to the radiocolloids and were reported in preliminary studies to be easily and safely applicable. However, up to now no larger series in OSCC patients have been reported. In a case series of three patients with tongue cancer, this technique was feasible and provided results comparable to 99mTc-based SLN detection [84]. SLNs were already visualized after 10 min in MRI. A further advantage is the intraoperative visualization of these brown-black particles [85]. Similar to blue dye magnetic nanoparticles can also be injected in the operating room, but even allow for detection by a handheld magnetometer without skin incision [85]. In theory, the entire magnetic procedure can be limited to the operating room performed by the surgeons themselves potentially preventing currently existing scheduling challenges; however, because of the complex lymphatic drainage a preoperative MRI scan to visualize the lymphatic drainage might remain necessary. Besides the daily clinically used gamma-emitting 99mTc tracers, the positron-emitting 89Zr nanocolloidal albumin has been recently introduced [86, 87]. In a feasibility study comparing this new PET tracer with conventional 99m Tcnanocolloid SPECT, the higher resolution of PET/CT allowed

a better visualization of SLNs in close spatial relation to the primary tumour, e.g. in level I or IIa nodes. The study showed that even small lymphatic vessels could be visualized [86, 87]. Despite increased resolution for preoperative imaging, intraoperative SLN detection by may be challenging due to the size and other characteristics of PET probes. Multimodal nanoparticles allowing preoperative high-resolution imaging as well as safe intraoperative SLN mapping may overcome this limitation [88]. Additionally, high-resolution images acquired (SPECT/CT or PET/CT) might be brought to the operating room in the future [74]. However, these approaches are experimental and not available for routine daily clinical use. For intraoperative detection of SLNs usually an acoustical gamma probe is used. The required characteristics and quality control of these probes are summarized in the practice guidelines [29]. For radionuclide imaging small field gamma cameras and a freehand SPECT (fhSPECT) system are now available [89–91] (Figs. 1 and 2). In 2010, Vermeeren et al. published promising results for a portable gamma camera [92] providing intraoperative planar images. In a cohort of 25 patients including patients with head and neck melanoma, the portable gamma camera enabled the localization of SLNs in difficult sites and detected additional nodes in 24 % of patients compared to preoperative scintigraphy [92]. Although the relevance of these additional nodes is not clear, portable gamma camera can be used to facilitate intraoperative detection of SLNs [93]. As recently shown in a simulation model, SLNs can be detected at a distance of 3 mm from the injection site using portable gamma cameras with pinhole collimation [94]. This approach specifically addresses the shine-through phenomenon, which is often present in floor of the mouth tumours. Exact positioning of the peritumoural injection deposits (with or without US guidance) with at least 3 mm distance to adjacent lymph nodes and intraoperative use of highresolution gamma cameras might further improve the SLN

Fig. 1 fhSPECT-guided SLNB in a patient with oral cancer. a Preoperative SPECT/CT showing an SLN dorsal to the glandula submandibularis on the right side. b fhSPECT scan in the operating room before incision demonstrating the injection site (dotted arrow) and corresponding to preoperative imaging a sentinel node (arrow). c First scan after sentinel node dissection showing residual activity, which

was also dissected. In the resected tissue another sentinel node was found. b, c The boxes display percentage distribution of radioactivity in the scanned region. Published with permission of the original authors and the publisher. (Adapted from [101]; permission license number 3556570662675)

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Fig. 2 High-resolution portable gamma camera-guided SLNB in a patient with oral cancer. Intraoperative SLN identification with a portable gamma camera (left image depicts localization of SLNs and right image shows remaining radioactivity after their excision). a The first preexcisional image (10 s of acquisition) shows right laterocervical SLN (red arrow), situated caudally to the injection site of the radionuclide (asterisk). b After its resection no significant residual activity is seen.

(Published with permission of the original authors and the Publisher. Originally published in Mayoral M, Paredes P, Sieira R, Vidal-Sicart S, Marti C, Pons F. The added value of a portable gamma camera for intraoperative detection of sentinel lymph node in squamous cell carcinoma of the oral cavity: A case report. Rev Esp Med Nucl Imagen Mol. 2014;33(4):237–40 Copyright © 2013 Elsevier España, S.L. y SEMNIM. Todos los derechos reservados)

identification rate. fhSPECT provides intraoperative 3-D images of the distribution of the injected radionuclide overlaid with a live video of the region of interest [95]. A conventional gamma probe is used as the detector. The system allows for additional depth measurements and a dedicated navigation to the SLNs. Promising results have been reported for melanoma [96] and breast cancer [97], and more recently for OSCC [98–103]. The detection rate and sensitivity using elective neck dissection as reference standard were 98 and 100 %, respectively, in a single-centre study with 23 patients [101] (Fig. 1). A larger patient cohort of 66 patients was recently published using clinical follow-up as reference standard. Corresponding reported detection rate, sensitivity and NPV were 94, 85 and 96 %, respectively [103]. fhSPECT might simplify

the planning of the incision, which might be important because the skin marking is often not helpful in the head and neck due to different positioning pre- and intraoperatively. While fhSPECT might also overcome the shine-through phenomenon in some patients, results have been inconsistent [98, 99, 101, 103]. This image-guided technique might further reduce the invasiveness of the procedure by allowing dedicated navigation. Using the navigation tool with depth measurement, safe resection of SLNs in the complex head and neck region with fragile anatomical structures appears to be possible. The successful resection of all preoperatively detected SLNs can be confirmed with post-resection images. Heuveling et al. reported that fhSPECT was of additional value in 24 % of 66 patients, whereas in 8 % the additional

Fig. 3 Fluorescence-guided SLNB of head and neck malignancies. a, b) show an SLN visualized with the fluorescence camera in the neck and demonstrate how the signal is blocked by a blood vessel (arrow); this exemplifies how fluorescence imaging is useful, but because of the limited penetration depth, the radioactive component remains indispensable. (Published with permission of the original authors and

the Publisher. Originally published in Borbón-Arce M, Brouwer OR, van den Berg NS, Mathéron H, Klop WMC, Balm AJM, et al. An innovative multimodality approach for sentinel node mapping and biopsy in head and neck malignancies. Rev Esp Med Nucl Imagen Mol. 2014;33(5):274-9 Copyright © 2013 Elsevier España, S.L. y SEMNIM. Todos los derechos reservados)

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information was disadvantageous due to artefacts [103]. Therefore, it is crucial that clinicians are trained and aware of potential limitations before using this novel technique. Results for the new integration of a small field gamma camera instead of a gamma probe into the fhSPECT system are not available yet. A further development of fhSPECT technology is the fusion of the 3-D images of fhSPECT with US [104]. A preoperative fhSPECT/US-guided biopsy of the SLNs is under evaluation in breast cancer patients and might also be applied to OSCC patients [105]. Besides intraoperative use of devices with higher resolution to overcome the limitations in SLN detection close to the injection site, a further technical innovation is near-infrared fluorescence imaging, which can be combined with 99mTcnanocolloids with promising results [74, 106–108] (Fig. 3). Fluorescence imaging is not impaired by the shine-through phenomenon as observed with radiolabelled tracers, but a limitation of the currently used tracers is the inability to detect deep SLNs due to the limited penetration of their signal. Therefore, hybrid tracers combining fluorescence and radioactive components appear to be a promising solution. Recently developed, more potent tracers have been tested in animal models [109]. The results of all these methods for intraoperative detection are promising, but multicentre studies are needed to validate the results before these techniques can be translated into daily clinical routine. Summary and outlook SLNB in patients with OSCC was first introduced in 1996 [18]. Almost 20 years later numerous studies have demonstrated the applicability of SLNB in cN0 patients as a reliable staging method with high reproducibility of the results. SLNB has recently become more accepted and is now integrated as an alternative to elective neck dissection in experienced centres according to the NCCN guidelines [38]. Patient selection criteria for SLNB vary and depend on the recommendations for staging of newly diagnosed early-stage OSCC. Whereas imaging is mandatory, the role of FDG PET/CT or even FDG PET/MRI remains to be determined. Well-known limitations such as the reduced detection rate of SLNs in close proximity to the injection site and the complex lymphatic drainage in the head and neck region have triggered studies investigating novel tracers and intraoperative imaging revealing promising results. Recently, the results of a multimodality approach including a hybrid tracer (fluorescence and radionuclide tracer), preoperative SPECT/CT and intraoperative use of a handheld gamma camera have been published [108]; 26 % additional nodes were found in a cohort of 25 patients using this multimodality approach. The impact of these results and the role of a multimodality approach have to be investigated in further multicentre studies. SLN

procedures might also be combined with radiotherapy, enabling a personalization of treatment. For example, Daisne et al. planned the irradiation of lymph nodes according to the drainage pattern demonstrated by lymphoscintigraphy [110]. In summary, the clinical implications of all these promising developments have to be confirmed in ongoing and future clinical trials. Updated accurate and reproducible clinical practice guidelines are mandatory for SLNB to be used as the standard procedure for patients with cN0 OSCC. Compliance with ethical standards

Conflicts of interest Author CB had received a research grant from IZKF (Interdisziplinäres Zentrum für Klinische Forschung) Würzburg. Author KH is cofounder of Surgiceye GmbH. All other authors declare that they have no conflict of interest. Research involving human participants and/or animals Not applicable—the manuscript is a review article. The study [101], for which reprint permission was obtained (Fig. 1), was approved by the local Ethics Committee, and all patients signed written informed consent forms.

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