Radioguided Surgery for Malignant Melanoma

  • Sergi Vidal-SicartEmail author
  • Federica Orsini
  • Francesco Giammarile
  • Giuliano Mariani
  • Renato Valdés Olmos
Living reference work entry


Melanoma is one of the most aggressive and therapy-resistant cancers, and currently, its incidence is increasing worldwide. The metastatic involvement of lymph nodes is of utmost importance for prognosis in patients with intermediate-thickness melanoma. Other prognostic factors include tumor thickness, presence of ulceration, and mitotic rate.

Radioguided surgery has a prominent role in melanoma, because the sentinel lymph node approach is nowadays a choice procedure for regional lymphatic staging of these patients. Sentinel lymph node biopsy sensitivity is superior than that of PET/CT for the detection of lymphatic micrometastases in early stages of the disease.

The sentinel lymph node approach involves a preoperative lymphoscintigraphy and the use of a handheld gamma probe and vital dyes. Presurgical lymphoscintigraphy constitutes the “roadmap” for guiding surgeons toward draining lymph nodes potentially harboring metastasis and is extremely useful for localizing unpredictable drainage patterns that otherwise would be unnoticed. In recent years, new refinements have been added to this approach in order to improve clinical results. In particular, SPECT/CT imaging increases the sentinel lymph node identification rate and overcomes some of the limitations of planar imaging. New tracers are now available and new intraoperative devices can be added to the classical ones. In general, this radioguided approach is cost-effective, although there is a scarcity of data and the different factors involved in the whole procedure are not equally considered by different analyses that have so far been performed.


Melanoma Sentinel node Lymphoscintigraphy Radiotracer Blue dyes Handheld gamma probe Portable gamma camera SPECT/CT Fluorescence Hybrid tracers PET/CT 





American Joint Committee on Cancer


Becquerel unit

Breslow thickness

A prognostic factor in cutaneous melanoma, based on description of how deeply tumor cells have invaded the skin (also called “Breslow depth”)

Clark level

A staging system for cutaneous melanoma based on description of the level of anatomic invasion of the melanoma in the skin (generally used in conjunction with Breslow’s depth)


X-ray computed tomography


Electron volt


United States Food and Drug Administration


Guided intraoperative scintigraphic tumor targeting


Homatropine methylbromide 45, a monoclonal antibody that reacts against an antigen present in melanomas


Indocyanine green


Kiloelectron volt (103 eV)


Melanoma antigen recognized by T cells 1, also known as Melan A


Mega-Becquerel (106 Becquerel)


Magnetic resonance imaging


Melanoma-specific survival


National Comprehensive Cancer Network




Polymerase chain reaction


Positron emission tomography


Positron emission tomography/computed tomography


Radioguided occult lesion localization


A low-molecular-weight calcium-binding protein expressed in melanomas, but also in other benign and malignant conditions


Sentinel lymph node


Sentinel lymph node biopsy


Single-photon emission computed tomography


Single-photon emission computed tomography/computed tomography






Melanoma is one of the most aggressive and therapy-resistant cancers. Moreover, it currently is a global health problem because its incidence is increasing worldwide [1].

In recent years the melanoma incidence stands for 10–14 cases/100,000 inhabitants in Central Europe and 6–10/100,000 inhabitants in Southern Europe. In the USA the incidence has risen to 10–25/10,000 inhabitants, and Australia and New Zealand have the highest incidence with 60 cases/100,000 inhabitants [2].

According to the American Cancer Society, more than 76,000 new cases of melanoma are currently diagnosed in the USA each year, and about 9,500 people are expected to die of metastatic disease [3].

There are several risk factors related for the development of melanoma (history of sunburn, previous melanoma within the family, high UV exposure, and red or blonde hair), and the appearance of regional or distant metastases is an ominous prognostic factor for the disease [4, 5].

Thus, the prognosis for a patient depends on the stage of the disease. In the case of early melanomas (<0.76-mm Breslow thickness), surgical wide excision is sufficient and there is no need for further invasive staging. Accurate evaluation is important in cases of a more advanced primary tumor. In general, lymph node metastases often occur first, and for this reason, the regional nodal status is the most important prognostic factor and stratifies the patients for adjuvant therapy [6, 7].

The metastatic involvement of lymph nodes is of utmost importance for prognosis in patients with intermediate-thickness melanoma (AJCC stage I or II). Other prognostic factors include tumor thickness, presence of ulceration, and the recently added mitotic rate. The Clark level of invasion was omitted from the recent AJCC classification [5, 8, 9, 10].

The Clinical Problem

The clinical outcome for patients with intermediate-thickness melanoma relies on adequate surgical control of the primary melanoma site and on the accuracy of regional and systemic staging at diagnosis. It is well known that physical examination of lymph nodes is inaccurate in up to 40% of patients. Noninvasive diagnostic imaging procedures (CT, MRI, US) have been employed to rule out nodal involvement, but despite their use, their findings are not sufficiently accurate so as to avoid invasive techniques, also because small lymph node metastases cannot reliably be detected with any imaging modalities. Approximately 20% of patients with a melanoma with a Breslow thickness >1 mm may have clinically occult lymph node metastasis, therefore making histopathologic assessment of the regional lymph nodes mandatory [11].

The traditional surgical approach to cutaneous melanoma is based on elective, or prophylactic, regional lymph node dissection to reveal these occult metastases. Randomized studies, however, showed no clear survival advantages when performing regional lymphadenectomy, a surgical procedure frequently associated with morbidity, such as lymphedema, nerve injury, wound infection or dehiscence, etc. [12].

In 1992 Morton et al. reported the results of a seminal study carried out in 223 patients with melanoma to test the concept of intraoperative identification of the sentinel lymph node (SLN) using blue dye as a minimally invasive surgical alternative for nodal staging. By employing this approach to perform SLN biopsy, these authors were able to detect clinically occult nodal metastasis, thus identifying a subgroup of patients who could actually benefit from complete lymphadenectomy [13].

The procedure assumes orderly diffusion of melanoma metastasis through the lymphatic system, and the SLN is defined as the first node on a direct lymphatic drainage pathway from the primary tumor [6, 14]. According to this hypothesis, tumor involvement or lack of involvement of the SLN predicts the overall nodal status with a high accuracy [15].

Shortly thereafter, radionuclide-based techniques were introduced to perform lymphatic mapping, by injecting a suitable radiocolloid agent around the melanoma. Following such interstitial administration of the radiopharmaceutical, scintigraphy allows the identification of SLNs in the lymph node basin and this or these nodes is/are harvested during surgery with the aid of a handheld gamma probe during surgery. This approach, which constitutes the mainstay of radioguided SLN biopsy as it is currently employed, overcomes some drawbacks intrinsic in the dye approach. The feature that characterizes radioguided surgery is the use of a radiotracer to “mark” the desired tissues and the intraoperative utilization of a handheld gamma probe that facilitates the task of the surgeon, that is, identification and removal of the target tissue, either a lymph node or the tumor itself – as in other applications of radioguided surgery. Intraoperative exploration of the surgical field with the handheld probe is made possible by the preoperative techniques employed by the nuclear medicine physician to achieve accumulation of the radiopharmaceutical in the specific target lesion. This is the most common method utilized to perform a SLN biopsy, because radiocolloid alone has been shown to be very safe and to have a low false-negative rate [16, 17]. Currently, this approach is widely validated and has been adapted to additional applications for SLN biopsy in other types of cancers, such as breast, urologic, gynecologic, and head and neck cancers [18, 19, 20, 21].

Radiotracers allow scintigraphic visualization with gamma camera of the physiology of lymphatic drainage, thereby changing the paradigm of “open and see” (blue dyes ) to “see (scintigraphy) to open.” In fact, preoperative lymphoscintigraphy constitutes the “roadmap” for guiding surgeons toward subsidiary lymph node sites of potential metastasis and is extremely useful for localizing unpredictable drainage patterns that otherwise would be unnoticed. The value of lymphoscintigraphy lies in different factors, as summarized in Table 1.
Table 1

Lymphoscintigraphy features for lymphatic mapping

Identification of the radioactive lymph nodes (although not all radioactive lymph nodes are SLNs nor the SLN is necessarily the most radioactive lymph node)

Identification of the lymphatic drainage basin(s) from the tumor site

Identification of the SLN and of second-tier lymph nodes

Identification of the aberrant or in-transit SLNs (lymph nodes localized outside the common drainage areas and those between the primary tumor and the region of lymph node drainage, respectively)

Confirmation of true radiotracer uptake versus false-positive uptake (originated from cutaneous folds, lymphatic dilatations, and lymphangiomas)

Nuclear medicine techniques and radioguided surgery are continuously evolving with the implementation of technological imaging advances. Even after 20 years of use, this technique of SLN biopsy may, sometimes, be challenging, especially in patients with high body mass index or in complex anatomical areas (e.g., the abdomen or head and neck). With the aim of finding more efficient methods to improve the preoperative and intraoperative images, hybrid fluorescent–radioactive tracers or more specific tracers, which enable high-quality preoperative lymphoscintigraphy and SPECT/CT imaging, have been developed. Moreover, intraoperative portable imaging technologies, such as freehand SPECT and small portable gamma camera s, have been introduced into the armamentarium available for improving intraoperative SLN identification procedure [22].

Lymphatics in Cutaneous Melanoma

The lymphatic system presents a high density of vessels in the dermis, especially in the layers between 50 and 200 μm below the epidermis. This density varies in different regions of the body, the highest vessel density being observed in the head and neck area and the lowest in the limbs.

Moreover, the velocity of lymphatic flow is not the same in all regions of the body and varies depending on the area of the skin. Thus, the average lymph flow velocity in the head and neck region is 1.5 cm/min, it increases in the posterior trunk to 3.9 cm/min, and even higher in the forearm and hand (5.5 cm/min). The highest velocity of lymph flow is seen from the lower limb (10.2 cm/min) [23].

On the other hand, the lymphatic drainage from the primary tumor is quite predictable when this tumor is located in the extremities. So, a melanoma located in the lower limb drains usually to the ipsilateral groin, while from the upper limb, it drains to the homolateral axilla. Computer analysis from a large lymphoscintigraphic database provided new important insights into the skin lymphatic drainage. In particular, it was demonstrated that lymphatic drainage of the skin is likely to be entirely symmetric. There are well-defined areas of the skin that nearly always drain to the ipsilateral axilla, groin, cervical level II, and preauricular node fields [24].

However, the drainage patterns from lesions in the head and neck area or in the trunk are less predictable. The concepts developed by Sappey in the nineteenth century about skin lymphatic drainage went largely unaltered until the last quarter of twentieth century, when new information became available from lymphatic mapping studies using lymphoscintigraphy. In fact, the more recent lymphoscintigraphic findings have modified the concept of Sappey, that is, that lymphatic watersheds with ambiguous skin drainage are limited to a narrowband about 2.5 cm on either side of the midline of the trunk (for right–left drainage) and/or the line between the umbilicus and the level of the second lumbar vertebra on the back (for cranial or caudal drainage, respectively) [25, 26].

Instead, the width of the area of ambiguous drainage has been extended to more than 20 cm instead of the original 5 cm (Fig. 1), because lymphatic drainage is highly variable among different patients and Sappey’s concepts would predict drainage to the wrong node basin in 30% of patients [27, 28].
Fig. 1

On the left, metastatic dissemination in melanoma: N1, metastasis in draining lymph node basin; M1a, distant skin, subcutaneous, or nodal metastases; M1b, lung metastases; M1c, all other visceral metastases. On the right, midline areas with ambiguous lymphatic drainage according to the classical skin watershed Sappey’s concept (blue) and its extension according to lymphoscintigraphy (slightly brown)

Indications and Advantages of SLN Biopsy in Melanoma

SLN biopsy is a minimally invasive procedure, which should be indicated or considered for patients with the following characteristics:
  • A risk of presenting occult metastasis >10%, which justifies the procedure.

  • The tumoral status of the SLN is useful for decision-making.

  • The prognostic information provided by the SLN biopsy is valuable for the patient and the physician (even for a decision to include patients in clinical trials).

The indication for SLN biopsy in melanoma should be offered and discussed to all patients with melanomas ≥1.0 mm in thickness, clinically negative regional lymph nodes on physical examination, fulfilling the abovementioned criteria and in whom the morbidity and risk are considered to be acceptable. However, SLN biopsy can also be offered to patients with melanomas ≤1.0 mm with some characteristics which increase the possibility of micrometastasis in the regional node basin (the presence of ulceration, mitotic index ≥1/mm2, and/or Clark IV/V invasion, especially in tumors >0.75 mm in thickness) [29].

Analysis of the AJCC database demonstrated an inverse correlation between the mitotic index and survival. Then, the greater the mitotic value, the shorter the survival. In patients with melanomas from 0.5 to 1.0 mm in thickness and with <1 mitosis/mm2, the 10-year survival was 93%. In the same group, this figure decreased to 87% when >1 mitosis/mm2 was present [30].

On the other hand, SLN biopsy may be considered in patients with melanocytic lesions with unknown metastatic potential. The NCCN guidelines are similar in regard to melanomas with a thickness >1 mm. However, the presence of ≥1 mitosis/mm2, which upstages IA to IB tumors, is not taken into account for indicating SLN biopsy in melanomas <1 mm in thickness. SLN biopsy is not recommended in lesions with a thickness <0.75 mm, while in tumors between 0.76 and 1 mm thick, the option to perform or not SLN biopsy should be discussed with the patient, since the proportion of metastasis is low in these patients (<6%) and its clinical impact is modest [31, 32].

Although no direct therapeutic advantage has been demonstrated for the SLN approach, the final report of the MSLT-I trial, which compared long-term outcome of SLN biopsy-positive patients with that of patients who developed regional lymphatic metastases in the observation group, showed a significant benefit in the arm of SLN biopsy with a 10-year melanoma-specific survival (MSS) advantage of 20.6%. Thus, it was concluded that SLN biopsy-based management prolongs MSS for patients with nodal metastases in the intermediate-thickness melanoma group. In addition, the information provided by the SLN may be useful for advising patients about inclusion in clinical studies.

Thus, SLN biopsy-based staging of intermediate-thickness or even thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy [33, 34, 35].

However, some criticism has been raised about this statement. According to van Akkooi, if both groups are equally compared, the MSS difference is minimal between groups (81.4% against 78.3%, respectively). There are some reasons to be considered in the critical analysis of these data (the false-negative rate, difference in nodal positivity between groups, and tumor load of metastasis, as well as an adequate statistical analysis). Moreover, the center that treated patients should be included as a potential confounding factor, because the results may differ significantly due to the diverse experience of each multidisciplinary medical team [36].

Finally, there is a certain time delay between melanoma excision and wide local excision for adequate margins and SLN biopsy. This delay is due to several factors, including surgical scheduling, preoperative evaluation, requested diagnostic tests, etc. The influence of this delay over the prognosis of the patient is not clear. Parrett et al. studied the time effect to perform SLN biopsy on node metastatic invasion, recurrence, and mortality. The study showed no significant differences in survival if SLN biopsy was performed within 40 days or beyond 40 days after excision of the primary tumor [37].

Tejera-Vaquerizo et al. reported surprising findings in a multicentric retrospective observational study with 1963 melanoma patients scheduled to SLN biopsy. The main outcome was disease-free survival and melanoma-specific survival. A delay of more than 40 days was associated with better 5-year disease-free survival (80.1% vs. 73.8%; P = 0.0839) and better 5-year melanoma-specific survival (89.5% vs. 82%; P = 0.0002). These results raise important issues, and the implication that early SLN biopsy reduces MMS needs to be further and prospectively explored. On the other hand, a delay in the procedure did not worsen the prognosis in any case [38].

Technical Issues


The term “colloid” indicates a class of macromolecules with similar chemical and biological behaviors. These particles vary between 5 and 1,000 nm in size. Colloids circulating in the lymph or blood are removed from the circulation by macrophages, located in the bone marrow, spleen, liver, and lymph nodes.

Following their arrival to lymph nodes through the afferent lymphatic channels draining from the injection site, these particles are phagocytized by macrophages located in the node sinusoids. Therefore, retention of radiocolloids in the lymph node is a physiological process, and it does not indicate the presence or absence of metastatic involvement in the node [28].

The speed of lymphatic drainage from the injection site and the amount retained in the SLN depend on the size of the radiocolloids. Small-sized radiocolloids (less than about 100 nm) migrate quite fast from the injection site through the lymphatic system and best visualize the lymphatic vessels. Lymphoscintigraphy can be completed in a relatively short time (within 45–60 min after injection). However, more than one lymph node, often as many as three to four, can be visualized along a single lymphatic draining channel. This may result in a misleading identification of the SLN, unless there are sequential or dynamic images acquired after injection. Intermediate-sized particles (50–200 nm) migrate more slowly from the primary lesion, but exhibit a more prolonged retention in the SLN. Larger-sized radiocolloids are retained more efficiently in the SLN, and lymphoscintigraphy usually visualizes one to two nodes only; nevertheless, migration of larger particles from the interstitial administration site is very slow, so that a longer time can be necessary to complete lymphoscintigraphy. Altogether, the choice of radiopharmaceutical varies according to geographic region and is usually guided by local legislation and the agent’s commercial availability [39].

Radiotracers for SLN lymphoscintigraphy include 99mTc-antimony trisulfide (particle size 3–40 nm) with a wide application in Australia, 99mTc-sulfur colloid (100–400 nm, mostly used in North America), and 99mTc-nanocolloidal albumin (<80 nm, predominantly used in Europe). It has been suggested that the optimal particle size for SLN detection is between 100 and 200 nm. There is no specific consensus regarding the activity to inject, which should be adapted to the local logistics and to the time lapse between the injection and surgery. Activities usually range from 5 to 120 MBq, depending on the specific 1-day or 2-day protocol employed. It has been demonstrated that both procedures are equally effective for SLN detection [40, 41].

Recently, a new agent, 99mTc-tilmanocept, has been prospectively evaluated in two nonrandomized phase III trials in comparison with vital blue dye . These trials showed 99mTc-tilmanocept to have a very high rate of SLN identification [42, 43]. This new radiotracer was approved by the US Food and Drug Administration (FDA) in 2013 and received a positive statement from the European Medicines Agency in 2014. 99mTc-tilmanocept (Lymphoseek®) is a mannosyl diethylene triamine penta-acetate (DTPA) dextran with a molecular size of 7 nm. However, its accumulation in SLNs is not dependent on particle size as with the other colloids. Tilmanocept binds to CD206 mannose receptors expressed by reticuloendothelial tissue including macrophages and dendritic cells within lymph nodes, which present it to T-cell lymphocytes. The advantages of this tracer include rapid clearance from the injection site and low migration to second-echelon nodes (see Fig. 2) [44, 45].
Fig. 2

Lymphoscintigraphy with 99mTc-Tilmanocept obtained in a patient scheduled for SLN biopsy for a 0.95-mm nonulcerated melanoma of the left forearm (site of injection visible in the first image, top row). A single axillary lymph node was visualized 20 min postinjection along with activity in lymphatic channels (variable-angle views in second through fourth image, top row). Radioactivity in the SLN visualized at 20 min was well retained at 24 h (image in bottom row). The SLN to background count ratio was >30:1 intraoperatively (Reproduced with permission from Sondak et al. [43])

In the PET/CT era, there is a scarcity of PET tracers dedicated to lymphatic mapping. However, some preliminary reports have been published on the use of 89Zr-nanocolloidal albumin for lymphatic mapping with PET imaging; the results reported are similar to those observed with 99mTc-nanocolloid. Interestingly, the use of PET tracer showed an improved visualization of nodes near the primary tumor site. These preliminary results warrant further comparative studies in this field [46].

Activity and Injection

There is general consensus that the radiotracer or dye should be injected within 1 cm from the tumor margin of the biopsy scar. Injection activities range from 3.7 to 37 MBq (0.1–1 mCi) per intradermal injection, depending on the time to surgery. The recommendation is two to four intradermal injections (depending on location of the melanoma) of 0.1 mL each around the tumor site or biopsy scar (within 1 cm away from the edge of the tumor or scar). The injected volume must be small to avoid the collapse of lymphatics; furthermore, the wheal raised on the skin surface may rupture and spill over the skin. Tracer injections should be placed either in each side of the biopsy scar or tumor, although in some circumstances they may be performed in only one side. In upper extremities adequate mapping may be accomplished by injecting two injections proximal to the scar and this approach can be employed also for lesions located in the foot and leg. When lesions are located in the thigh, it is advisable to inject in both sides of the scar or tumor. In other sites (the trunk, head, and neck), it is mandatory to inject at least four aliquots around the lesion.

Topical anesthetic medications may be used to diminish the pain, especially when the primary melanoma is in a sensitive location (or when using some radiocolloid with low pH, such as 99mTc-sulfur colloid). To avoid contamination, a sheet should be placed next to the injection site, and after each injection, the skin should be covered with a swab before the needle is removed [28, 45, 47].

The tracer is injected 1 day before surgery or, alternatively, on the same day. No differences in SLN detection rate or false-negative rate have been found between these two protocols [48]. The 2-day protocol may present some advantages with flexibility in timing of lymphoscintigraphy and surgery. The 1-day protocol requires a good cooperation between the nuclear medicine staff and surgeons with respect to the estimated speed of lymphatic drainage in the affected region and the time to surgery. Intraoperative injection is not recommended because lymphatic drainage in melanoma may be aberrant or delayed to more than one nodal basin and because it is not always possible to obtain intraoperative imaging [45].

Presurgical Lymphoscintigraphy

An accurate procedure for SLN biopsy relies on preoperative lymphoscintigraphy, careful surgery guided both by vital blue dye and by a gamma probe, and finally thorough histopathologic examination.

Lymphoscintigraphy is considered to be an essential part of SLN mapping in general, and it is mandatory for melanoma. It demonstrates the flow of radioactive tracers through the lymphatic structures and visualizes any alternative routes to different regional lymphatic basins. Visualization of nodes located along the route of the lymph will be displayed, and other nodes or paths will be seen if flow has been rerouted because of, for example, block of the original lymphatic flow pattern by massive metastatic involvement of the lymph nodes or by other causes. So, lymphoscintigraphy provides a visual roadmap of nodal locations before surgery and may show the timely order in which lymphatic flow reaches those nodes, especially when a dynamic study is acquired [49, 50, 51, 52].

All possible drainage basins must be explored during image acquisition. Therefore, a dual-head gamma camera with large field of view detectors is preferred to reduce the examination time. Nevertheless, a single-head gamma camera can equally be adequate.

Low-energy, high-resolution, or ultrahigh-resolution collimators are recommended to better distinguish individual SLNs. The energy window in gamma camera settings should be 15% or 20% centered on the 140-keV photopeak of 99mTc [53]. During image acquisition, a 57Co- or 99mTc-flood source positioned on the opposite side of the camera head for transmission imaging or alternatively a radioactive pointer can be used to delineate the body contours.

The tracer must be injected with the patient lying in the most convenient position on the bed of the gamma camera, depending on the location of the primary tumor. Starting image acquisition immediately after the injection may help to identify lymph nodes next to the injection sites and to differentiate true SLNs from second-echelon nodes. Dynamic imaging (one frame per 30 s or per 60 s in a 128 × 128 matrix) during the first 10–20 min after injection is recommended. Although acquisition of dynamic images is time consuming, it is nevertheless crucial because a lymphatic channel directly draining to a lymph node identifies this node as a true SLN.

In melanomas of the hand/forearm or foot/leg, dynamic imaging should start over the injection site and follow the lymphatic drainage to the elbow and axilla and knee/groin, respectively, to reveal ectopic basins and in-transit lymph nodes (popliteal, epitrochlear, etc.) (Fig. 3). For head and neck melanomas, immediate imaging reduces the chance of missing a SLN because of rapid drainage from intradermal injections with uptake by superimposed nodes. Imaging at a rate of 1–5 s/frame in this particular area may solve these drawbacks.
Fig. 3

Early planar image showing the radiotracer injection performed in the ventral part of the elbow, some lymphatic channels, an epitrochlear in-transit sentinel node (red arrow), and an axillary sentinel node (a). Delayed image that depicts the epitrochlear uptake (red circle) and the axillary sentinel node and subsequent second-tier axillary nodes (b). Volume rendering 3D reconstruction that depicts the sentinel nodes in the epitrochlear area (yellow circle) and the left axilla (c). Skin marking of near-epitrochlear node (yellow square) and confirmation using a gamma probe (d)

After dynamic imaging, static planar 3- to 5-min images (anterior, oblique, posterior, and lateral) should be acquired, if indicated, with a 256 × 256 matrix over the visualized lymph node basin drainage. Early images help to discriminate true SLNs from second-tier nodes. In melanomas of the trunk, usually bilateral static images of the axilla, trunk, and groin are necessary. In lower limb melanomas, several superimposed lymphatic channels are often depicted. In this case, an oblique view helps to distinguish different channels. Second-echelon nodes are more frequently observed in the groin than in other parts of the body, due to the highest velocity of lymph occurring in the lower limb (Fig. 4) [45, 54].
Fig. 4

Lymphoscintigraphy. Early (a, b) and delayed (c, d) planar images in anterior and oblique views. Two well-depicted lymphatic channels are visualized in (a) and b images directly connecting the injection site with right groin sentinel nodes. Yellow arrow in picture (a) shows a faint lymphatic channel cranial to one of the sentinel nodes. It could be a second-echelon node but also a real sentinel node if this channel passes below the first depicted node directly from the injection site. Oblique view can provide a more accurate assessment. Yellow arrow in picture (c) shows a high uptake in the aforementioned node, as well as in the other nodes upstream. Second-echelon nodes are more frequently observed in the groin than in other parts of the body, due to the highest velocity of lymph that is observed in the lower limb. Performing only delayed images is not accurate in those cases because it is hard to distinguish between the real sentinel nodes and the second-tier nodes

To detect SLNs close to the injection site, it may be useful to mask the injection site with lead material during image acquisition. Delayed images (2–4 h or more after radiotracer injection) allow the correct SLN identification and their external marking on the skin. The SLNs are usually identified in the first 30 min after injection, although images should be obtained also at 2 h, due to possible slow lymph flow to other areas. The great variability of cutaneous drainage should be taken into account, as well as the possibility of detecting lymph nodes outside the conventional regional areas (called aberrant or in-transit nodes).

Lymphoscintigraphy for SLN mapping must be accurate and reproducible. Some studies have addressed this issue in several different malignancies. In particular, in melanoma patients a good correlation (84–96%) between two separated lymphoscintigraphic studies has been demonstrated [55, 56, 57, 58, 59, 60].

Lymphoscintigraphy may, to some extent, predict the metastatic burden in lymph nodes. In this regard, an interesting study in 509 melanoma patients scheduled for SLN biopsy showed that clear depiction of an afferent lymph vessel may be a sign of micrometastasis. On the other hand, the presence of macrometastasis was associated with prominent afferent vessels, delayed display of the first radioactive node, and higher number of depicted hot spots. Moreover, in patients with bidirectional or lymphatic drainage to three basins, the SLN metastatic involvement rates for the first, second, and third basin were 25%, 12%, and 0%, respectively (P = 0.002) [61].

Additional SPECT/CT Imaging

Planar lymphoscintigraphy provides clear visualization of the SLN, thus providing information on their number and facilitating the localization on their skin projection. However, the depth and anatomical correlates of the SLN are not easily obtained. For example, deep SLNs in the neck or in other areas (i.e., deep paravertebral, mediastinal, or para-aortic nodes) are challenging during surgery, and in certain cases, they cannot be removed (Fig. 5).
Fig. 5

Planar lymphoscintigraphic anterior view of a melanoma patient with a lesion in the left–central periumbilical area (yellow arrow). The image shows several hot spots in both axillae and para-costal areas and two hot spots central in the abdomen. All of them were considered as sentinel nodes (a). 3D reconstruction showing the anatomical location of these nodes (b). Sagittal view of selectively assessed “abdominal” uptake (c). The CT scan showed two tiny nodes in para-aortic and paravertebral areas (green lines) (d). Fused SPECT/CT images showed focal radiotracer uptake in these locations (e). These nodes are sentinel nodes. However, they were not resected in the surgical procedure due their deep location

The use of SPECT/CT has gained importance because this tomographic approach is more successful than planar imaging in identifying SLNs [62]. SPECT/CT is basically used for anatomical localization of SLNs and is performed in addition to lymphoscintigraphy. A requirement for accurate SLN localization is that the CT component of SPECT/CT system must be of sufficient quality to provide adequate anatomical landmarks to be recognized by surgeons. SPECT/CT may be of great utility in obese patients to demonstrate SLNs not detected on planar images, as well as to show additional SLNs in other areas. For fused SPECT/CT images, a gray scale is used to display the anatomy (CT), whereas a color scale is employed to show the SLNs in the SPECT image. Usually, a radioactive hot spot corresponds to a single lymph node on CT, but in some cases, this image correlates with a group of lymph nodes adjacent to each other (cluster) [63, 64].

Tomoscintigraphic images improve SLN identification and overcome some of the limitations of planar imaging (Table 2). Fusion with CT images shows the SLN in 2D and 3D modalities. In this way, SPECT/CT facilitates recognition of non-lymph node accumulations of the radiotracer and helps to clarify drainage in inconclusive planar images. With the use of volumetric rendering techniques with 3D viewing, images can be obtained with high anatomical detail, thus facilitating the interpretation of lymphoscintigraphy and helping to assess the images obtained with the planar study in anatomically complex areas of the body. In melanoma of the head and neck, where SLNs may be located very close to the primary site, SPECT/CT may be of outmost importance in localizing SLNs masked during planar imaging because of their proximity to injection sites (Fig. 6) [65, 66].
Table 2

Advantages of SPECT/CT over planar imaging

Improved anatomical SLN localization

Better sensitivity than planar images (additional lymph nodes)

Reduction of false-negative cases

Reduction of false-positive cases

Clarification of inconclusive scintigraphic patterns in planar images

Higher SLN detection rate in difficult cases (obesity, faint uptake)

Fig. 6

Lymphoscintigraphy . Anterior (a) and left oblique (b) views showing several hot spots in the occipital and left cervical area after a radiotracer injection in left parietal scalp. 3D reconstruction after SPECT/CT acquisition (c). Skin marks in the areas where sentinel nodes were considered to be (d). Sagittal slice corresponding to the occipital uptake level (e). Fused SPECT/CT images showed two separate radiotracer uptakes in this area. The faint uptake (green asterisk) was a very tiny node (3 mm) that was positive for metastatic involvement. SPECT/CT images helped to better assess the planar images (only one hot spot depicted in that zone due to the higher activity of one of the nodes masked the tiny node)

Clinical Impact of SPECT/CT in Melanoma

SPECT/CT allows an accurate lymphatic mapping by increasing the number of SLNs resected during surgery. Moreover, SPECT/CT may also detect more SLNs in aberrant drainage locations or when planar images show no clear radiotracer migration. SPECT/CT in melanoma has been validated for specific indications. An initial study demonstrated that SPECT/CT had a definite added value in 30 out of 85 patients (35%), by detecting extra SLNs, not visualized on planar images, by localizing SLNs in other basins, or by modifying the surgical incision planning. In seven patients, 12 additional SLNs were detected (two of them with metastatic involvement) [67].

Mucientes et al. showed, in another study with 18 patients, a visualization rate of 100% for SPECT/CT versus 89% for planar lymphoscintigraphy. Moreover, SPECT/CT provided accurate anatomical information leading to refine the surgical incision in four patients [68].

A Dutch study confirmed in a series of 35 melanoma patients that SPECT/CT detected more SLNs than planar images in 7 of them, contributing also to modify surgery in 10 patients [69].

Fairbairn et al. showed that SPECT/CT and planar lymphoscintigraphy detected SLNs in 32 patients (SLN detection rate of 97% for both techniques). The additional anatomic information provided by SPECT/CT contributed to the adjustment of surgical approach in 12 cases [70].

Kraft and Havel reported in 113 melanoma patients that SPECT/CT allowed higher SLN detection rate than planar images (95% vs. 89%, respectively). Furthermore, lymphatic drainage was visualized in eight patients without SLN visualization on planar study [71].

From the surgical point of view, the value of SPECT/CT in adjusting the operating approach is also important. Such added value was observed in 14 out of 63 (22%) melanoma cases, whereas the SLN visualization rate was similar between planar images and SPECT/CT (98% vs. 100%, respectively) [72].

SPECT/CT is able to detect also more potential metastases. A study comparing the results in 149 patients with additional SPECT/CT information with a group of 254 patients who only underwent planar imaging showed that SPECT/CT detected more SLNs than planar images (average 2.4 vs. 1.87 per patient, respectively). SPECT/CT detected more metastatic SLNs (average 0.34 vs. 0.21 per patient), and its use was associated with a significantly higher rate of disease-free interval (93.9%) in comparison with those patients without the use of SPECT/CT (79.2%) [73].

Recently, a multicenter collaborative study promoted by the International Atomic Energy Agency (IAEA), conducted in 15 centers from 10 different countries, included 262 melanoma patients. No SLN was visualized on planar images in three patients. SPECT/CT revealed an axillary SLN in a trunk melanoma patient and persistent non-visualization in two patients with head and neck melanoma. In the latter, cervical lymphadenectomy was positive for metastasis. SPECT/CT revealed 70 additional SLNs in 53 patients (25% additional nodes in head and neck melanoma: 25.5% in patients with upper limb melanoma, 20.5% in patients with trunk melanoma, and 12.9% in patients with lower extremities melanoma). The surgical approach was modified in 97 patients (37%): 41%, 39%, 33%, and 30% of head and neck, trunk, lower limb, and upper limb lesions, respectively [74].

Nevertheless, based on evidence currently available, SPECT/CT must be considered as complementary rather than alternative to planar lymphoscintigraphy. SPECT/CT is able to provide anatomical landmarks with a significant improvement of the surgical roadmap and clinical benefit for the patient as demonstrated by Stoffels et al. [73]. In a recent survey in Spain, data from 37 different nuclear medicine centers were collected. SPECT/CT studies were performed in all the melanoma patients in 24.3% of the centers (9/37), while this study was performed according to patient-based considerations in the remaining centers (28/37), the most common indication being the presence of head/neck drainage [75].


Besides the information provided by preoperative lymphoscintigraphy, the other main cornerstone of the technique is the ability of the detector probe to guide the dissection and to identify the SLN. It is recommended to make a preliminary search, with the patient properly positioned on the operating table, with gamma probe prior to making the incision. The scan with the gamma probe should be slow and systematic and should start between the area of the injection and the area of drainage visualized in the lymphoscintigraphy, until an increase in activity is observed. This activity should optimally be matched with the skin markings made by the nuclear medicine staff at the time of lymphoscintigraphic imaging. Precaution should be taken when the injection site overlies or is within the field of view of the detector probe, and thus, if possible, mobilization maneuvers or attempt to direct the gamma probe opposite to the injection site should be made. In vivo radioactivity (counts/sec) is measured in the surgical field opened, typically with a 2–4-cm incision over the area of highest activity determined by external counting/skin marking. SLN to background ratios are usually between 10:1 and 20:1, depending on activity injected, time to surgery, etc. After in vivo SLN identification and retrieval, the ex vivo activity of the SLN should be recorded, as should also be the remaining activity in the surgical fields to rule out the presence of other potential SLNs. Although the SLN is visualized in the lymphoscintigraphy, in practice there may be two adjacent lymph nodes seen as one in the images (especially if SPECT/CT imaging is not available); therefore, the lymphatic bed should always be reassessed. It is also advisable to palpate the lymphatic region searching for enlarged or matted lymph nodes, especially if an ultrasound study has not previously been performed [45, 76].

Vital dyes may help to visually confirm the lymphatic vessels from the primary tumor to the SLN. Combining the information provided by presurgical lymphoscintigraphy with the intraoperative use of dyes and the detector gamma probe offers the highest accuracy in SLN identification; therefore, their use in combination is recommended. The vital dye is especially important when the primary tumor is very close to the lymphatic basin, since the injected radioactivity (even after lesion removal) causes a high background count rate which does not allow the detector probe to distinguish the SLN. Isosulfan blue (Lymphazurin) and Patent Blue V are the dyes of choice for SLN mapping. Methylene blue is also used because of its lower cost, its lesser risk of anaphylaxis, and its similar ability to detect the SLN compared with the other two dyes [77].

In general, the success rate of combining presurgical lymphoscintigraphic information with intraoperative gamma probe reaches about 98% in melanoma, whereas the vital blue dye alone identifies about 80% of cases. The addition of dye improves radioguided SLN identification, to reach a 99% success rate (Fig. 7), especially when lymphatic drainage to the SLN is blocked by metastatic tumor cells and/or when the SLN capacity to retain the radiocolloid is hampered by massive replacement of the normal lymph node structure with metastatic cells.
Fig. 7

Classical intraoperative approach for sentinel node biopsy. Injection of blue dye around the biopsy scar in a patient with a melanoma in the right ear (a). Skin marks corresponding to the depicted sentinel nodes in preoperative lymphoscintigraphy (b). Blue stained lymphatic channel (blue arrow) to the parotid area sentinel node (c). Blue stained node (blue circle) in the surgical field (d)

Nonetheless, from a practical point of view, many centers around the world consider that lymph node resection should continue up to achieving lymph node activity in the surgical bed <10% of the activity of the most active SLN (10% rule), in order to reduce the potential false-negative cases [78]. However, almost all the involved lymph nodes can be identified following the concept of the SLN and using a rigorously conducted procedure [79]. In this regard, a recent revision of the 10% rule showed a 21% positive SLN rate in 665 melanoma patients. More than one SLN was removed in 105 regional basins. In 18 of these, a less radioactive node was positive for tumor when the most radioactive node was negative. Blue dye was used and stained 157 out of 175 positive SLNs (90%). In those cases, in which the involved SLN was not the hottest node, the positive node was blue in all cases. Thus, the authors concluded that, in this particular series, removing just the hottest node and all blue nodes would not have missed a positive SLN, but at the same time would have avoided to resect more nodes in comparison with the 10% rule [80].

Sentinel Lymph Node Analysis and Its Importance for Clinical Decision

Histopathologic evaluation of the SLNs is, currently, the “gold standard” in patients scheduled for SLN biopsy. The SLN status predicts prognosis and indicates the necessity or not for further surgical treatment.

The SLN approach enables pathologists to thoroughly review this particular node or nodes using multiple sections and several staining techniques. Intraoperative frozen section histology is not reliable in the case of melanoma. The conventional approach involves, after usual sectioning and staining with hematoxylin and eosin, immunohistochemistry employing antibodies against the melanoma-associated S-100 antigen (very sensitive) and HMB-45 and MART-1/Melan A (very specific) antigens. Serial sectioning and additional immunohistochemistry may detect additional micrometastases in up to 12% of the cases [81].

Molecular analysis methods (PCR) are not part of clinical routine up to now, because they are time consuming and lack in reproducibility. However, some studies have advocated their use due to a higher sensitivity to detect metastases against conventional pathology methods and a lower rate of false-negative cases [82, 83].

It has been shown that small deposits of metastatic cells are associated with a worse prognosis in patients with negative SLN. Although isolated tumor cells (especially in the subcapsular sinuses) have been described to bear an adverse biological feature in melanoma [84, 85, 86], nevertheless the AJCC concluded that there is no definitive evidence enabling to define a minimum threshold of tumor load for defining the stage of lymph node metastasis [87].

The current practice is to wait for definitive histopathologic examination before making the choice between no further surgery (when the SLN is tumor-free) or to perform an elective regional lymphadenectomy (when the SLN bears metastasis). Patients with positive SLN biopsy are offered complete lymph node dissection, and 12–25% of them will have additional lymph nodes involved. The final analysis of data from the MSLT-I trial has demonstrated the importance of SLN biopsy for the identification of patients with node involvement who may benefit from immediate lymphadenectomy [35].

However, recent studies indicate that lymph node dissection does not have an effect on the global survival after a positive SLN with minimal tumor load (<0.1 mm in diameter). It has therefore been suggested that lymph node dissection can safely be omitted in these patients [88, 89]. The Multicenter Selective Lymphadenectomy Trial II has been designed to assess the role of lymphadenectomy of the regional node basin in patients with positive SLN, with the intent to determine whether lymphadenectomy has any benefit in regional control or survival. The study started in 2004 and reached its scheduled accrual in 2014 [90]. Follow-up is still in progress for assessing the long-term outcomes of the trial.

Refinements for the Classical Technique

Despite the successful results in SLN localization based on lymphoscintigraphy (especially if complemented with SPECT/CT), precise localization for surgical planning may sometimes be difficult. Intraoperative use of the gamma probe provides a good overview of radioactivity distribution in the surgical field, with SLN identification rates close to 99% in patients with melanoma. Nonetheless, the technique can be further improved. The combination of vital dye and gamma probe has prevailed for many years as the standard technique. However, the dye is less effective in areas with aberrant lymphatic drainage and in deep-seated lymph nodes (i.e., head and neck region where the SLN identification rate is around 85%).

The current technological advances in portable devices and the possibility of using new signatures (i.e., fluorescence) in addition to the conventional radiotracers have led to a changing paradigm: from the “see to open” approach to the “see, open, and see again.” The combination of SPECT/CT information with new portable imaging devices enhances the reliability of the gamma probe, especially in complex drainage regions and in areas where the SLN is very close to the injection site. These advances have led to the definition of the concept of “Guided intraOperative Scintigraphic Tumour Targeting” (GOSTT) to include the whole spectrum of basic and advanced nuclear medicine procedures required for providing a roadmap that would optimize surgery [91, 92].

Portable Gamma Cameras

These gamma cameras have been designed for intraoperative use, with sensitivity and resolution parameters that make them optimally suited for imaging small areas [93]. The use of these imaging devices in the surgical theater enables to precisely adapt in real time the surgical incision to the skin marks previously made in the nuclear medicine suite at the time of lymphoscintigraphy and confirms the exact SLN location, considering that position of the patients on the operating table may be different from that on the imaging table. This is especially important for melanomas located in the head and neck area, since even small changes in lateralization of the neck may imply an important change in the anatomical setting of the subjacent SLN position in relation to the cutaneous marks.

In general, when these devices are used, an overview image is recorded before the start of SLN biopsy in the operating room. To verify the completeness of SLN removal, another image must be acquired after excision. If a residual radioactive spot is visualized at the location of a previously harvested SLN, this additional node must also be resected and be assessed as a part of a cluster of nodes to be considered as additional SLNs. Furthermore, a high-resolution portable gamma camera, positioned close to the skin, is able to detect SLNs at distances as small as only 3 mm from the injection site [92]. Nevertheless, it should be emphasized that portable gamma camera designed for use during radioguided surgery procedures do not serve as an intraoperative guidance in the same manner as conventional handheld gamma probes, since their size is not small enough for insertion in the surgical bed through the surgical incision.

The added value in the use of these devices is that they allow resection of additional SLNs, some of which result to be metastatic. Therefore, this technique may reduce the false-negative rate of SLN biopsy, while the SLN identification rate is increased and correct application of this intraoperative imaging procedure ensures that no SLNs are left in the surgical field [94, 95].

Vidal-Sicart et al. described the use of a portable gamma camera in five difficult melanoma cases. In this group, 80% of patients showed a primary lesion in the head region, and the remaining patient had a lower limb lesion. In total, 12 SLNs were detected using only the gamma probe, while two additional SLNs were found by the portable gamma camera [96].

Dengel et al. compared the performance of a portable gamma camera with preoperative conventional lymphoscintigraphy and intraoperative gamma probe findings in 20 melanoma patients. Lymphoscintigraphy depicted 29 node basins containing SLNs, while the pre-incision images with portable gamma camera detected only 27 node basins. The authors explain these somewhat disappointing results with the delay of more than 20 h between radiocolloid injection and intraoperative imaging with the portable gamma camera, an interval during which physical decay caused an important decline in radioactivity levels retained in the lymph nodes. Nevertheless, intraoperative imaging detected two additional previously undetected lymph nodes in 2/20 (10%) of the patients [97].

Stoffels et al. enrolled 60 patients (38 with melanoma, 22 with other cutaneous malignancies) for a SLN procedure using the same portable gamma camera as that used by Vidal-Sicart and colleagues. The portable gamma camera visualized all 126 SLNs identified preoperatively by SPECT/CT. More importantly, 23 additional SLNs in 15 patients (25%) were identified using the portable gamma camera device; two of these additional nodes were metastatic, thus preventing a false-negative SLN biopsy in two patients. Intraoperative imaging extended the operating time by a maximum of only 5 min [98].

Olcott et al. showed in 39 patients that intraoperative imaging using a handheld gamma camera successfully visualized 86 of the 92 SLNs detected by the gamma probe and detected 12 additional nodes that were missed by the gamma probe [99].

New perspectives in radioguided surgery may be opened by the fusion of the scintigraphic images with an optical image, thus providing a more “friendly,” real-time anatomical environment during surgery [100]. New multimodality system configurations have been described that combine optical and gamma imaging. Haneishi et al. have proposed a parallel optical and gamma camera configuration resulting in a portable hybrid camera system that projects the scintigraphic image onto an optical image [101].

Hellingman et al. have recently evaluated a prototype portable hybrid camera for preoperative lymphatic mapping in SLN procedures. Fused optical and gamma imaging makes it easier to relate the position of the radioactive hot spots and the image field of view with the real-life situation (Fig. 8) [102].
Fig. 8

Preoperative lymphoscintigraphy . Right lateral (a) and anterior (b) views from a patient with an upper right back melanoma. A clear hot spot (with several lymphatic channels to it) is visualized. Fused optical and gamma imaging is achieved in a new portable hybrid camera. The sentinel node is well depicted, and it can be precisely marked in the skin (c) and assessed with the handheld gamma probe (d) in real time

Freehand SPECT

The use of a positioning system technology allows spatial localization based on two tracking devices that are attached to a conventional gamma detector probe and to the patient, respectively. The localization system consists of an optical camera and an infrared-based localization device. Virtual 3D images are generated. After scanning the area of interest with the gamma probe, images are displayed on a screen. These images may be seen in real time and provide information about the depth at which the SLN (or the tissue to be resected) is found. The procedure is called freehand SPECT and is designed for intrasurgical navigation. This method combines the acoustic signals with a 3D image to localize the SLN in the operating room [103] (Fig. 9).
Fig. 9

3D reconstruction (a, c) and SPECT/CT fused images (b, d) of a patient with a left upper arm melanoma. These images show sentinel nodes in left axilla and left supraclavicular area. Freehand SPECT device depicted the same distribution after accurate scan (e). Virtual reconstruction provides real-time information about the depth at which the sentinel node is found

Specific training in the use of the technique is required for data acquisition and for making several readings during surgery, a procedure that might prolong the operation time. Nevertheless, in both cases the results may refine the conventional technique [104]. The use of freehand SPECT is currently yielding excellent results for SLN biopsy in melanoma and breast cancer [105].

In melanoma, Sulzbacher et al. studied 39 patients with primary lesion in different sites of the body. Surgery using radioguided freehand SPECT was performed the day after acquisition of preoperative lymphoscintigraphy (planar + SPECT/CT). Interestingly, SPECT/CT data were integrated into the 3D navigation system to enable fast and direct localization of the SLN by displaying the depth of the node from the skin surface to the gamma probe. Comparable preoperative imaging and intraoperative localization were observed in 18/39 patients. In 10 of 14 patients in whom more SLNs were resected during surgery than those visualized preoperatively, intraoperative freehand SPECT revealed additional lymph node sites. The mean surgical time using this device was 66 min (range 36–133) [106].

Fluorescent and Hybrid Tracers

The use of fluorescent agents for lymphatic mapping and SLN localization is expanding rapidly. Organic fluorescent dyes such as fluorescein or indocyanine green (ICG) have been used for human studies, as an alternative to nuclear imaging methods. Their excited light emissions are in the near-infrared (NIR) spectrum, which has several advantages over ultraviolet and mid-infrared radiation. In particular, NIR emissions have better tissue penetration and are therefore more suitable for intraoperative guidance in a surgical field. Since the NIR window lies beyond the visible spectrum, the pathways of lymphatic drainage following interstitial injection of ICG can only be visualized by using a dedicated NIR fluorescence camera [107].

Motomura et al. first described the NIR imaging technique with ICG for SLN detection in breast cancer, reporting a 74% SLN identification rate [108]. Once injected, the fluorophore ICG binds to serum proteins, and within several minutes, it drains through the lymphatic vessels to the SLN. Similar to blue dyes and due to its small size, ICG migrates rapidly within the lymphatic channels and is not retained in lymph nodes, thus resulting in a rather short diagnostic detection window that requires a very strict surgical protocol to reliably detect the SLN. However, sensitivity of signal detection is much better with ICG than with the blue dye, because it enables real-time percutaneous and intraoperative visualization of lymphatic channels and superficial (<1 cm in depth) SLN. Nevertheless, visualization of lymphatic drainage and SLN detection can be problematic in patients with high body mass index [109].

Van der Vorst et al. demonstrated the feasibility of NIR fluorescence for SLN mapping using an ICG:HSA conjugate and a dedicated fluorescence camera in patients with melanoma. SLN was similarly detected with fluorescence as with radiocolloids, with superior performance compared to blue dye. In particular, combining NIR fluorescence and radiotracer led to a 100% SLN detection rate, but only 73% of the SLNs were stained blue [110].

In other studies, however, the radiocolloid-based approach proved to be superior to other tracers. In a recent study with 52 melanoma patients, the SLN identification rates were 96.2% for the radiocolloid, 88.5% for ICG, and 59.6% for the blue dye [111]. In another group of patients with melanoma, Stoffels et al. observed inferior results with ICG guidance when compared to 99mTc-nanocolloid in defining lymphatic basins at risk for metastases before surgery. They detected and excised 147 SLNs in 80 patients using the radiocolloid, whereas in only 21% of the patients (17/80) was the SLN detectable by ICG before skin incision [112]. These findings are consistent with other studies showing that, although fluorescence imaging allowed intraoperative identification of the SLNs, the limited tissue penetration does not allow accurate SLN mapping prior to surgery.

Since preoperative lymphoscintigraphy is an essential component of SLN approach, novel hybrid compounds have been designed (i.e., a lymphatic mapping agent that is both radioactive and fluorescent) for combining the relative advantages of each approach. In particular, preoperative lymphoscintigraphy and SPECT/CT are possible because of the radioactive “signature” of the hybrid agent, while the fluorescent “signature” would allow recording high-resolution images in the operating room [113].

In this regard, a seminal clinical study has demonstrated the stability and reproducibility of one of these potential hybrid tracers (ICG-99mTc-nanocolloidal albumin) versus the current standard tracer in Europe, 99mTc-nanocolloidal albumin, in 25 patients with melanoma or penile cancer. Indeed, with this approach it was possible to detect fluorescent SLN up to 23 h after administration of the hybrid compound, thereby increasing the useful time window for planning surgery (Fig. 10) [114].
Fig. 10

Injection of hybrid tracer (ICG-99mTc-nanocolloid) in a patient with melanoma on the back (a). During surgery, an axillary node was retrieved (both active and fluorescent). Fluorescence is depicted on the screen when tissue is exposed to a fluorescence camera (b). Surgery was performed 18 h after administration of the hybrid compound

The combination of the properties of the two tracers (high tissue penetration of the radiotracer and high-resolution imaging of the fluorescent agent) implies greater accuracy for SLN detection, especially in areas with complex lymphatic drainage [115]. An additional hybrid approach based on ICG-99mTc-nanocolloid has recently been validated in 104 patients with melanoma. Optical SLN identification rate, made possible by the fluorescent signature of the hybrid tracer, was superior to that achieved with the blue dye, since SLNs were intraoperatively visualized in 97% of the cases with fluorescence , whereas only 62% of these nodes were stained blue. Interestingly, ex vivo examination of the excised SLNs confirmed the combined presence of a radioactive and fluorescent signature [116].

In another study, Stoffels et al. reported the results of a randomized prospective trial comprising 40 patients with different types of skin malignancies (melanoma, squamous cell, Merkel cell carcinoma) and sweat gland carcinoma in the head and neck region. Twenty patients received a derivative of the previously described ICG-99mTc-nanocolloid tracer, while the rest of the patients were given the standard 99mTc-nanocolloid. Primary study endpoints were the number of excised SLNs and duration of surgery. It was concluded that the use of the hybrid tracer for SLN biopsy is feasible in these patients and that by combining fluorescence and radioactivity in one single tracer, discrepancies between both signatures are less likely to occur [117].

Nevertheless, it should be emphasized that each type of signal (radioactive or optical) must be explored with dedicated, single-modality imaging/detection devices. Ongoing efforts aim at developing multimodal devices capable of providing all the potential of intraoperative imaging, thereby achieving greater reliability in the surgical procedures [100]. In this scenario, a hybrid tracer integrating radioactivity and fluorescence in one signature constitutes the basis of a novel approach to combine the best of both diagnostic worlds for the SLN procedure in melanoma as well as in other malignancies [118].

Particular Issues for SLN Mapping in Melanoma

In-Transit, Aberrant, or Ectopic Lymph Nodes

Although the majority of melanomas scheduled for SLN biopsy drain to a predictable regional lymphatic basins based on localization of the primary tumor, drainage to lymph nodes outside the expected lymphatic basins may be observed. Any lymph node visualized along the lymphatic channel between the primary localization and a regional lymphatic basin is called in-transit, interval, aberrant, or ectopic (depending on the definitions set by different investigators) lymph node and must be considered as a SLN regardless of its localization.

The presence of such nodes has been described especially in the parascapular and supraclavicular spaces (lying between muscles or, even more frequently, in the subcutaneous fat); the para-aortic, paravertebral, and retroperitoneal regions; the intercostal zones; the internal mammary lymph node chain (epitrochlear, popliteal); and even the skull. Lymph nodes have been reported in these areas between 6% and 12% of the cases, and the probability of metastatic involvement of these nodes is similar to that of the SLN in areas of classical drainage. So, melanomas in the upper extremities and the trunk are more likely to present aberrant nodes. On the other hand, tumors localized in the head and neck and the genital area show a lower rate of these nodes [51, 54, 119].

The need to identify the SLNs prior to surgery is as important as identifying and resecting them during surgery. An in-transit SLN may indicate involvement in the lymphatic basin, but may also be the unique site with metastatic cells. Thus, in most studies the incidence of metastasis in the in-transit/aberrant SLN is quite similar, in the 14–22% range. In a review of 900 melanoma patients, Ortín-Pérez et al. reported that 19.5% of in-transit/aberrant lymph nodes bore metastasis; 11 out of 15 of these patients also presented metastatic involvement of at least one SLN in the expected lymphatic region, while the remaining 4 patients only had metastasis in the in-transit/aberrant SLN [120]. Several other studies have resulted in similar values, thus reinforcing the concept that it is necessary to identify and harvest these particular in-transit/aberrant lymph nodes since they may constitute the only focus of metastasis [121].

In this regard, the use of SPECT/CT and intraoperative imaging may refine the procedure, especially in these difficult to found lymph nodes, with the aid of precise anatomical localization (SPECT/CT) and intraoperative checking of a definite area of the body with a portable gamma camera. The use of this technology results in increased surgeon’s confidence, as well as in improved preoperative planning and better staging [122, 123, 124, 125] (Fig. 11).
Fig. 11

Right popliteal sentinel nodes depicted on planar image (a), 3D reconstruction from SPECT/CT data (b), portable gamma camera (c), hybrid (gamma + optic) camera (d). During surgery, new pictures were acquired to precisely depict the nodes’ situation (e). Surgical removal (in the pincette) of one of these nodes (f)

Head and Neck Location

About 15–35% of primary melanomas are located in the head and neck and are associated with a worse prognosis. Several authors have demonstrated a greater rate of recurrence in this area after a negative SLN biopsy compared to other areas of the body [126]. SLN biopsy of tumors in the head and neck region is especially challenging both because of the great number of lymph nodes (>300) and because of the huge network of lymphatic vessels that contributes to the complexity of lymphatic drainage in this area, with melanomas often draining to multiple, aberrant, and bilateral lymph nodes [127].

Furthermore, during lymphoscintigraphy the radioactivity remaining at the site of injection may mask a SLN on planar imaging, and it is often hard to distinguish SLNs from second-echelon nodes. In a review of several studies comprising more than 3,400 head and neck melanomas, the sensitivity of SLN biopsy was reported to be in the range 80–100%, with a false-negative rate as high as 20% [128]. Another study with 246 patients demonstrated that melanomas located in the facial region presented a better prognosis than those in the skull, ears, or cervical region, even for thin tumors (Breslow index <1 mm). The presence of ulceration, elevated Clark level (IV/V), and young age were the strongest predictive factors to determine the presence of cervical lymph node metastasis [129].

A recent study of 152 patients with melanomas located in head or neck area compared the results of the actual presurgical lymphoscintigraphy with the expected drainage pattern derived from a predictive software based on a database of 929 patients. The concordance was complete in 80.4% of patients for all SLNs and partial in 12.2% of patients. Discrepancy was observed in 7.4% of patients. The authors concluded that lymphoscintigraphy provided an added value to personalize lymphatic mapping in each individual patient and that this imaging step is crucial to accurately detect the SLNs in head and neck melanomas, especially when faced with aberrant lymphatic drainage in unpredictable locations [130].

As mentioned above in this chapter, SPECT/CT imaging is currently considered to be mandatory for better assessing and depicting SLN located in the head and neck area. Zender et al. showed that the SPECT/CT findings led to a change in the management in 57% of patients with melanoma and suspected drainage to the parotid region. SPECT/CT precisely discriminated between parotid zone and cervical level II lymph nodes and visualized additional nodes, not visualized on planar lymphoscintigraphy, in 28% of the cases [131]. Taking into consideration that nearly 25% of cases in the head and neck area may show metastasis outside clinically predicted neck levels, it is necessary to ascertain these sites of potential involvement with the best approach, namely, to investigate the lymphatic drainage patterns using dynamic planar lymphoscintigraphy and SPECT/CT [132].

A more refined technique may include, if available, preoperative SPECT/CT, intraoperative imaging using portable devices, and hybrid tracer (multimodal approach). One study including 25 patients with head and neck malignancies demonstrated that the use of conventional lymphoscintigraphy, SPECT/CT, and the additional help of a portable gamma camera in one case were able to display 67 SLNs (55 visualized on planar images, 11 additional on SPECT/CT, and 1 additional with the portable gamma camera). Intraoperatively, 89 SLNs were resected (67 + 22 additional nodes). Twelve out of the 22 additional SLNs were located close to the injection site. The other ten additional SLNs were found by post-resection imaging with the portable gamma camera of the excision SLN site. Thus, the combined approach seems to be useful especially for tumors located approximately in the expected area of lymphatic drainage [133] (Fig. 12).
Fig. 12

Surgical approach with a portable hybrid camera. A sentinel node near the ear’s injection site is depicted (a) and assessed with the use of gamma probe (b). Surgical localization and identification of the sentinel node (c) and “ex vivo” checking with the hybrid camera (d)

Cost-Effectiveness of SLN Biopsy in Melanoma

Currently, SLN biopsy is recommended in cases of primary melanoma without evidence of regional or distant metastasis when the risk of lymphatic node metastasis is at least 10% (AJCC stages IB and IIA, B, and C in the 7th edition). Selection criteria have not yet been standardized for cases with a Breslow thickness of less than 0.75 mm, which nevertheless account for 60–70% of melanomas diagnosed in large hospitals [134].

There is scarcity of data about the overall costs of this procedure in melanoma patients. On the other hand, the different items comprised in the whole procedure are not equally considered between different analyses. Thus, in a very complete study recently performed in 99 patients treated at a Spanish hospital, the cost of the procedure was estimated between € 9,486 and € 10,471. This analysis included an approach with radiotracer only, a major outpatient surgery operating room with only 1-day hospitalization in case of no complications and a thorough pathological analysis. These costs are similar of those calculated in a US institution, ranging from $10,000 to $15,000 (€ 7,600–11,400) [135]. Almazán-Fernandez et al. calculated the costs of SLN biopsy in cutaneous melanoma, but they only included 1 day of hospitalization and re-excision of the melanoma scar with margins of 2 cm. The general costs reached € 682, but the authors did not take into account histopathologic analysis [136]. Similar findings were reported in an Australian study, with an estimated cost of € 1,900 [137].

Thus, it can be assumed that histologic processing increases to a great extent the overall costs of the SLN procedure; therefore, the indication criteria for SLN biopsy turn out to be crucial, especially in the patients with low risk for metastasis. On the other hand, the refinement of the procedure can save extra costs associated with extended surgery. In this regard, Stoffels et al. compared a cohort of patients in whom only planar lymphoscintigraphy was performed with a cohort of patients in whom SPECT/CT imaging was added. The fixed costs per SLN biopsy concerning infrastructure and consumables were € 71 per procedure, while SPECT/CT imaging in that hospital represents an added cost of € 116. Obviously, the costs for SLN biopsy with either local or general anesthesia differed, with lesser costs in the group with planar imaging only (as SPECT/CT frequently visualized more deep-seated SLNs that required general anesthesia). However, a more detailed analysis demonstrated a cost saving of € 1,045 in the hospital stay expenses between patients with local or general anesthesia. Moreover, the addition of SPECT/CT imaging in the SLN biopsy group with local anesthesia saved about € 1,069 per procedure, and its use resulted in the upstaging of a proportion of patients, by detecting more metastatic SLNs. Costs for preoperative imaging increased, of course, but costs of surgery and hospital stay decreased remarkably. The economic study demonstrated that the routine use of preoperative SPECT/CT reduces the total cost of SLN biopsy per patient by € 710 [138].

In the use of hybrid tracers, the potential advantages also need to be weighed against the complexity of implementing this approach in the clinical routine and its associated costs. The cost of ICG vial is relatively cheap (about € 85 per vial). However, the highest additional costs lie in purchasing a NIR fluorescence camera system, with commercial values that range from several thousand € to hundreds of thousand €, depending on the system chosen [116].

Role of PET/CT Imaging for Radioguided Surgery

Many patients with stage I/II melanoma have no metastasis, or, if present, they are usually minimal-extent metastases. In contrast to the SLN biopsy, where diagnostic sensitivity is enhanced to the microscopic level by histologic analysis (and even to submicroscopic level by molecular analysis), the diagnostic performance of [18F]FDG PET/CT in patients with micrometastasis is impaired by the relatively limited spatial resolution of imaging [139]. Indeed, the limited diagnostic value of [18F]FDG PET/CT for assessing the presence of metastasis in patients with a clinically localized melanoma has been reported [140]. Some authors, however, consider that [18F]FDG PET/CT can be useful in certain clinical situations where the risk of metastasis is increased (e.g., Breslow thickness >4 mm, presence of ulceration, and high mitotic index) [52].

Kell et al. assessed the preoperative value of [18F]FDG PET/CT in patients with melanoma scheduled for SLN biopsy. Out of the initial 83 patients in their series, 37 were selected to undergo a preoperative [18F]FDG PET/CT scan because of higher risk for metastasis. SLN biopsy demonstrated metastatic involvement in 9 of these 37 patients (24%), but only 2/9 patients had a positive [18F]FDG PET/CT scan (22% positive predictive value). These results do not support the clinical validity of [18F]FDG PET/CT in this population, as SLN biopsy was a more sensitive staging modality for the detection of lymph node metastasis [141]. After reviewing their findings in 30 patients with melanomas with Breslow thickness >1 mm, Constantinidou et al. observed that performing an [18F]FDG PET/CT after a positive SLN biopsy did not alter the clinical management of melanoma [142]. Klode et al. reported similar findings in 61 melanoma patients and concluded that SLN biopsy is much more sensitive than [18F]FDG PET/CT for the assessment of lymph node metastasis [143]. In another study, a combination of [18F]FDG PET/CT and ultrasound was preoperatively employed in 20 melanoma patients scheduled for SLN biopsy, in whom 52 SLNs were eventually harvested. Ultrasound correctly identified 2 out of the 17 tumor-bearing SLNs, none of which had been identified by PET/CT [144]. In a study reported by Barsky et al. in 149 patients with at least an intermediate-thickness melanoma, [18F]FDG PET/CT was positive in 41/149 cases (27.5%). Invasive procedures were subsequently performed in 18 of these 41 cases, but metastatic involvement was confirmed in only six patients; therefore, in the experience of these authors, [18F]FDG PET/CT had a quite high rate of false-positive results, resulting in a low positive predictive value [145].

Although [18F]FDG PET is not currently recommended as a routine investigation for staging patients with positive SLN biopsy, the technique could be justified in patients with palpable lymph node before resection, due to its potential impact on decision-making regarding subsequent clinical management. In 70 melanoma patients with palpable lymph nodes but no clinical evidence of distant metastasis, Aukema et al. found that [18F]FDG PET/CT led to change the indication for regional lymphadenectomy in 37% of the patients. The overall sensitivity of PET/CT in this subgroup of patients was 87% and specificity of 98% in the detection of additional metastases in melanoma patients with palpable lymph nodes [146].

One potential application for the intraoperative use of systemically administered [18F]FDG in combination with a handheld PET detection probe has been proposed and reported in the clinical management of selected cases of metastatic melanoma [147]. Although the concept is in principle attractive, further evaluation of this approach is needed (especially regarding PET probes). A more practical approach is the intralesional administration of a radioactive or hybrid tracer in order to enable resection of isolated melanoma metastases aided by the use of a conventional handheld gamma probe (i.e., ROLL-like approach) after the PET/CT scan [148, 149].


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Sergi Vidal-Sicart
    • 1
    • 2
    Email author
  • Federica Orsini
    • 3
  • Francesco Giammarile
    • 4
  • Giuliano Mariani
    • 5
  • Renato Valdés Olmos
    • 6
    • 7
  1. 1.Nuclear Medicine DepartmentHospital Clínic BarcelonaBarcelonaSpain
  2. 2.Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS)BarcelonaSpain
  3. 3.Section of Nuclear Medicine“Maggiore della Carità” University HospitalNovaraItaly
  4. 4.Nuclear Medicine, Centre Hospitalier Lyon Sud Biophysique, Faculté Charles Mérieux LyonUniversité “Claude Bernard”LyonFrance
  5. 5.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly
  6. 6.Nuclear Medicine Section and Interventional Molecular Imaging Laboratory, Department of Radiology C2-SLeiden University Medical CentreLeidenThe Netherlands
  7. 7.Diagnostic Oncology Division, Nuclear Medicine DepartmentNetherlands Cancer Institute – Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands

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