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Radioguided Surgery for Head and Neck Cancer

  • Federica OrsiniEmail author
  • Erinda Puta
  • Renato A. Valdés Olmos
  • Sergi Vidal-Sicart
  • Francesco Giammarile
  • Giuliano Mariani
Living reference work entry

Abstract

Tumor status of locoregional lymph nodes is an important prognostic factor in patients with squamous cells carcinomas of the head and neck (HNSCC). Sentinel lymph node biopsy (SLNB) approach meets the expectations of accurately staging the lymph node status of these patients. The procedure consists of preoperative peritumoral injection of the tracer followed by lymphoscintigraphy using planar and single photon emission tomography/computed tomography (SPECT/CT) imaging. Based on the preoperative lymphoscintigraphy findings, the position of the sentinel lymph node (SLN) is marked on the skin. Intraoperative detection of the SLN is guided by combination of a portable handheld gamma ray detection probe (radionuclide detection) and dissection/harvesting of the radioactive lymph node(s). After surgical removal, the SLN is subjected to meticulous histopathological examination.

Keywords

Head and neck cancers Radioguided surgery Radioguided occult lesion localization Sentinel lymph node biopsy SLNB SLN ROLL Sentinel lymph node 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

AJCC

American Joint Committee on Cancer

Bq

Becquerel unit

CT

X-ray computed tomography

DTC

Differentiated thyroid cancer

EMA

European Medicines Agency

FDA

United States Food and Drug Administration

GOSTT

Guided intraoperative scintigraphic tumor targeting

H&E

Hematoxylin and eosin staining

HNM

Melanoma located in the head and neck

HNSCC

Squamous cells carcinomas of the head and neck

ICG

Indocyanine green

LN

Lymph node

MBq

Mega-Becquerel (106 Becquerel)

MRI

Magnetic resonance imaging

MTC

Medullary thyroid cancer

N

Lymph node status according to the AJCC/UICC TNM staging system

NCCN

National Comprehensive Cancer Network

OSCC

Oral squamous cell carcinoma

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

ROLL

Radioguided occult lesion localization

RT-PCR

Reverse transcriptase polymerase chain reaction

SLN

Sentinel lymph node

SLNB

Sentinel lymph node biopsy

SPECT

Single-photon emission computed tomography

SPECT/CT

Single-photon emission computed tomography/computed tomography

T

Tumor status according to the AJCC/UICC TNM staging system

TNM

AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status) and “M” (distant metastasis status)

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasonography

The Clinical Problem

Tumor status of locoregional lymph nodes is an important prognostic factor in patients with squamous cells carcinomas of the head and neck (HNSCC). In these patients a locoregional metastatic sentinel lymph node is an unfavorable prognostic factor [1], and cervical node dissection has a potential curative role [2]. The management of clinically node-negative patients remains controversial, because the probability of finding an occult metastasis is approximately 20% [3]. Furthermore, there is still debate about performing prophylactic lymph neck node dissection versus a wait-and-see approach [4].

Preoperative evaluation of patients with newly diagnosed HNSCC includes physical examination, ultrasound (US) examination (possibly with US-guided fine-needle aspiration cytology [5]), and other radiology-based imaging procedures such as CT and MRI [6]; occasionally, PET/CT with [18F]FDG is also performed, depending on specific indications[7, 8]. However, all these modalities have suboptimal sensitivity for the detection of microscopic lymph node involvement; on the other hand, elective lymph node dissection is burdened with important morbidity. These considerations justify the notion that sentinel lymph node biopsy (SLNB) has the potential of enabling accurate selection of patients for elective lymph node dissection and of accurately staging the clinical and radiological N0-neck in patients with head and neck cancer.

Evaluation of the pattern of lymph drainage in the head and neck region is cumbersome due both to anatomic complexity and to unpredictable routes of lymphatic drainage. The neck contains over 300 lymph nodes and it is necessary to determine the nodes at risk of metastasis in individual patients for all head and neck cancers.

The patterns of lymph drainage from the oral cavity, oropharynx, larynx, and hypopharynx exhibit numerous intraindividual variations, even from the same primary tumor site. Unexpected aberrant lymphatic drainage can be found in 20–30% of patients with clinically negative or positive necks, a feature that has a definite impact on treatment planning on an individual patient’s basis [9, 10, 11, 12].

Lymph drainage from a primary tumor located in the midline may be directed to either side; furthermore, contralateral drainage is often seen even in well-lateralized malignancies of the tongue or floor of the mouth [13]. Although lymph drainage to submandibular nodes is expected from the anterior floor of the mouth and lingual apex, bilateral drainage to higher-level lymph nodes and to the middle jugular chains is not infrequently observed [14].

Thus, due to individual patient variability of lymphatic drainage, selective neck dissection limited to those nodal levels at highest risk has been shown to have 15–20% of “skip metastases” that have bypassed the expected first nodal basin [15]. It is conceivable that, similar to breast cancer and cutaneous melanoma), the SLNB approach can accurately stage the lymph node status of patients with head and neck cancer.

The SLNB technique has been investigated mostly for those head and neck cancers whose anatomic location allows direct and easy access to the tumor for injection of the radiocolloid (or of other lymphatic mapping agents). For this reason the procedure has already been sufficiently standardized in patients with oral squamous cell carcinoma (OSCC) [16], while it is still experimental in head and neck cancers arising at other sites.

In the last decade, the technique has undergone extensive validation against the gold-standard elective node dissection, for tumors located in the oral cavity and accessible subsites of the oropharynx. In 2013 SLNB in early oral cancer was recognized by the National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology of Head and Neck Cancers now include the following statement: “Sentinel lymph node biopsy is an alternative to elective neck dissection for the identification of occult cervical metastasis in patients with early (T1 or T2) oral cavity carcinoma in centers where experience for this procedure is available” [8].

Current indications for SLNB include clinical T1 or T2 node-negative oral and selected oropharyngeal squamous cell carcinomas, where it may be considered a valid alternative to elective node dissection. Clinically T1 or T2 patients includes resectable tumors with size <4 cm in maximum diameter. In fact, in case of larger tumors, it is difficult to perform tracer injection all around the tumor; furthermore, large tumors tend to drain to multiple lymphatic basins and in the majority of patients require a neck dissection for access to the primary tumor or for defect reconstruction [17].

The clinically negative neck is defined by physical examination and clinical imaging by CT, contrast-enhanced MRI, US-guided fine-needle aspiration cytology, and/or [18F]FDG PET/CT.

The first and most frequent target for SLNB is staging the ipsilateral clinically node-negative neck in patients with a unilateral primary tumor. A second target is the assessment of bilateral clinically node-negative necks in primary tumors close to, or crossing, the midline. The third indication is for assessment of the contralateral clinically node-negative neck in primary tumors close to the midline with an ipsilateral clinically node-positive neck, in order to decide whether these patients need bilateral neck dissections, or an ipsilateral neck dissection and contralateral SLNB only. Patients should also be fit enough preoperatively to withstand a neck dissection.

Exclusion criteria include patients who have received prior radiation or surgical treatment to the neck. These patients are generally excluded from SLNB protocols on the assumption that the previous intervention can distort the normal lymphatic pathways and give rise to unexpected patterns of metastasis; nevertheless, these patients should be evaluated on an individual basis, taking into account the time window elapsed between such forms of treatment and the SLNB procedure. In pregnant women, the urgency and the necessity for staging the neck should be discussed. However, SLNB protocols should be modified in pregnant patients to minimize the risks of radiation exposure and blue-dye injections. SLNB can be performed in lactating women, but it is advised that breast-feeding be discontinued for 24 h following the procedure.

The routine SLNB procedure consists of preoperative peritumoral injection of the tracer (such as 99mTc-nanocolloid of albumin or similar radiopharmaceutical; see below) followed by lymphoscintigraphy using planar and single photon emission tomography/computed tomography (SPECT/CT) imaging. Based on the preoperative lymphoscintigraphy findings, the position of the SLN is marked on the skin. SLNB is performed under general anesthesia, and intraoperative detection of the SLN is guided by combination of a portable handheld gamma ray detection probe (radionuclide detection) and dissection/harvesting of the radioactive lymph node(s). Ideally, one or more radioactive (“hot”) SLNs are identified and excised. After surgical removal, the SLN is subjected to meticulous histopathological examination using step serial sectioning and immunohistochemistry.

Lymphatic Drainage and Lymph Node Anatomy of the Neck

Surgical anatomy of the head and neck region is complex due to the small size of vital organs and to the close relation among different tissues. The lymph nodes in the neck are generally subdivided into specific anatomic subsites and grouped into seven levels on each side of the neck (Fig. 1), according to the so-called Robbins’ Classification [18], incorporated into the AJCC-UICC TNM staging system [19].
Fig. 1

Lymph node levels of the neck . (a) Volume rendering of the head and neck showing the anatomical levels of the neck according to Robbins. (bd) Fused axial SPECT/CT images showing examples of SLNs located in right levels I and II (b), right level III (c), and level V of the left side of the neck (d) (Reproduced with permission from Valdés Olmos et al. [14])

Submental (sublevel IA) and submandibular (sublevel IB) lymph nodes are included in level I. Upper jugular nodes extend from the inferior border of the hyoid bone to the base of the skull and are classified as level II; in relation to the vertical plane defined by posterior surface of the submandibular gland, the lymph nodes located anteriorly constitute sublevel IIA, and the nodes located posteriorly correspond to sublevel IIB. Level III includes the middle jugular nodes (from hyoid bone up to the inferior border of the cricoid cartilage), and level IV includes lower jugular nodes (from the inferior border of the cricoid cartilage to the clavicle). The posterior border of regions II, III, and IV is the posterior border of the sternocleidomastoid muscle. Level V nodes are those located posteriorly to the posterior border of the sternocleidomastoid muscle. This latter group is further divided into sublevels VA including the spinal accessory nodes, whereas sublevel VB includes the nodes following the transverse cervical vessels and the supraclavicular nodes. Level VI contains the pretracheal and paratracheal nodes, the precricoid node, and the perithyroidal nodes including the lymph nodes along the recurrent laryngeal nerves. Finally, level VII includes the superior mediastinal lymph nodes.

Radiopharmaceuticals

A variety of colloidal and soluble tracers have been used for imaging the pattern of lymph flow. It is commonly held that radiocolloids are taken up by macrophages in lymph nodes, whereas the transit of macromolecules through lymph nodes is delayed simply because of their large molecular size [14, 16].

The nuclear medicine physicians’ experience and commercial availability of the various agents affect the choice of radiopharmaceutical. 99mTc-albumin nanocolloid (that has a quite narrow range of particle size, with over 90% of the particles being smaller than 80 nm) and 99mTc-sulfur colloid (with a wide range of particle size between about 20 and 400 nm) are commercially available and widely employed in Europe and in the USA, respectively. These tracers migrate to the SLN within minutes after interstitial injection, yet their prolonged retention in lymph nodes allows surgery to take place even the following day [14, 16].

Recently a new tracer, 99mTc-tilmanocept, has been approved for SLNB in OSCC patients, both by the by US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA). Its smaller particle size and specific targeting of mannose receptors (CD206) located on cells within lymph nodes result in rapid clearance, reduced or no drainage to second-echelon lymph nodes, and greater SLN retention, thus enabling improved SLN detection both preoperatively and intraoperatively with respect to the conventional radiocolloids. In a multicenter validation study, all SLNs could be detected and no false-negative results were reported in 20 patients with floor of mouth cancer. Nevertheless, the actual additional value of this new technique has still to be investigated in larger and comparative studies [20, 21, 22].

As an alternative to the radioactive label, near-infrared fluorescent tracers (e.g., indocyanine green – ICG) have been used that are potentially helpful for SLNB [23, 24, 25]; moreover, the combination of such fluorescent tracers with common 99mTc-labeled radiocolloids is an attractive option for improving the SLN detection rate in patients with head and neck malignancies [26, 27, 28].

Injection

Small syringes with minimal dead space are recommended; otherwise 0.1 mL of air may be drawn into the syringe behind the radiocolloid suspension to ensure complete administration. A 25- or 27-gauge needle should be used. The total activity to be injected may vary (from 15 to 120 MBq among different studies), depending on the size and location of the primary tumor. However, the total injected activity should be adjusted according to the timing of lymphoscintigraphy with respect to surgery. Greater activities are required for a 2-day protocol, in order to ensure the remaining activity exceeds 10 MBq at the time of surgery.

Small volumes of 0.1–0.2 mL per aliquot injected at a short distance from primary lesions are needed to avoid masking of SNs in the vicinity of the injection site and are recommended also to minimize contamination due to the resistance of the tongue tissue. Tracer should be injected at 0.1–0.5 cm from the tumor or scar margin. The number of aliquots to be injected varies (two to four) according to the size and location of the lesion. The tracer should be administered on each side of the tumor/scar, keeping as a reference the orientation of the surgical scar [16].

The use of a local anesthetic for topical application (10% xylocaine spray) a few minutes before radiocolloid injection is recommended for oral cavity tumors.

The most frequent pitfall is skin contamination due to spillage of the lymphatic mapping agent either during injection and/or immediately thereafter (e.g., during washing of the mouth to remove excess radioactivity possibly sipped out at the injection site). The hot spots due to contamination may be confused with sentinel lymph nodes in the vicinity of the tumor, thus leading to unnecessary intraoperative pursuit. In these cases skin decontamination is mandatory. Complementary SPECT/CT may also be helpful in detecting these artifacts, as mentioned above.

Preoperative Lymphoscintigraphy

Preoperative lymphoscintigraphy should be performed using a large-field-of-view gamma camera to assess the drainage of injected radiotracer via the lymphatic capillaries to the larger collector lymphatics until it either passes through, or is retained within, the regional lymph nodes. Accurate preoperative localization and cutaneous marking of the skin projection of SLN location correlate well with the precision of the surgical procedure.

Dynamic acquisition for 20–30 min starting immediately after radiotracer injection will show the drainage pattern and help to differentiate between SLNs (which can appear very early following injection) and second-echelon lymph nodes.

Static images in the anterior and lateral projections are acquired to localize the nodes in a pseudo-tridimensional manner. If hot nodes are not clearly depicted, static imaging can be repeated later, or even just before surgery. Alternatively, delayed images are useful to differentiate SNs from second-echelon lymph nodes. Planar images provide a two-dimensional overview, and sentinel lymph nodes can be localized and marked on the patient’s skin with the use of an external radioactive marker, such as a 57Co-source pen.

SLNs are generally identified 15–60 min after radiotracer injection as one or more foci to which lymphatic drainage passes, and may be multiple, in one or several areas of the neck, ipsilateral, and/or contralateral to the primary tumor [14, 16]. Delayed planar images (2–4 h postinjection) are only considered when tumors are located in the midline (including those located in the mobile portion of the tongue or laterally in the floor of mouth), or if no SLN can clearly be identified during early imaging [29]. The SLNs so identified are marked on the skin of the neck on the basis of lateral views, in order to reproduce the patient’s position during surgery.

Failure to detect SLNs may be related to an incorrect injection technique or close proximity of SLNs to the injection site (e.g., floor of mouth tumors). In addition, massive metastasis in lymph nodes may block and reroute lymphatic drainage, thus causing non-visualization of the true SLNs and possible visualization of alternative routes of lymphatic drainage. Repeat radiocolloid injection and imaging may be considered in case of totally absent visualization of lymph nodes; however, proceeding to neck dissection is preferred in these cases in order to avoid a false-negative SLNB.

Individual lymphatic mapping by lymphoscintigraphy has been reported to detect “in-transit” lymph nodes, i.e., SLNs lying between the primary tumor and the regional lymph basin [30]. These have been described in the context of malignant melanoma, but to date there have been no reports of in-transit SLNs in OSCC.

Contribution of SPECT/CT

SPECT/CT can optimize sentinel lymph node visualization and localization in the head and neck region and is therefore crucial for adequate lymphatic mapping and sentinel lymph node localization in head and neck malignancies [31] (see Fig. 2).
Fig. 2

In a patient with a tongue carcinoma bilateral neck drainage is observed on anterior planar scintigraphy (a). On SPECT/CT displayed with volume rendering (b), an additional sentinel node (SN) is also seen left from the injection site (arrow); on transversal SPECT/CT (c) and corresponding CT (d), this SN is localized in the submandibular area (circle). Two additional SNs are seen in the lower part of the neck (e, f)

A number of studies have shown the added values of SPECT/CT over planar imaging; these include:
  • Greater number and location of visualized hot spots and identification of SLNs missed on planar imaging. SPECT/CT has visualized one or more additional SLNs in more than half of the studies. These additional sentinel lymph nodes found on SPECT/CT imaging might be tumor positive. Especially lymph nodes adjacent to the injection site are more frequently detected by SPECT/CT, while they are frequently missed on planar imaging [32, 33]. In a recent study, SPECT/CT detected additional SLNs in 9 out of 42 patients (21.5%); in particular, a total of 16 (13.44%) additional SLNs, 1 of them in the sublingual space, were detected using SPECT/CT [34].

  • Exclusion of ambiguous SLNs. Non-nodal radioactivity accumulation (radiocolloid leakage or contamination) can be more easily identified on the basis of SPECT/CT imaging [35].

  • Better anatomic localization in 30–47% of patients [36], thanks to the anatomical details provided with CT in hybrid images (Fig. 3). SPECT/CT appears to be very useful for exact anatomic localization of the sentinel lymph nodes. In the head and neck area, it is very important to identify the relation of sentinel lymph nodes to several vital vascular and neural structures, to be able to safely remove these lymph nodes. SPECT/CT can localize these sentinel nodes in relation to structures such as the mandible, parotid gland, jugular vein, and sternocleidomastoid muscle. SPECT/CT also shows whether the nodes are located superficially underneath the skin or hidden below other structures. SPECT/CT thus gives anatomical reference landmarks for planning the best surgical approach. The superior information on anatomic location provided by SPECT/CT frequently leads to adapt the surgical approach, with significant shortening of operation times.
    Fig. 3

    An 81-year-old man with a T1 carcinoma on the right side of the lingual apex. After administration of 82 MBq 99mTc-nanocolloid in four injections into the mucosa around the tumor, early drainage to both sides of the neck is seen on anterior planar imaging (a), with subsequent increasing lymph node uptake on delayed images (b). Volume rendering (ce) and axial SPECT/CT fusion images (f, g) show the SLNs in level II on the right and in level III on the left. All SLNs were tumor-free at histopathology (Reproduced with permission from Valdés et al. [14])

Nevertheless, it must be emphasized that SPECT/CT imaging does not replace planar lymphoscintigraphy. A thorough integration of SPECT/CT data together with planar imaging is necessary to identify radioactive lymph nodes as SLNs and to attribute to categorize the nodes as definite SLN, probable SLN, etc. for guidance during the intraoperative procedure.

Even if the benefits of SPECT/CT have not been universally accepted [37, 38], both planar and SPECT images demonstrate good or excellent inter- and intra-observer agreement for the detection/identification of SLNs [32].

A combination of the integration of modern high-end CT in hybrid scanners, the acquisition of high-resolution scans with or without contrast enhancement provides a precise anatomic reference of the SLNs displayed in 5-mm or even 2-mm slices on axial, coronal, sagittal views and maximum intensity projection, respectively. Additional volume rendering for 3-D may also be helpful. These improvements in preoperative lymphatic mapping translate into improved minimally invasive surgical approaches to SLNB that some authors have epitomized with the emblematic new paradigm of “see and open” as opposed to the former surgical attitude of “open and see” for radioguided surgery [34].

Surgical Procedure

Blue Dye

The use of blue dye in addition to radiolocalization with intraoperative gamma probe in head and neck mucosal cancer SLN surgery is optional and may be a useful adjunct to aid SLN localization and harvesting [14, 16].

The blue dye should be injected at the time of surgery, under general anesthesia. It takes approximately 10–15 min for a significant amount of dye to travel from the injection site to the SLN. Following injection, blue dye drains to the SLNs via the same lymphatic pathways as radiocolloid, staining the channels, which can then be followed to the first-echelon nodes. It allows a direct visualization of SLNs.

Rarely, nonradioactive blue nodes may contain metastases in the absence of a tumor-positive radioactive node; two such SLNs were reported in a series of 40 patients undergoing SLNB with both radiocolloid and blue-dye injections [39]. Therefore, blue dye may aid performance of SLNB, in terms of both technical success of the procedure and identification of subclinical nodal metastasis.

However, sentinel lymph nodes in the head and neck region are frequently not stained blue, due to the fast lymphatic migration of vital blue dyes. This limitation has led to the developmentof agents combining radiotracers with optical tracers.

Intraoperative Detection of Sentinel Lymph Nodes

A gamma ray detection handheld probe is routinely used for intraoperative detection of the sentinel lymph nodes in the operative filed. The handheld probe is a radiation-sensitive detector that is able to provide a count rate from gamma rays. It is connected to an analyzer unit, which receives electrical signals from the radiation detector. The analyzer provides a response related to the detected count rate, usually by audible pitch or volume variation and by a visual display as a dial or digital count rate (counts per second, cps) [14, 16]. Thus, the gamma probe provides an acoustic signal when pointing straight toward the radioactive lymph node, thereby helping the surgeon in localizing the radioactive node.

To better plan the skin incision, the surgeon or the nuclear medicine physician should usually check the skin projection of the sentinel node with the gamma probe. Sometimes the SLNs can be masked due to the close proximity of the injected radiocolloid with the first draining LN (the so-called shine-through phenomenon), which leads to reduced detection, especially in OSCC with tumors of the floor of the mouth [40]. Also after removing sentinel nodes, the activity of the injection site can complicate measurement of the residual activity in the excision fossa. For these reasons removal of the primary cancer should be performed before the SLN search. Furthermore, deep sentinel lymph nodes can be difficult to detect because of tissue attenuation; in this case accurate preoperative imaging with SPECT/CT can help surgeons for skin incision.

To sort these problems out, a number of portable and handheld mini gamma cameras have recently been developed to provide direct intraoperative visualization of radioactive foci, with the purpose of improving detection of sentinel nodes in the head and neck region. With this new tool, the entire lymph node excision procedure in the head and neck area can be monitored. Sentinel lymph nodes located close to the injection can be visualized. Most importantly, by determining residual radioactivity after excision of the sentinel lymph nodes, the gamma camera can help to assess completeness of the procedure. Imaging after excision can also lead to identifying additional sentinel lymph nodes in more than 20% of the cases [41].

Recently the use of intraoperative gamma cameras has been combined with fluorescence cameras for synchronous sentinel node signal detection using the abovementioned hybrid tracer 99mTc-nanocolloid combined with indocyanine green. Furthermore, the technology of freehand SPECT (fhSPECT) was introduced for navigational surgery, combining the acoustic information of a conventional gamma probe and intraoperative 3-D images with real-time visualization of radiotracer distribution within the surgical field. This aspect is discussed in depth in chapter “Radioguided Surgery – Novel Applications. ”

SLN Pathology

Histopathologic analysis of sentinel lymph nodes is extremely effective and can detect the presence of micrometastasis (<2 mm) and clusters of several cells or even isolated tumor cells. By focusing on only a few lymph nodes, the pathologist can completely dissect and examine at 50–100 mm intervals each sentinel node. Sections may be stained with hematoxylin and eosin (H&E) for conventional light microscopy, and if such examination is negative, adjacent sections may be used for immunohistochemistry.

Other methodologies such as frozen sections, imprint cytology, and molecular analysis with reverse transcriptase polymerase chain reaction (such as cytokeratin RT-PCR) have been described. However, in OSCC the performance of SLNB has been evaluated only in the context of relatively small observational cohort studies. The clinical role of these methods in the future remains uncertain due to the fact that, at present, the significance of finding micrometastasis and isolated tumor cells is unknown in OSCC [14].

Dosimetric Considerations for Patients and Medical Staff

The currently available data on radiation dosimetry burden are derived from the SLNB literature pertinent to breast cancer, where the absorbed doses to patients are determined to be extremely low; therefore, the radiation risk associated with this procedure is very low. While no specific data exist for OSCC, the radiopharmaceuticals and administered activity are identical, leading to the assumption that SLNB is a safe procedure from the radiation protection point of view also for OSCC patients. Monitoring of operating room personnel or staff in the pathology department for occupational exposure during the procedure is therefore unnecessary, and additional shielding is not required [16].

Accuracy of Radioguided Sentinel Lymph Node Biopsy

After the SLN concept in OSCC was validated in several studies in which all patients underwent elective neck dissection following SLNB, several prospective observational studies have been reported in the last decade, with overall 1 up to almost 7 years of follow-up. In 91–99% of the cases, the SLN was successfully harvested; a sensitivity of 86–95% and a negative predictive value of 88–100% has been reported. Nine to 37% of patients were upstaged [42, 43, 44, 45, 46, 47, 48]. These data confirm that SLNB is a reliable and safe technique for staging the clinically N0 neck in patients with T1 and T2 oral cancer.

Lower sensitivity rates are reported for floor of mouth cancers as compared to other oral subsites: 80–86% versus 94–97%, respectively. In these patients, the close spatial relation between the injection site and the SLN seems to result in a lower identification rate due to the “shine-through effect.” In order to improve the accuracy, especially in floor of mouth cancer, new techniques have been developed (see chapter “Radioguided Surgery – Novel Applications”).

Besides these results in terms of diagnostic accuracy, patients who underwent SLNB had significantly less shoulder morbidity, as assessed by subjective and objective measurements, than patients after elective neck dissection. Patients also experienced fewer complications and less skin numbness and had shorter incisions [49, 50].

Given the current evidence and costs of the SLNB procedure followed by nodal dissection in case of metastasis versus the “wait-and-see” approach in case of a tumor-free SLN, SLNB appears to be a cost-effective strategy for diagnosing and treating OSCC patients [51, 52]. Nevertheless, this procedure should still be considered within controlled clinical trials, since no definite conclusion has been reached on some important issues, including the possibility of omitting neck dissection in patients with a negative SLNB. In this regard, a European multicenter study that included 109 OSCC patients with positive SLNB showed additional (non-SLN) metastasis in 34.4% of the neck dissection specimens. Interestingly, the risk of non-SLN metastasis far from the adjacent lymphatic areas of the positive SLN was low (7.1%), thus suggesting that the information provided by the SLNB lymphatic neck dissections can be helpful to tailor the surgical approach to the patient on an individual basis [53].

SLNB in Head and Neck Melanoma (HNM)

SLNB status is the most important prognostic factor in melanoma, including melanoma located in the head and neck region. As in HNSCC, lymphatic drainage is often aberrant and can result in identification of the sentinel node in more than one nodal basin or in an atypical, bilateral, or contralateral nodal basin. In particular, in periauricular melanomas ipsilateral drainage to both periparotid and level II of the neck is not infrequent [54]. Also, the existence of SLN clusters is not uncommon in the head and neck [55].

For this reason, SLNB has been established as the preferred staging modality to assess nodal involvement in patients with intermediate-thickness melanomas and selected thin and thick melanomas. In the evaluation and staging of the patient with melanoma, SLNB has shown increased sensitivity to detect regional metastases, limited morbidity compared with elective nodal dissection, and capability to identify patients who may benefit from further therapies such as a neck dissection or systemic adjuvant therapy. It also has the potential of halting the regional progression of metastatic disease.

Some authors have noted a wide range of false-negative rates (3.4–10.4%) for HNM SLNB as well as a decreased HNM SLN positive rate (10–15%) compared with cutaneous melanoma elsewhere (16–23%) [56, 57]. Others have reported SLN positive rates in HNM that are not significantly different from other cutaneous melanomas, although the small patient numbers in these studies limit their interpretation. A worse survival in HNM with positive SLN compared with other anatomic locations has also been suggested (Fig. 4).
Fig. 4

In a patient with a left preauricular melanoma ipsilateral drainage to the neck is seen on lateral planar image (a). On SPECT/CT displayed with volume rendering (b), besides neck drainage, an additional sentinel node (SN) is also seen near the lower part of the injection site. On axial SPECT/CT (c, d), this SN is observed behind the upper pole of the parotid gland. Note that SPECT/CT (e, f) is able to localize another SN in the lower parotid pole and a SLN cluster in level II

Radioguided Surgery in Thyroid Cancer

SLNB in Thyroid Cancer

Differentiated thyroid cancer (DTC), which includes the papillary and follicular histologic patterns, is the most common endocrine malignancy and generally has a more favorable prognosis compared to other cancers (see chapter “Diagnostic Applications of Nuclear Medicine: Thyroid Tumors” of this book), regardless of the more or less aggressive surgical approach. For this reason, there is considerable variability when planning surgery regarding the decision to explore and remove the central and/or lateral compartment lymph nodes, considering that dissection of the central compartment can cause complications such as a damaged recurrent laryngeal nerve or permanent hypoparathyroidism.

The SLN concept in DTC has been developed as an alternative to elective lymph node dissection in patients with clinically node-negative disease, in the perspective of obtaining information about cervical lymph node involvement in patients undergoing thyroidectomy. Nevertheless, so far there is no definite evidence that SLNB is associated with long-term clinical and survival benefits.

However, several studies have shown that radioguided SLNB can easily be carried out and is feasible and safe [58], even if the actual clinical impact of this procedure is yet to be determined. The most widely used technique involves intranodular injection of 15–37 MBq 99mTc-nanocolloidal albumin in a volume of 0.1–0.5 mL, under ultrasound guidance (Fig. 5).
Fig. 5

SLN mapping in a 27-year-old woman with papillary thyroid carcinoma. (a) Ultrasound-guided intratumoral injection of 99mTc-nanocolloidal albumin. (b) Ultrasound monitoring of radiocolloid deposit within the thyroid nodule (b). (c) Planar scan: anterior view showing two hot spots in the left cervical area in addition to the obvious activity at the injection site. (d) Volume rendering SPECT/CT image showing the two hot spots in the left cervical levels III and IV, respectively. (e) Axial CT section showing anatomical appearance of the level IV SLN. (f, g) Preoperative assessment with a portable gamma camera and with freehand SPECT, respectively

In principle, SLN mapping allows the identification of micrometastatic disease, thus potentially reducing patient morbidity by avoiding unnecessary de novo lymph node dissection [59]. However, the general prognostic significance of lymph node involvement in DTC is still debated.

One of the most important targets of SLNB in this scenario could be the selection of those patients with locally advanced thyroid disease at highest risk to develop cervical lymph node metastasis, who can benefit from complete neck dissection. Lymphatic mapping and SLNB may also have a role in minimally invasive surgical technique to detect metastatic lymph node spread in thyroid cancers [60, 61].

SLNB has been also proposed for medullary thyroid carcinoma (MTC), which is generally characterized by a more aggressive behavior and early spread in lymphatic vessels than papillary/follicular carcinoma. Initial surgery for MTC with no evidence of lymph node involvement in neck compartments consists of total thyroidectomy and prophylactic central neck dissection. SLNB has been used for a more precise N staging of the lateral compartments, possibly driving the extent of prophylactic neck dissection to the involved cervical lymphatic chains [62].

Radioguided Occult Lesion Localization in Thyroid Cancer

Radioguided surgery enables the surgeon to identify lesions or tissues that have been preoperatively “marked” with radioactive substances. The radioguided occult lesion localization (ROLL) approach is being widely used to identify occult lesions in patients with breast cancer. However, few studies have reported the use of this technique in patients with recurrence of thyroid cancers in cervical lymph nodes after initial treatment (i.e., thyroidectomy and ablation of postsurgical remnants with 131I-iodide.

The ROLL technique can be useful in selected cases where suspected lesions may be difficult to identify intraoperatively, due to their dimensions or location, especially in patients who have had cervical surgical procedures in whom fibrotic scar tissue or adhesions can make identification of the target lesions difficult during surgery. The procedure allows for more conservative excisions and reduces the surgery-related morbidity [63, 64, 65].

In this case, injection of 99mTc-sulfur colloid or 99mTc-macroaggregated human albumin is performed directly inside or near the suspicious lesion, generally under US guidance up to 24 h prior to the surgical procedure. Intraoperative lesion detection is carried out using a handheld gamma probe, and preoperative SPECT/CT in addition to conventional planar scintigraphy can provide an accurate three-dimensional road map for better surgical exploration of the neck [66].

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Federica Orsini
    • 1
    Email author
  • Erinda Puta
    • 1
  • Renato A. Valdés Olmos
    • 2
    • 3
  • Sergi Vidal-Sicart
    • 4
  • Francesco Giammarile
    • 5
    • 6
  • Giuliano Mariani
    • 7
  1. 1.Section of Nuclear Medicine“Maggiore della Carità” University HospitalNovaraItaly
  2. 2.Nuclear Medicine Section and Interventional Molecular Imaging Laboratory, Department of RadiologyLeiden University Medical CentreLeidenNetherlands
  3. 3.Nuclear Medicine DepartmentAntoni van Leeuwenhoek Hospital, The Netherlands Cancer InstituteAmsterdamNetherlands
  4. 4.Nuclear Medicine DepartmentHospital Clinic BarcelonaBarcelonaSpain
  5. 5.Médecine Nucléaire – Groupement Hospitalier EstUniversité Claude Bernard Lyon 1BronFrance
  6. 6.Biophysique – Faculté Charles Mérieux LyonOullinsFrance
  7. 7.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly

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